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Ana Sayfa : Recent BD News : Review of published papers : Nonclinical - Scientific : Listed during May 2005 -September 2006

Listed during May 2005 -September 2006

Lısted during: May 2005 – September 2006
REVIEW OF PUBLISHED PAPERS: NONCLINICAL SCIENTIFIC
Prepared by: G. Wallace (UK) E-mail: g.r.wallace@bham.ac.uk
1 – 3 Reviews
31 – 67 Immunology
68 – 74 Thrombophilia
75 – 82 Metabolism

Reviews

(1) Behcet's disease.

Bonfioli AAOrefice F.
Semin Ophthalmol. 2005 Jul-Sep;20(3):199-206.

Behcet's disease is a chronic, relapsing vasculitis that can affect most organ systems. The prevalence varies geographically, and the disease is more common in countries along the ancient Silk Road, including Italy, Turkey, Israel, Saudi Arabia, Iran, China, Korea and Japan. Behcet's is more common in men than in women, and typically affects young adults. The classic finding in Behcet's patients is the presence of recurrent mucocutaneous ulcers, and oral aphthous ulcerations are usually the initial symptom. Other manifestations include genital ulcers, skin lesions, vascular, neurological, articular, and ocular disease. The disease can affect the anterior and/or posterior segments of the eye, and the main manifestations include iridocyclitis, hypopyon, mild to moderate vitreitis, retinal vasculitis and occlusion, optic disc hyperemia, and macular edema. There is no pathognomonic laboratory test in Behcet's disease, and the diagnosis is based in systemic and ocular clinical findings. Treatment of ocular Behcet is based in corticosteroids and immunosuppressive agents, to suppress acute inflammation and reduce its recurrence frequency. Ocular lesions may improve with immunosuppressive therapy, but usually are not fully reversible, and generally progress over time. The prognosis of anterior uveitis is usually good, but patients with posterior lesions tend to have some degree of visual loss, even with adequate treatment.

(2) Behcet's disease: familial clustering and immunogenetics.

Fietta P.
Clin Exp Rheumatol. 2005 Jul-Aug;23(4 Suppl 38):S96-105.

Behcet's disease (BD) is a relapsing, multisystemic inflammatory disorder, characterized by major symptoms consisting of recurrent orogenital ulcerations, eye and skin lesions. Other clinical features may include musculoskeletal, vascular, gastrointestinal, renal, cardiopulmonary or neurological involvement. Vasculitis affecting all types and sizes of blood vessels is the main histopathologic process, in a third of cases complicated by thrombosis. The etiopathogenesis is presently unknown, but BD likely represents the result of a peculiar immune response to hitherto unidentified environmental factors in genetically predisposed subjects. The prevalent distribution in a specific geographical area spanning the Mediterranean basin and Asia, the close association with human leukocyte antigen B*51 in different ethnic groups, and the familial clustering of BD are hallmarks accounting for the strong contribution of a genetic background. The BD familial aggregation is characterized by both genetic anticipation and higher prevalence in childhood patients, likely defining a subset with stronger immunogenetic influences. Polymorphisms in genes encoding for host effector molecules may have a supplementary role in disease susceptibility and/or severity. The contribution of prothrombotic mutations and polymorphisms in the pathogenesis of BD thrombosis is controversial. In this paper, the available reports on BD familial clustering and the evidence for the role of immunogenetic predisposing factors are reviewed.

(3) Behcet's disease as an autoinflammatory disorder.

Gul A.
Current Drug Targets - Inflammation & Allergy. 4(1):81-3, 2005 Feb.

Autoinflammatory diseases are a group of heritable disorders that are characterized by seemingly unprovoked episodes of inflammation at certain locations and and relative lack of high-titer autoantibodies or antigen-specific T cells. Behcet's disease is an inflammatory disorder of unknown aetiology, and many of its characteristic recurrent manifestations overlap with those of autoinflammatory diseases. Behcet's disease has a complex genetic aetiology, and it is more prevalent in certain geographic regions and/or in particular ethnic groups. Enhanced inflammatory response and over-expression of proinflammatory cytokines are the prominent features of Behcet's disease, and they are compatible with the findings in other autoinflammatory disorders. There are also evidences of antigen-driven immune response in Behcet's disease, but it possibly develops on the background of enhanced innate immune reactivity. Delineation of the similarities of Behcet's disease to other hereditary autoinflammatory diseases may help to clarify its pathogenesis and also to identify the missing links in the shared inflammatory pathways
Genetics
(4) 5,10-Methylenetetrahydrofolate reductase C677T gene polymorphism in Behcet's patients with or without ocular involvement.

Ozkul YEvereklioglu CBorlu MTaheri SCalis MDundar MIlhan O.
Br J Ophthalmol. 2005 Dec;89(12):1634-7.

BACKGROUND: Increased serum levels of homocysteine (Hcy) have been reported in patients with Behcet's disease (BD) with an established risk factor for vascular involvement. Recently, the authors demonstrated that elevated Hcy levels are associated with ocular involvement in such patients. On the other hand, elevated levels of Hcy can result from genetic errors. Indeed, a mutation in the 5,10-methylenetetrahydrofolate reductase (MTHFR C677T) gene influences Hcy metabolism and, therefore, MTHFR C677T polymorphism provokes hyperhomocysteinaemia. AIM: To investigate the possible genetic factor for the elevation of plasma Hcy level in patients with BD by examining gene interaction with the MTHFR C677T polymorphism, a crucial factor of the Hcy metabolism. In addition, the authors aimed to evaluate if there is an association between the C677T polymorphism and the presence of ocular involvement in such patients. METHOD: A total of 59 patients with BD (25 men, 34 women) with a mean age of 34.9 years and 42 age and sex matched healthy control subjects (19 men, 23 women; mean age 32.2) were included in this investigation. MTHFR gene polymorphism was investigated by the polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) of a genomic DNA fragment at nucleotide 677 in all subjects in both groups. The genetic equilibrium is assumed for the gene frequencies of the MTHFR polymorphism in both samples. RESULTS: The genotype of the MTHFR gene differed between the Behcet's patients and control subjects (TT: 11.9 v 2.4%; CT: 55.9 v 61.9%; CC: 32.2 v 35.7 %). TT homozygous genotype was more frequently in BD patients than the controls, though the difference was not significant (p = 0.063). In BD patients with ocular involvement, however, the frequencies of MTHFR TT homogenetic type (27.8%) were significantly and statistically higher than those in BD patients without ocular involvement (4.9%, p = 0.022, odds ratio = 7.5), or the controls (2.4%, p = 0.003, odds ratio = 20.0). TT homozygous genotype was associated with an increased risk for ocular involvement. CONCLUSION: Elevated serum levels of Hcy seem to be a result of C677T polymorphism of the MTHFR gene, with increased TT individuals over CC and CT genotype BD patients. Although no association was shown between the MTHFR reductase C677T polymorphism and the increased risk of oral aphtahe or genital ulcers, a mutation in this gene was associated with an increased risk of ocular involvement, suggesting genetic instability with a potential initiation of Hcy lowering therapy in this patient group.

(5) Evaluation of the association between null genotypes of glutathione-S-transferases and Behcet's disease.

Uzunoglu SAcar HOkudan NGokbel HMevlitoglu ISariota F.
Arch Dermatol Res. 2006 Jan;297(7):289-293.

Glutathione S-transferases (GST) play an important role in oxidative stress related syndromes. An imbalance of the oxidant and antioxidant systems is important in the pathogenesis of Behcet's disease (BD). The objective of this study was to evaluate the association of null genotypes of GST-M1 and GST-T1 with BD since some preliminary molecular genetic data were recently published. Ninety-four Turkish BD patients (42 male, 52 female, 37.1+/-10.4 years) and 140 healthy volunteers (70 male, 70 female, 36.8+/-11.7 years) matched for age and gender with the patients as the control group were included in the study. Distributions of GST-M1 and GST-T1 genotypes were determined by multiplexed PCR using three sets of primers for GST-M1, GST-T1, and beta-globulin genes. There was no association between BD and the frequencies of GST-M1 and GST-T1 null genotypes when compared to controls by separate analysis. However, by cross and pooled combination analysis there was a significant association between the frequencies of pooled GSTs with one or both null genotypes in BD and controls. This is the first evidence that the association between the frequencies of GST-M1 and GST-T1 null genotypes and BD might be dependent on the interaction of multiple null allele polymorphisms rather than a single null allele of GST-M1 and GST-T1.

(6) Behcet's disease and hereditary periodic fever syndromes: casual association or causal relationship?

Espinosa GArostegui JIPlaza SRius JCervera RYague JFont J.
Clin Exp Rheumatol. 2005 Jul-Aug;23(4 Suppl 38):S64-6.

OBJECTIVE: Mutations in the MEFV and the type 1 TNF receptor (TNFRSF 1A) genes have recently been linked to familial Mediterranean fever (FMF) and TNF receptor-associated periodic syndrome (TRAPS), respectively. A higher prevalence of Behcet's disease (BD) among FMF patients has been described compared to the general population. The aim of this study was to evaluate whether FMF TRAPS and BD could be genetically related. METHODS: We screened a cohort of 50 BD patients and 100 healthy subjects for the common MEFV and TNFRSF 1A mutations. An initial screening of exons 10 and 2 of the MEFV gene and exon 4 of the TNFRSF 1A was performed in all chromosomes. RESULTS: The heterozygous MEFV mutation (K695R) was found in one (2%) BD patient. Analysis for FMF mutations in the control group revealed that 5 (5%) individuals bore MEFV gene mutations (3 were heterozygous for the E148Q and 2 were heterozygous for the A744S). At codon 202, there were no differences in allele frequencies between BD and control population: 73%R 27%Q in the BD patients vs 75%R 25%Q in controls. Concerning mutations in the TNFRSF 1A gene, the R92Q mutation was present in heterozygous state in one (2%) BD patient and in 4 (4%) controls without differences between allele frequencies: 99%R 1%Q in BD patients vs 98%R 2%Q in controls, respectively. There was no association between the clinical manifestations of BD patients and the presence of a particular polymorphism or a mutation. CONCLUSIONS: Neither FMF nor TRAPS are genetically associated with BD in our cohort of Spanish patients.

(7) Interleukin-18 gene polymorphisms in Korean patients with Behcet's disease.

Jang WCPark SBNam YHLee SSKim JWChang ISKim KTChang HK.
Clin Exp Rheumatol. 2005 Jul-Aug;23(4 Suppl 38):S59-63.

OBJECTIVE: There is strong evidence that Th1-type cytokines play an important role in the pathogenesis of Behcet's disease (BD). Interleukin (IL)-18 is a proinflammatory cytokine that mediates Th1-polarized immune responses, and elevated levels of IL-18 have been observed in the sera and bronchoalveolar lavage fluid of patients with active BD. Therefore, the aim of this study was to investigate the potential associations of two single nucleotide polymorphisms (SNPs) at positions -137 (G/C) and -607 (C/A) in the promoter region of the IL-18 gene with a susceptibility to BD in the Korean population. METHODS: Ninety-eight patients with BD and 105 healthy controls were studied. All of the subjects were genotyped using sequence specific PCR. The genotypes and alleles between patients with BD and controls were compared using the chi2 test, together with Yate's correction where appropriate. Haplotype analysis was assessed using the EH program. RESULTS: The genotype and allele distributions of the two SNPs did not differ significantly between patients with BD and controls. The haplotype frequencies of the IL-18 promoter polymorphisms were also similar between patients with BD and controls. However, the frequency of the GG genotype at position -137 was significantly higher in BD patients with ocular lesions than in those without ocular lesions (p = 0.026, pc = 0.048, OR = 4.1). CONCLUSION: Although the IL-18 gene polymorphisms were not associated with a susceptibility to BD in the Korean population, the patients carrying the GG genotype at position -137 had a higher risk of developing the ocular lesions. Further studies in other populations are required to confirm these results.

(8) Genetic analysis of MEFV gene pyrin domain in patients with Behcet's disease.

Dursun ADurakbasi-Dursun HGZamani AGGulbahar ZGDursun RYakicier C.
Mediators Inflamm. 2006;2006(3):41783.
OBJECTIVES: Behcet's disease (BD) is a systemic vasculitis with recurrent oral and genital ulcers and uveitis. MEFV gene, which is the main factor in familial Mediterranean fever (FMF), is also reported to be a susceptibility gene for BD. The pyrin domain of MEFV gene is a member of death-domain superfamily and has been proposed to regulate inflammatory signaling in myeloid cells. This study was designed to determine if mutations in pyrin domain of MEFV gene are involved in BD. METHODS: We analyzed the pyrin domain of MEFV gene in 54 Turkish patients with BD by PCR-analysis and direct sequencing. RESULTS: Neither deletion or insertion mutations nor point mutations in pyrin domain were found in any patient. CONCLUSION: Although pyrin gene mutations have been reported in patients with BD, pyrin domain is not mutated. However, alterations in other regions of MEFV gene and interaction between pyrin domains are needed to be further investigated.

(9) Evaluation of leptin level and Ob gene polymorphism in patients with Behcet's disease.

Okudan NAcar HGokbel HMevlitoglu ISari F.
Arch Dermatol Res. 2006 Aug;298(3):127-130. Epub 2006 Jun 20.

The present study was aimed to evaluate serum leptin level and the frequency of oligopolymorphic codon 25 (CAA/CAG) of Ob gene in Behcet's disease. Eighty-seven patients with Behcet's disease and 85 healthy controls with matched age, gender and body mass index were included in the study. Serum leptin level was determined and genotype of codon 25 of Ob gene was performed by using the PCR amplification after DNA extraction. Serum leptin concentration of the patients with Behcet's disease (23.8 +/- 22.8 ng/ml) was higher than that of the control groups (17.1 +/- 14.7 ng/ml). The patients with Behcet's disease and control subjects showed CAA/CAA genotype, indicating the presence of no polymorphism. Neither Behcet's disease nor serum leptin level was found to be related to codon 25 polymorphism. We concluded that leptin 25CAG polymorphism is not associated with Behcet's disease and serum leptin level.

(10) TNF-alpha gene 1031 T/C polymorphism in Turkish patients with Behcet's disease.

Akman ASallakci NCoskun MBacanli AYavuzer UAlpsoy EYegin O.
Br J Dermatol. 2006 Aug;155(2):350-6.

BACKGROUND: Genetic factors that predispose individuals to Behcet's disease (BD) are considered to play an important role in development of the disease. The tumour necrosis factor (TNF)-alpha gene, which is closely linked to the HLA-B51 gene, is involved in susceptibility for BD. Recently, a polymorphism at position -1031 within the TNF-alpha promoter region was demonstrated to be responsible for susceptibility to BD in a British population. However, the functional effects of this polymorphism have not yet been determined. OBJECTIVES: To investigate the possible relation of the TNF-alpha-1031 T/C polymorphism with susceptibility to BD in a Turkish population and to determine the functional importance of this polymorphism. METHODS: Ninety-nine unrelated patients (47 women, 52 men; mean +/- SD age, 34.10 +/- 10.53 years) with BD and 103 ethnically matched healthy controls (52 males, 51 females; mean +/- SD age, 40.25 +/- 14.15) were enrolled in the study. For genotyping, polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP) analysis was employed. The functional importance of TNF-alpha-1031 T/C polymorphism was determined with an enzyme-linked immunospot (ELISPOT) assay. For this purpose, mononuclear cells obtained from BD patients and controls were analysed for TNF-alpha and interferon (IFN)-gamma production. RESULTS: A significant difference was observed between BD patients and controls with respect to the allele frequency of TNF-alpha-1031C [P = 0.018, OR = 1.83, 95% confidence interval (CI) = 1.07-3.13]. When the allele frequencies were analysed according to the clinical features, the T allele in patients with positive skin pathergy test (SPT) was significantly increased when compared with those of patients without these findings (P = 0.004, OR = 2.75, 95% CI = 1.3-5.86). To demonstrate the frequency of TNF-alpha and IFN-gamma producing cells, mononuclear cells from four representative individuals of each genotype were used and the spontaneous and stimulated TNF-alpha and IFN-gamma values (spot numbers) were analysed. Compared with the control groups, a significant increase was observed in the number of cells producing TNF-alpha obtained from BD patients (P < 0.001). Moreover, the stimulation index for TNF-alpha [bacterial lipopolysaccharide (LPS) stimulated/unstimulated] was higher for the CC genotype (9 +/- 9.5) with respect to the other genotypes (TT; 1.3 +/- 0.3 and TC; 1.2 +/- 0.2). While the difference in the spontaneous IFN-gamma values between groups were not statistically significant, the stimulated IFN-gamma values were found to be significantly increased in the BD group when compared with the healthy control group (P = 0.004). CONCLUSIONS: Our results showed that, in the Turkish population the TNF-alpha-1031C allele is associated with susceptibility to BD. On the other hand, carrying the T allele may render patients more prone to developing a positive skin pathergy test. In addition, ELISPOT assays revealed that BD patients exhibited a significantly higher number of mononuclear cells producing TNF-alpha, and cells obtained from patients with a CC genotype had a stronger response to LPS stimulation. The strong IFN-gamma response upon LPS stimulation in BD patients supports the previous findings that BD is a Th1 driven disease. These findings suggest that the TNF-alpha-1031 polymorphism may have a functional effect and could explain the reason for high levels of TNF-alpha production observed in BD patients.

(11) Association of TNFA promoter region haplotype in Behcet's Disease.

Park KKim NNam JBang DLee ES.
J Korean Med Sci. 2006 Aug;21(4):596-601.

Although the etiology of Behcet's Disease (BD; MIM 109650) remains to be clearly elucidated, levels of tumor necrosis factor alpha (TNF-alpha) have been reported to be significantly elevated in BD patients, and TNF-alpha blockers have been demonstrated to exhibit some degree of therapeutic efficacy for a certain subset of BD sufferers. In this study, we have conducted an analysis of the TNFA haplotypes in the promoter response element that affect the binding affinity of specific transcription factors, in order to characterize their association with the clinical features of BD. Six polymorphisms in the promoter region of TNFA were genotyped in 254 BD patients and 344 control subjects, via the PCR-RFLP technique. TNFA -1031*C, -863*A and -308*G alleles were associated with an increased risk of BD (p=0.030, OR=1.4; p=0.008, OR=1.5; p=0.010, OR=1.8, respectively). The sole TNFA haplotype -1031C-863A-857C-376G-308G-238G, was associated with a 1.6 fold increase in the risk of BD, whereas the TNFA haplotype -1031T-863C-857C-376G-308A-238G was associated with a 0.6 decreased risk of BD. The TNFA -1031*C, -863*A, -857*C and -308*G alleles were significantly associated with BD. The findings of this study, collectively, indicate that TNFA haplotypes in the promoter response elements may exert significant influence on susceptibility to BD.

(12) Toll-like receptor 2 Arg753Gln gene polymorphism in Turkish patients with Behcet's disease.

Bacanli ASallakci NYavuzer UAlpsoy EYegin O..
Clin Exp Dermatol. 2006 Sep;31(5):699-701

Having considered the impact of the function of TLR2 in the recognition of several microorganisms that are thought to have an association with Behcet's disease (BD), we aimed to determine a possible association between the TLR2 Arg753Gln polymorphism and susceptibility to BD. We genotyped 83 patients with BD, 95 ethnically matched healthy controls, 12 patients with recurrent aphthous stomatitis (RAS) and 21 patients with rheumatoid arthritis (RA) by restriction fragment length polymorphism after PCR amplification of the genomic region encompassing the polymorphic site. Comparison of the TLR2 Arg753Gln A allele and A/G genotype frequencies did not show a significant difference between patients with BD and healthy controls (1.2% vs. 0.6%, and 2.1% vs. 1.1%, respectively). None of the patients from the RAS and RA groups had the A allele or A/G genotype. Our results indicate that the TLR2 Arg753Gln polymorphism does not play a role in the aetiopathogenesis of BD.

(13) Single nucleotide polymorphisms of Ficolin 2 gene in Behcet's disease.

Chen XKatoh YNakamura KOyama NKaneko FEndo YFujita TNishida TMizuki N.
J Dermatol Sci. 2006 Sep;43(3):201-5. Epub 2006 Jul 12.

BACKGROUND: Genetic susceptibility to Behcet's disease (BD) is well documented for HLA-B51 positivity. However, BD is not a simple hereditary disease and it is exaggerated by exogenous stimuli such as microorganisms' infections. Ficolin 2 is a lectin that binds to the surface of microbial cells and kills microbial cells through the activation of complement system. Novel single nucleotide polymorphisms (SNPs) of human Ficolin 2 gene (FCN2 gene) have been recently identified in Caucasian people. OBJECTIVE: The aim of the study was to elucidate the contribution of FCN2 gene in the pathogenesis of BD. METHODS: The frequencies of genotypes and alleles of FCN2 gene SNPs in the promoter regions (-987, -602, -557, -64, -4) and exon 8 (+6359, +6424) were examined in 83 patients with BD and 64 healthy controls by genotyping with a DNA sequencing method. RESULTS: There were no significant differences in genotype and allele frequencies of FCN2 gene SNPs between BD patients and healthy controls. No significant differences in genotype and allele frequencies of FCN2 gene SNPs were detected among different clinical subgroups in BD patients. Significant differences in allele frequencies of FCN gene SNPs at both -557 and -64 sites in the promoter regions were found between HLA-B51 positive groups and HLA-B51 negative groups of BD patients. CONCLUSION: The significant differences in allele frequencies of FCN2 gene SNPs in the promoter lesions (-557 and -64 sites) among HLA-B51 positive BD patients may reveal the possibility that ficolin may contribute to the innate immunity of BD among HLA-B51 haplotypes in BD patients.
(14) Allelic diversity and affinity variants of MICA are imbalanced in Spanish patients with Behcet's disease.

Munoz-Saa ICambra APallares LEspinosa GJuan APujalte FMatamoros NMila J,Julia MR.
Scand J Immunol. 2006 Jul;64(1):77-82.

The aetiology of Behcet's disease (BD) is still unknown, but genetic and environmental factors are involved. HLA-B*51 is considered a susceptibility marker and some MICA alleles have also been associated. Cytotoxic T lymphocytes have been suggested as responsible for BD lesions by engaging MICA through NKG2D surface molecules. In the present study, HLA-B and MICA alleles were typed by polymerase chain reaction using sequence-specific primers, in 165 healthy Spanish controls and 42 BD patients. In the healthy group, MICA*008 (28.48%), MICA*004 (17.58%), MICA*002 (14.24%) and MICA*009 (9.39%) were the predominant alleles and the most common haplotype was MICA*004-B*44 (12.12%). MICA*001 (5.15%), MICA*004, MICA*011 (4.54%) and MICA*018 (5.15%) were more frequent, and MICA*010 (1.81%) and MICA*008 were less prevalent than in other Caucasoid populations. Similar results have been reported in North African individuals and this could support the hypothesis of a common ancestral origin of both populations. The frequencies of MICA*009 and MICA*019 were significantly increased in our BD patients in comparison with controls: 22.62% versus 9.39% and 10.71% versus 1.81% respectively. The increase of MICA*019 had not been described in other BD cohorts, and it corroborates the genetic heterogeneity at MICA locus in BD patients. High-affinity MICA alleles for NKG2D were more frequent in controls than in patients. Moreover, high-affinity alleles were not found in homozygous BD patients. These results argue against the hypothesis of an autoaggressive response in BD patients through MICA-NKG2D interactions.

(15) Microsatellite polymorphisms of the MICA gene among Japanese patients with Behcet's disease.

Nishiyama MTakahashi MManaka KSuzuki SSaito MNakae K.
Can J Ophthalmol. 2006 Apr;41(2):210-5.

BACKGROUND: Behcet's disease (BD) is a multisystemic inflammatory disease of unknown origin. Because some researchers have recently suggested a primary association of BD with the A6 allele of the human major histocompatibility complex class I chain-related A (MICA) gene, we investigated microsatellite polymorphisms of the MICA gene in subjects with and without BD. METHODS: This was a case-control study of 23 Japanese patients with BD and 23 Japanese volunteers without BD who were compared for MICA microsatellite polymorphisms using the polymerase chain reaction (PCR). We also analysed associations between 5 MICA alleles and the clinical features of patients. RESULTS: There was no significant difference between case patients and control subjects in phenotype frequencies. The MICA-A6 allele showed the strongest positive correlation with the human leukocyte antigen allele HLA-B51. Allele A5 showed a strong positive correlation with age at onset and a strong negative correlation with iridocyclitis and HLA-B51. A4 showed a strong negative correlation with ocular lesions and HLA-B51. Patients with the MICA-A6 allele had significantly higher HLA positivity than patients without the allele. INTERPRETATION: While the MICA-A6 allele had no significant association with BD, it showed a strong association with HLA-B51. This finding suggests that an association between MICA-A6 and BD may be a secondary phenomenon related to HLA-B51. As several associations with MICA alleles and clinical features have been found, further investigation is expected to elucidate the biological mechanism of action of the MICA protein relative to disease onset.
(16) Four-digit allele genotyping of the HLA-A and HLA-B genes in Japanese patients with Behcet's disease by a PCR-SSOP-Luminex method.

Itoh YInoko HKulski JKSasaki SMeguro ATakiyama NNishida TYuasa TOhno S,Mizuki N.
Tissue Antigens. 2006 May;67(5):390-4.

The present study represents the first four-digit allele genotyping of HLA-A and -B in Japanese Behcet's disease (BD) patients and controls using a new genotyping method (named the PCR-SSOP-Luminex method) to determine the association of certain HLA-A or -B alleles with BD. Peripheral blood lymphocytes were collected from 180 Japanese BD patients and 170 healthy controls. The genotype frequency of HLA-B*5101 was significantly increased in the patients (61.7%) as compared with the controls (15.9%) (Pc = 1 x 10(-16), OR = 8.5). When we recalculated the phenotype frequencies after excluding the HLA-B*51-positive patients and controls to account for the effects of the linkage disequilibrium and the abundance of the HLA-B*51 allele, the frequencies of HLA-A*2602 and HLA-B*3901 had a weak association in the patient group without HLA-B*51 as compared with the control group without HLA-B*51 (A*2602; Pc = 0.130, OR = 4.3, B*3901; Pc = 0.099, OR = 3.5). This study confirmed on the basis of using a new and more accurate genotyping method that Japanese BD patients have a strong primary association with HLA-B*5101. The significant increase of HLA-A*2602 and B*3901 in the patient group without HLA-B*51 suggests that these two alleles might also have some secondary influence on the onset of BD.

(17) Role of IL-12B promoter polymorphism in Adamantiades-Behcet's disease susceptibility: An involvement of Th1 immunoreactivity against Streptococcus Sanguinis antigen.

Yanagihori HOyama NNakamura KMizuki NOguma KKaneko F.
J Invest Dermatol. 2006 Jul;126(7):1534-40. Epub 2006 Mar 2.

Adamantiades-Behcet's disease (ABD) is a chronic inflammatory multisystem disorder. Although the precise etiology is unclear, high prevalence of human leukocyte antigen (HLA)-B51 predisposition and predominantly involved T-helper type 1 cells (Th1)-type proinflammatory cytokines and extrinsic Streptococcal infection suggest a substantial association with an immunogenetic basis and strengthens the hypothesis that IL-12, a potent inducer of Th-1 immune reaction, is a putative candidate in its pathogenesis. These clinicopathological findings led us to examine interleukin 12 p40 (IL-12B) promoter polymorphism, for which the 4-base pair (bp) heterozygous insertion has been shown to affect the gene transcription and subsequent protein production. We analyzed IL-12B promoter genotypes in 194 Japanese subjects (92 with ABD and 102 normal controls) by PCR-based restriction enzyme digestion. The frequency of the insertion heterozygosity was significantly higher in patients than in controls (49/92, 53.3% vs 39/102, 38.2%, respectively). Comparing these with HLA haplotype data, this trend was more significant in HLA-B51-negative patients (29/42, 69.0% vs 20/50, 40.0%; P = 0.005). As assessed by semiquantitative reverse transcription-PCR and ELISA, stimulation with Streptococcal antigens specifically increased expression of IL-12 p40 mRNA and protein, in conjunction with IL-12 p70 induction, in peripheral blood mononuclear cells from heterozygous patients. Our results provide evidence for anti-bacterial host response toward Th1-immunity mediated by IL-12 in patients with ABD, and the possible insight into the genetic susceptibility that is independent of HLA background.
(18) Polymorphisms in the endothelial nitric oxide synthase gene are associated with Behcet's disease.
Karasneh JA. Hajeer AH. Silman A. Worthington J. Ollier WE. Gul A
Rheumatology. 44(5):614-7, 2005 May.
Abstract
OBJECTIVE: Reduced plasma nitric oxide (NO) levels in Behcet's disease (BD) patients have been implicated in the development of the endothelial abnormalities and thrombotic complications occurring in these patients. This study investigated the association of the endothelial NO Synthase (eNOS) gene polymorphisms with BD. METHODS: A case-control study was carried out using 193 unrelated Turkish BD patients and 106 healthy controls. All individuals were genotyped by PCR for two single-nucleotide polymorphisms (SNPs): -786 T-->C in the promoter region and 894 G-->T in exon 7 (Glu298Asp). A variable number of tandem repeats (VNTR) polymorphism in intron 4 was also investigated. RESULTS: The VNTR polymorphism was associated with BD, detected by an increased frequency of the b allele (odds ratio = 1.9, P = 0.0069) and b/b genotype (odds ratio = 2.2, P = 0.002) in patients. After the stratification of cases according to the family history, a significant difference between familial cases and controls in the -786 SNP was observed, with an increase in the frequency of the T allele (odds ratio = 2.5, P = 0.0016) and T/T genotype (odds ratio = 2.5, P = 0.0085), and the association of the VNTR polymorphism with BD became stronger. The -786*T and VNTR*b alleles were in linkage disequilibrium (D' = 0.65, P <0.0001), and the number of individuals homozygous for the -786*T/VNTR*b haplotype was significantly increased in the patients. CONCLUSIONS: eNOS gene polymorphisms are associated with BD, which might contribute to the reduced NO activity observed in BD patients.

(19) Lack of evidence for association between endothelial nitric oxide synthase gene polymorphism (glu298asp) with Behcet's disease in the Turkish population.

Kara NSenturk NGunes SOBagci HYigit STuranli AY.
Arch Dermatol Res. 2006 Apr;297(10):468-71. Epub 2006 Feb 7

Endothelial nitric oxide synthase (eNOS) could be a candidate gene for Behcet's disease (BD). This study investigated the relationship of the eNOS Glu298 --> Asp polymorphism with the presence and severity of BD in the Turkish population. Ninety-two patients with BD and 100 controls were studied. Analyses of Glu298Asp polymorphism in exon 7 of the eNOS gene were made by the polymerase chain reaction (PCR)-restriction fragment length polymorphism technique. The frequencies of the eNOS genotypes were similar for BD patients (GG:GT:TT = 58.7%:38%:3.3%) and controls (59.2%:33.7%:7.1 %), P = 0.335. No evidence of difference was found in the frequency of the T allele between BD patients (22.3%) and controls (24%), [OR = 0.91, 95% CI (0.55-1.50), P = 0.690]. Glu298 --> Asp polymorphism of the eNOS gene does not appear to be associated with the presence of BD in the Turkish population.

(20) The alteration of sister chromatid exchange frequencies in Behcet's disease with and without HLA-B51.

Ikbal MAtasoy MPirim IAliagaoglu CKaratay SErdem T.
J Eur Acad Dermatol Venereol. 2006 Feb;20(2):149-52.

BACKGROUND: The analysis of sister chromatid exchange (SCE) is a cytogenetic technique used to show DNA damage as a result of an exchange of DNA fragments between sister chromatids. It is known that there is an increased SCE frequency in Behcet's disease (BD). OBJECTIVE: To investigate whether human leucocyte antigen (HLA)-B51-positive patients with Behcet's disease exhibit higher SCE frequencies than those without HLA-B51. METHODS: Lymphocytes from 75 patients (38 women, 37 men) and from 50 controls (28 women, 22 men) were cultured in darkness for 72 h in the presence of bromodeoxyuridine. Metaphase chromosomes were stained with a fluorescence plus Giemsa technique after a standard harvest procedure. For HLA-B51 typing, DNA was extracted from ethylenediaminetetraacetic acid blood samples and HLA-B5 allele genotyping was performed by the polymerase chain reaction (PCR)-sequence specific primer method. RESULTS: Thirty-nine of 75 patients with BD (52%) and 15 of 50 controls (30%) were found HLA-B51-positive. The SCE frequencies in HLA-B51-positive patients were higher than in HLA-B51-negative ones (P < 0.001), whereas no difference was detected in the control group. CONCLUSION: This study revealed that there was a significant association between elevated SCE frequencies and existence of HLA-B51 patients with BD.

(21) Association of vascular endothelial growth factor gene polymorphisms with Behcet’s disease in a Korean population.

Nam EJHan SWKim SUCho JHSa KHLee WKPark JYKang YM.
Hum Immunol. 2005 Oct;66(10):1068-73.

Vascular endothelial growth factor (VEGF) is important for angiogenesis and inflammation, both of which are codependent and contribute to the pathophysiology of Behcet disease (BD). The increased expressions of VEGF have been observed in the active stage and in the ocular inflammation of BD. Polymorphisms of the VEGF gene have been associated with chronic inflammatory disease including rheumatoid arthritis. We sought to investigate whether polymorphisms on the regulatory region of the VEGF gene are associated with susceptibility of Korean patients with BD. One hundred one native Korean patients with BD and 138 healthy unrelated controls were recruited. Genotype and allele frequencies of the four selected polymorphisms (-2578, -1154, -634, and 936) were not different between the BD group and controls. Among the BD patients, the frequency of the -634 CC genotype decreased in patients with uveitis (2.6% vs. 20.6%, adjusted OR = 0.100, 95% CI 0.011-0.875, p = 0.037), although it became insignificant after correction for multiple comparisons. These results indicate that the VEGF gene polymorphisms are not associated with BD in the Korean population, but they may be involved in the development of the ocular inflammation of BD.

(22) Deep venous thrombosis in a patient with Behcet's disease and homozygous prothrombin (factor II) G20210A mutation on oral contraceptive pills.

Uthman IOtrock ZTaher A.
Rheumatol Int. 2006 Jun;26(8):758-9.

Behcet's disease (BD) is a multisystemic disease of unknown aetiology characterized by chronic relapsing oral aphthous lesions, genital ulcers, uveitis, and vasculopathy of both arteries and veins of all sizes. We present the case of a female patient, with BD on oral contraceptive pills, who sustained deep venous thrombosis of the long saphenous vein. The patient was found to be a carrier of a homozygous mutation of the prothrombin (factor II) G20210A gene. Our case suggests that a thrombophilia work-up may be warranted in BD patients, especially young women before they are prescribed oral contraceptives.

(23) Lack of association of tumor necrosis factor-alpha gene polymorphisms with disease susceptibility and severity in Behcet's disease.

Ates AKinikli GDuzgun NDuman M.
Rheumatol Int. 2006 Feb;26(4):348-53.

Although it has been reported that the MHC class I molecule, HLA-B51, is a risk factor for Behcet's disease (BD), contribution of the tumor necrosis factor (TNF) genes, which are located in the vicinity of the HLA-B locus, to the genetic susceptibility for BD has yet to be elucidated. The purpose of this study was to analyze the effect of TNF-alpha promoter polymorphisms at positions -308, -238 and -376 on the susceptibility, severity and clinical features of BD. The TNF-alpha gene sequences from 107 patients with BD and 102 healthy subjects were amplified by the polymerase chain reaction. Sequence analysis of the TNF-alpha gene locus, which contains promoter polymorphisms at positions -376, -308, and -238, was performed with a DNA sequencing kit on automated sequencer. The patients were classified according to disease severity and clinical features. Serum TNF-alpha level in the study groups was measured by sandwich enzyme immunoassay. In patients with BD the frequencies of TNF-alpha -308 (19.4% vs 18.4%), -238 (3.7% vs 5.9%), and -376 (0.9% vs 2.9%) gene polymorphisms were not found to be significantly different from those in healthy subjects. The TNF-alpha gene polymorphisms did not show any association with disease severity or clinical features. Serum TNF-alpha level was significantly higher in patients with BD than in healthy controls (3.10 +/- 1.45 pg/ml vs 2.43 +/- 1.94 pg/ml, P < 0.01). Serum TNF-alpha level was not found to be significantly associated with disease severity, activity, clinical findings and TNF-alpha genotypes. The results of this study suggest that the TNF-alpha gene polymorphisms are unlikely to play an important role in the pathogenesis and severity of BD.
(24) MEFV gene is a probable susceptibility gene for Behcet's disease.
Imirzalioglu N. Dursun A. Tastan B. Soysal Y. Yakicier MC Scandinavian Journal of Rheumatology. 34(1):56-8, 2005.

OBJECTIVE: Behcet's disease (BD) is a rare, chronic, multisystem inflammatory disorder. The prevalence of BD is higher in the Middle Eastern and Mediterranean populations. Another chronic inflammatory disease, familial Mediterranean fever (FMF), is also known to be highly prevalent in these populations. The prevalence of BD is higher in the FMF patient population than in populations known to be rich in BD . Both BD and FMF have some pathophysiological features in common and they result from inappropriate activation of neutrophils. Clinical manifestations of both diseases can mimic each other and the coexistence of both diseases in the same patient has been reported. Given that BD and FMF have similar pathophysiological, epidemiological, and clinical features, we hypothesized that the gene responsible for FMF, MEFV, may also play a role in the pathogenesis of BD. METHODS: Forty-two BD patients who had no symptoms and family history for FMF and 66 healthy controls were scree!
ned for common MEFV gene mutations (E148Q, M680I, M694V, and V726A). RESULTS: Fifteen patients (36%) displayed MEFV mutations (nine M694V, five E148Q, and one M680I) and mutation rates were significantly elevated compared to 66 (11%) healthy controls (p = 0.0034). CONCLUSION: The occurrence of frequent MEFV mutations in BD patients suggests that the MEFV gene is involved in the pathogenesis of Behcet's disease.

(25) Specific interleukin-1 gene polymorphisms in Turkish patients with Behcet's disease.
Coskun M. Bacanli A. Sallakci N. Alpsoy E. Yavuzer U. Yegin O
Experimental Dermatology. 14(2):124-9, 2005 Feb.

Genetic factors that predispose individuals to Behcet's disease (BD) are considered to play important roles in the development of the disease. The pro-inflammatory cytokine interleukin-1 (IL-1) has been implicated in the pathogenesis of BD. Our aim was to determine a possible association of specific polymorphisms of IL-1alpha, IL-1beta, and IL-1 receptor antagonist genes with susceptibility for BD. We genotyped 72 patients with BD and 163 healthy controls for IL-1alpha-889, IL-1beta-511, and +3953 (nt5887) single-nucleotide polymorphisms besides IL-1 receptor antagonist variable number of tandem repeat polymorphism (for five different alleles). Comparison of the IL-1beta+3953 T allele and TT genotype frequencies showed a significant difference between patients with BD and controls (54.2 vs. 40.5%, OR = 1.74, P = 0.024, and 40.3 vs. 19.6%, OR = 2.76, P = 0.009, respectively). However, no difference was observed in the genotype or allele frequencies of IL-1alpha-889, IL-1bet!
a-511, and IL-1 receptor antagonist between the patients with BD and the controls. Our results indicate that susceptibility to BD is increased in individuals carrying the IL-1beta+3953 T allele and TT genotype.
(26) Polymorphisms of the IL-8 and CXCR2 genes are not associated with Behcet's disease.
Duymaz-Tozkir J. Yilmaz V. Uyar FA. Hajeer AH. Saruhan-Direskeneli G. Gul A.
Journal of Rheumatology. 32(1):93-7, 2005 Jan.

OBJECTIVE: Genetic susceptibility to Behcet's disease (BD) is well documented for HLA-B51; however, contribution of other genetic polymorphisms is estimated to be substantial. Interleukin 8 (IL-8), a potent chemoattractant for neutrophils, has been found to be elevated in BD serum, and the serum concentrations correlate with disease activity. Novel polymorphisms in IL-8 (CXCL8) and in one of its receptors, CXCR2 gene, may have a role in enhanced IL-8 activity in BD. METHODS: Three single nucleotide polymorphisms (SNP; -353 A/G, +1530 T/C, +3331 A/G) of the IL-8 gene and 2 SNP (+785 C/T and +1208 T/C) of the CXCR2 gene were screened in 100 patients with BD (61 men, 39 women, mean age 42.1 yrs) and 100 healthy controls (50 men, 50 women, mean age 36.8 yrs) by genotyping with PCR-RFLP and PCR-SSP methods. RESULTS: No differences were observed between BD patients and controls for the allele and genotype frequencies of the screened IL-8 and CXCR2 gene polymorphisms. Distributio!
n of these polymorphisms revealed no significant differences between clinical subgroups of BD patients. Each pair of the SNP -353/+1530, -353/+3331, and +1530/+3331 of IL-8 and +785/+1208 of CXCR2 showed strong linkage disequilibrium in both patients and controls (p < 0.001 for all). The distribution of the estimated IL-8 and CXCR2 haplotypes revealed no association with BD or any of its clinical subsets. CONCLUSION: These results suggest that the IL-8 gene -353 A/G, +1530 T/C, and +3331 A/G and the CXCR2 gene +785 C/T and +1208 T/C polymorphisms have no role in the increased expression of IL-8 in BD.
(27) N-acetyltransferase 2 polymorphisms in patients with Behcet's disease.
Tamer L. Tursen U. Eskandari G. Ates NA. Ercan B. Yildirim H. Atik U. Clinical & Experimental Dermatology. 30(1):56-60, 2005 Jan.
It is possible that dietary, environmental factors and/or genetic polymorphisms in xenobiotic-metabolizing enzymes may contribute to the development of Behcet's disease. As N-acetyltransferase (NAT) 2 is an important xenobiotic-metabolizing enzyme and theoretically the nonacetylated xenobiotics may induce an autoimmune mechanism, the aim of the present study was to investigate whether the genetic polymorphism of NAT2 plays a role in susceptibility to Behcet's disease. Forty Behcet's disease patients and 82 control subjects were enrolled in the study. NAT2*5A, NAT2*6A, NAT27*A/B and NAT2*14A polymorphisms were detected by using real time PCR with LightCycler (Roche Diagnostics GmbH, Mannheim, Germany). The NAT2*5A and NAT2*6A mutant genotypes carried an increased risk of developing Behcet's disease [odds ratio (OR) = 66.29, 95% confidence interval (CI) = 8.21-535.33; and OR = 24; 95% CI = 2.04-304.98, respectively]. The NAT2*7A/B and NAT2*14A gene polymorphisms were not an !
increased risk for developing Behcet's disease. As a result of this study we conclude the NAT2 slow acetylator status may be a determinant in susceptibility to Behcet's disease. This finding may have implications for the theories of the pathogenesis of the disease as well as for therapeutic aspects.


(28) Behcet's disease, myelodysplastic syndrome, trisomy 8, gastroenterological involvement--an association.

Eder LRozenbaum MBoulman NAayubkhanov EWolfovitz EZisman DRosner I.

Internal Medicine A, Carmel Medical Center, Haifa, Israel. ben@usha.org.il
Clin Exp Rheumatol. 2005 Jul-Aug;23(4 Suppl 38):S91-5.
Only a limited number of cases of Behcet's disease and hematological malignancies have been reported in the literature. We report the case of a 45 year old female patient with Behcet's disease who developed myelodysplastic syndrome, refractory anemia with excess blasts in transformation subtype, with complex chromosomal abnormalities, including excess of chromosome 8, following several years of treatment with chlorambucil for Behcet's disease. As has been described in most such cases, gastrointestinal involvement was most prominent. This case is described and the occurrence of myelodysplastic syndrome in Behcet's disease reviewed.

(29) Constitutional trisomy 8 mosaicism with myelodysplastic syndrome complicated by intestinal Behcet disease and antithrombin III deficiency.

Ando SMaemori MSakai HAndo SShiraishi HSakai KRuhnke GW.

Department of Hematology, Teine Keijinkai Hospital, Hokkaido, Japan. a-sachi@abox.so-net.ne.jp
Cancer Genet Cytogenet. 2005 Oct 15;162(2):172-5.
Trisomy 8 is the most common acquired chromosomal abnormality associated with myeloid malignancy. As a constitutional trisomy 8 mosaicism (T8M), it exhibits an extremely variable phenotype. In addition, Behcet disease (BD) has been reported as an unusual complication of myelodysplastic syndrome (MDS). To our knowledge, 12 case reports of various hematologic malignancies in patients with T8M and 18 case reports of MDS with acquired trisomy 8 complicated by BD have been published to date. We report a case of constitutional T8M with MDS complicated by intestinal BD and antithrombin III deficiency.

(30) Behcet's disease associated with trisomy 8 in a male Caucasian patient from Great Britain--a case report.

Kuttikat AHaskard DChakravarty K.
Clin Exp Rheumatol. 2005 Jul-Aug;23(4 Suppl 38):S108-9.


Immunology

(31) Cytokine inhibitors: soluble tumor necrosis factor receptor 1 and interleukin-1 receptor antagonist in Behcet's disease.
Duzgun N. Ayaslioglu E. Tutkak H. Aydintug OT.
Rheumatology International. 25(1):1-5, 2005 Jan.

Serum levels of proinflammatory cytokines, interleukin-1 beta (IL-1beta), tumor necrosis factor alpha, (TNF-alpha), and their inhibitors, IL-1 receptor antagonist (IL-1ra) and soluble TNF receptor 1 (sTNFR1), were determined by enzyme-linked immunosorbent assay in 104 patients with Behcet's disease (65 active, 39 inactive) and 40 healthy controls. The levels of IL-1beta and IL-1ra were significantly higher in both active and inactive patients than in control subjects (P<0.01 and P< 0.01, respectively). The concentrations of TNF-alpha and sTNFR1 were found to be higher in active patients than in controls (P< 0.01 and P< 0.001, respectively). There were no significant differences in the serum levels of these cytokines and their inhibitors between active and inactive patients. Significant increases in mean C-reactive protein level and erythrocyte sedimentation rate were found in patients with active vs inactive disease (P< 0.001 and P< 0.05, respectively). C-reactive protein !
values correlated with erythrocyte sedimentation rate but not with cytokines or their inhibitors. Our conclusion is that elevated serum TNF-alpha and sTNFR1 seem to be important inflammatory mediators in Behcet's disease. The statistically significant increase in these levels may arise from the severity of inflammation in the tissue or organ involved.

(32) Decreased serum level of antibody against human cytomegalovirus in patients with Behcet's disease.
Lee EB. Kwon YJ. Shin KC. Song YW. Park CG. Hwang ES. Cha CY.
Rheumatology International. 25(1):33-6, 2005 Jan.

Behcet's disease (BD) is a connective tissue disorder characterized by recurrent orogenital ulcer, uveitis, and skin lesions. Recurrent aphthous ulcer is associated with human cytomegalovirus (HCMV). To investigate the possible role of HCMV in BD, we measured the titers of IgG, IgM, and IgA anti-HCMV antibodies in 73 Korean patients with BD, 50 with scleroderma, 70 with systemic lupus erythematosus, and 50 from healthy controls by indirect immunofluorescent staining. The titer of IgG anti-HCMV antibody was significantly lower in patients with BD than in controls (geometric mean 3115.4 vs 9687.6, P = 0.0001 by Wilcoxon's rank sum test), as was the titer of IgA anti-HCMV antibody (geometric mean 1.9 vs 15.7, P = 0.0001, Wilcoxon's rank sum test). In conclusion, we found significantly lower antibody responses to HCMV in patients with BD.
(33) Levels of soluble E-selectin in patients with active Behcet's disease.
Sari RA. Kiziltunc A. Taysy S. Akdemyr S. Gundogdu M.
Clinical Rheumatology. 24(1):55-9, 2005 Feb.

Behcet's disease is a systemic vasculitis of unknown aetiology. Endothelial cell injury plays an important role in the pathogenesis and immunopathology of Behcet's disease. E-selectin is expressed by activated endothelial cells. Because the selectin adhesion molecules are shed from activated cells, soluble forms of these proteins can be used as activation markers of endothelium (E-selectin). The pathogenesis of Behcet's disease (BD) is closely related to endothelial cells, leucocyte functions and immunity. The aim of this study was to investigate circulating E-selectin adhesion molecules, which are known to play a significant part in the immune response especially by regulating interaction of the leucocytes with endothelium in BD. Plasma E-selectin concentrations were evaluated in 23 patients with BD and 20 healthy control subjects. The disease activity was evaluated by clinical manifestations (oral aphthous ulcer, genital ulceration, positive pathergy test, skin lesions, !
eye involvement, thrombophlebitis and arthritis) and by laboratory investigations [erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)]. The patients were newly or previously diagnosed cases not taking any drug for BD. Levels of E-selectin were measured with commercially available sandwich enzyme-linked immunosorbent assay (ELISA) kits using human sE-selectin (cat. no: BMS 205). Plasma E-selectin concentrations of patients and controls were compared with the Mann-Whitney U test. Statistical significance was assigned to p values lower than 0.05. Serum levels (mean+/-SD) of soluble E-selectin (sE-selectin) were significantly higher in 23 patients with BD than in 20 healthy controls (53.2+/-18.2 ng/ml vs 33.8+/-7.5 ng/ml, p<0.0001). A statistically significant positive correlation was observed between sE-selectin levels and CRP and ESR in patients with BD (r=0.78, p<0.001 and r=0.56, p<0.01, respectively). Increases in the E-selectin in BD may be a direct consequence of the leucocyte and endothelium activations observed during the disease process. The noninvasive investigations can be used as biochemical markers for inflammation. This may provide additional information regarding disease activity along with the traditional indices such as ESR and CRP.

(34) CXCR2 Expression on neutrophils is upregulated during the relapsing phase of ocular Behcet disease.
Qiao H. Sonoda KH. Ariyama A. Kuratomi Y. Kawano Y. Ishibashi T.
Current Eye Research. 30(3):195-203, 2005 Mar.
PURPOSE: To search for markers of Behcet disease (BD) activity,we measured CXCR1 and CXCR2 levels on the circulating leukocytes of patients suffering from ocular BD. METHODS: Peripheral blood leukocytes were harvested from healthy volunteers (n = 16) and ocular BD patients (n = 35). The patients consisted of 15 individuals in relapsing phase (6 with prednisolone treatment) and 20 individuals in remission phase (9 with prednisolone treatment). Expression of CXC chemokine receptors (CXCRs) on leukocytes (including lymphocytes, monocytes, neutrophils) was measured using flow cytometry. RESULTS: Without prednisolone treatment, CXCR2 expression (on both total leukocytes and neutrophils) in relapsing phase was significantly higher than in remission-phase patients or normal individuals. By contrast, no significant difference was detected in the expression of CXCR1 between any ofthe groups. Importantly, low-dose prednisolone therapy reduced CXCR2 expression on neutrophils. CONCLUS!
IONS: CXCR2 has a potential role in promot-ing uveitis during ocular attack and might also be a useful marker for disease activity.

(35) The significance of serum nitric oxide levels in Behcet's disease and recurrent aphthous stomatitis.
Yildirim M. Baysal V. Inaloz HS. Doguc D
Journal of Dermatology. 31(12):983-8, 2004 Dec.

Behcet's disease (BD) is an inflammatory multisystem disorder characterized by recurrent oral and genital aphthous ulcers, arthritis, uveitis, and thrombophlebitis; it can involve several organs. However, recurrent aphthous stomatitis (RAS) can be seen without a confirmed diagnosis of BD. Moreover, there is no way of predicting whether a patient with RAS will develop BD. Nitric oxide (NO) is a free radical synthesized from L-arginine by one of the family of nitric oxide synthase (NOS) enzymes. Increased production of NO during several inflammatory and infectious processes has been recently postulated. Our aim was to investigate the serum NO levels in patients with active and inactive BD and RAS. Forty-six patients with BD, 30 patients with RAS and 30 healthy controls were enrolled in the study. The patients with BD were separated into two groups: clinically active (n = 24) and inactive (n = 22). A blood sample was collected from all subjects in order to determine their ser!
um NO levels. In patients with active BD, higher serum levels of NO metabolite were found in comparison with patients with inactive BD, in patients with RAS, or healthy controls (p < 0.05). We also found higher serum NO metabolite levels in patients with RAS than in healthy controls (p < 0.05). In patients with inactive BD, statistically significant higher levels of serum NO levels were found in comparison with the control group (p < 0.05). However, we found no statistically significant difference between the patients with inactive BD and RAS, which indicated that inactive BD cannot be distinguished from RAS by serum NO levels. We conclude that serum NO levels may be an important marker for estimating the severity of BD. However, further studies are needed to confirm our findings.

(36) Abnormal expression of chemokine receptors in Behcet's disease: relationship to intracellular Th1/Th2 cytokines and to clinical manifestations.
Houman H. Hamzaoui A. Ben Ghorbal I. Khanfir M. Feki M. Hamzaoui K.
Journal of Autoimmunity. 23(3):267-73, 2004 Nov.
Dynamic interplay between cytokines and chemokines directs trafficking of peripheral blood mononuclear cells to tissues in autoimmune and/or viral diseases. The aim of the current study was to define the expression on CD3+ T cells of six chemokine receptors associated with inflammatory sites and the expression of intracellular cytokines, such as interferon-gamma (IFN-gamma) and interleukin-4 (IL-4), in Behcet's disease (BD). Flow cytometry was used to detect chemokine receptor and intracytoplasmic cytokines' expression. We observed that CD3+ T cells in the peripheral blood express a restricted array of inflammatory chemokine receptors, specifically, CCR5, CCR6 and CXCR3, but little CCR1-3. The highest expression of CXCR3 on CD3+ T cells is associated with the presence of central nervous system (CNS) manifestations or pulmonary involvement. CXCR3 is the principal inflammatory chemokine receptor involved in BD. CCR5 chemokine receptor is increased in BD regardless of clinica!
l manifestations. The frequency of IFN-gamma-producing cells expressing CXCR3+ CD3+ cells is significantly increased in patients with BD compared with normal controls. IL-4-producing cells are decreased in BD. These results demonstrate the predominance of type 1 cytokine producing cells in CXCR3+ CD3+ T cells during BD. We hypothesize that CXCR3 is the principal inflammatory chemokine receptor involved in BD, particularly during CNS and pulmonary manifestations.

(37) Alpha tropomyosin as a self-antigen in patients with Behcet's disease.
Mahesh SP. Li Z. Buggage R. Mor F. Cohen IR. Chew EY. Nussenblatt RB.
Clinical & Experimental Immunology. 140(2):368-75, 2005 May.

We report for the first time a significant increased lymphoproliferative response to alpha tropomyosin as well as observing autoantibodies to tropomyosin observed in Behcet's disease (BD) patients with posterior uveitis. Peripheral blood mononuclear cells (PBMCs) from 18 BD patients with posterior uveitis, 18 patients with other forms of noninfectious uveitis, 9 patients with retinal damage due to photocoagulation as well as 18 healthy donors were evaluated for antigen-specific lymphoproliferative responses to alpha tropomyosin and its derivative peptides. The proliferative responses of PBMCs to these antigens were studied using (3)H thymidine incorporation assay. Serum samples were also screened by ELISA for autoantibodies against tropomyosin. Six of the 18 (33%) BD patients with posterior uveitis showed increased proliferative response to alpha tropomyosin or its derivative peptides, while none of the healthy, disease controls were positive. The mean lymphoproliferative responses to tropomyosin were significantly higher (P < 0.02) in the BD patients compared to healthy or disease controls. Higher titres of anti-tropomyosin antibodies were also seen in four of the 18 BD patients but none in the healthy or disease control groups (P < 0.002). The occurrence of these abnormalities supports a possible role for alpha tropomyosin as a self-antigen in a subset of patients with Behcet's disease.
(38) Circulating soluble CD28 in patients with Behcet's disease: relationship to clinical manifestations.

Hamzaoui KHamzaoui ABouajina LHouman H.
Clin Exp Rheumatol. 2005 Jul-Aug;23(4 Suppl 38):S49-52.

OBJECTIVE: This study evaluates the presence of serum soluble CD28 (sCD28) in Behcet's disease (BD) and its relationship with clinical manifestations. METHODS: Soluble CD28 concentration was determined by ELISA in 120 patients with BD (80 patients in active stage), 60 patients with rheumatoid arthritis (RA) and 60 healthy subjects. RESULTS: Concentrations of sCD28 were significantly higher in patients with BD and RA than in healthy subjects. Patients with active BD expressed the highest level of sCD28 in serum. Soluble CD28 exhibited a drastic increase in active BD patients, compared to BD in remission. Soluble CD28 concentrations were higher in patients with active BD patients having vasculitis. Significant positive correlation was observed in a longitudinal study of 15 BD patients, between sCD28 and C-reactive protein. CONCLUSION: Our study suggests that fluctuations of sCD28 in BD reflects disease activity and should be assessed in evaluating disease activity.


(39) Nicotine inhibits the production of proinflammatory mediators in human monocytes by suppression of I-kappaB phosphorylation and nuclear factor-kappaB transcriptional activity through nicotinic acetylcholine receptor alpha7.

Yoshikawa HKurokawa MOzaki NNara KAtou KTakada EKamochi HSuzuki N.

Clin Exp Immunol. 2006 Oct;146(1):116-23

Macrophages/monocytes and the proinflammatory mediators, such as tumour necrosis factor (TNF)-alpha, prostaglandin E(2) (PGE(2)), macrophage inflammatory protein (MIP)-1alpha and MIP-1alpha, play a critical role in the progression of immunological disorders including rheumatoid arthritis, Behcet's disease and Crohn's disease. In addition, the nicotinic acetylcholine receptor-alpha7 (alpha7nAChR) subunit is an essential regulator of inflammation. In this study, we evaluated the expression of the alpha7nAChR subunit on human peripheral monocytes and the effect of nicotine on the production of these proinflammatory mediators by activated monocytes. Fluorescein isothiocyanate (FITC)-labelled alpha-bungarotoxin demonstrated the cell surface expression of the alpha7nAchR subunit. Pretreatment with low-dose nicotine caused inhibition of TNF-alpha, PGE(2), MIP-1alpha and MIP-1alpha production, and mRNA expression of TNF-alpha, MIP-1alpha and MIP-1alpha and COX-2 in lipopolysaccharide (LPS)-activated monocytes. These suppressive effects of nicotine were caused at the transcriptional level and were mediated through alpha7nAChR. Nicotine suppressed the phosphorylation of I-kappaB, and then inhibited the transcriptional activity of nuclear factor-kappaB. These immunosuppressive effects of nicotine may contribute to the regulation of some immune diseases.

(40) Nicotine and Biochanin A, but Not Cigarette Smoke, Induce Anti-Inflammatory Effects on Keratinocytes and Endothelial Cells in Patients with Behcet's Disease.

Kalayciyan AOrawa HFimmel SPerschel FHGonzalez JBFitzner RGOrfanos CE,Zouboulis CC.

J Invest Dermatol. 2006 Sep 28; [Epub ahead of print]

During periods of smoking, patients with Behcet's disease have less oral aphthae than in abstinence. To elucidate this observation, human keratinocytes and dermal microvascular endothelial cells (HMEC-1) were incubated with serum of 20 patients with Behcet's disease and 20 healthy controls for 4 hours. Maximum non-toxic concentrations were determined and the cells were further treated with 6 muM nicotine, 3.3% cigarette smoke extract (CES), 100 muM biochanin A, and 6.25/12.5 muM pyrrolidine dithiocarbamate alone and in combinations for 24 hours. Serum IL-8 levels of patients were significantly lower than those of controls. However, after 4 hours incubation with patients' sera, IL-8 release by both cell types was markedly increased when compared with the corresponding serum levels. The levels of IL-6 and vascular endothelial growth factor (VEGF) release were after 4 hours similar with the corresponding levels in serum. IL-1 was not detected. Nicotine significantly decreased IL-8 and -6 release by HMEC-1 maintained in both patients' and controls' sera, but only IL-6 release by keratinocytes maintained in patients' sera. VEGF release by both cells was markedly increased after nicotine treatment in either serum. CES significantly decreased IL-8 release and increased production of VEGF in keratinocytes maintained in patients' serum. The phytoestrogen biochanin A alone and in combination with nicotine further decreased the secretion of IL-8, -6, and VEGF in all experimental settings. Our data support a specific anti-inflammatory effect of nicotine on keratinocytes and endothelial cells maintained in the serum of patients with Behcet's disease. Moreover, biochanin A is likely to exhibit similar and even more profound results than nicotine.


(41) Intraocular cytokine environment in active Behcet uveitis.

Ahn JKYu HGChung HPark YG.
Am J Ophthalmol. 2006 Sep;142(3):429-34.

PURPOSE: To determine cytokine profiles in aqueous humor and peripheral blood from patients with Behcet uveitis. DESIGN: Prospective, experimental, and case-control study. METHODS: Aqueous humor and peripheral blood samples from 24 patients with Behcet uveitis, 28 patients with other causes of endogenous uveitis, and 20 healthy subjects after uncomplicated cataract surgery were obtained. Cytokines (interferon gamma (IFN-gamma), interleukin [IL]-2, IL-4, IL-10, IL-12, IL-15, and tumor necrosis factor alpha (TNF-alpha)) were measured by enzyme-linked immunosorbent assay and compared between the uveitis groups. RESULTS: Aqueous interferon gamma (IFN-gamma) levels were higher in patients with Behcet uveitis in contrast to higher concentrations of IL-4 in patients without Behcet uveitis. Aqueous levels of tumor necrosis factor alpha (TNF-alpha) were higher in patients with Behcet uveitis than in patients without Behcet uveitis. Aqueous and serum IL-10 were detected in all patients without Behcet uveitis, but were below detection limits in all patients with Behcet uveitis. Furthermore, IL-15 was exclusively increased in the aqueous humor of Behcet uveitis. The aqueous IL-2 or IL-12 levels were similar regardless of the presence of Behcet uveitis. CONCLUSIONS: Our results showed that an extreme Th1 polarization, a high proinflammatory condition, a low immunosuppressive status, and the presence of natural killer (NK) or CD8+ T cell-activating cytokine were unique features in aqueous humor with Behcet uveitis, suggesting that different immunopathogenic mechanisms may be involved in the ongoing intraocular inflammation of Behcet uveitis.

(42) A study of antiendothelial cell antibodies in Behcet's disease.

Zheng WJZhao YTang FLDong Y.
Zhonghua Nei Ke Za Zhi. 2005 Dec;44(12):910-3.
OBJECTIVE: To investigate the clinical significant of antiendothelial cell antibodies (AECA) in Behcet's disease. METHODS: With human umbilical vein endothelial cell as substrate cell, sera from 59 Behcet's disease patients were detected for the presence of AECA by using fixed cell-ELISA. The associations of AECA to clinical disease activity were analyzed. In addition, Sera from other 70 systemic vasculitis (including 28 Takayasu arteritis, 20 Wegener's granulomatosis, 8 polyarteritis nodosa, 9 microscopic polyangiitis, 5 Churg-Strauss syndrome), 57 systemic lupus erythematosus (SLE), 25 rheumatoid arthritis and 85 healthy donors were screened for AECA. The associations of AECA to clinical disease activity were analyzed. RESULTS: The prevalence of AECA by human umbilical vein endothelial cell cell-ELISA was 47.5% in Behcet's disease. Compared with patients with rheumatoid arthritis (4.0%) and normal group (1.2%), AECA were more frequently found in patients with Behcet's disease, other systemic vasculitis (68.6%) and SLE (45.7%) (P < 0.01). The positive result on pathergy testing was more frequently found in AECA-positive patient with Behcet's disease (P < 0.05). After the treatment, patients with active disease entering remission showed a decrease in both AECA titers and the mean level of ESR (P < 0.05). CONCLUSIONS: AECA could be found more frequently in patients with Behcet's disease, associated closely with disease activity, which suggest that AECA may be used as an index in monitoring disease activity and effect of therapy in Behcet's disease. But AECA could also be found in other systemic vasculitis and SLE.



(43) T cell-regulated neutrophilic inflammation in autoinflammatory diseases.

Keller MSpanou ZSchaerli PBritschgi MYawalkar NSeitz MVilliger PMPichler WJ.
J Immunol. 2005 Dec 1;175(11):7678-86

Previous studies of acute generalized exanthematous pustulosis, a peculiar drug hypersensitivity reaction, suggested that CXCL8-producing T cells regulate sterile, polymorphonuclear neutrophil-rich skin inflammations. In this study, we test the hypothesis of whether CXCL8-producing T cells are present in autoinflammatory diseases like pustular psoriasis and Behcet's disease. Immunohistochemistry of normal skin revealed few CD4+ and CD8+ T cells, few CXCL8+ cells, and no neutrophilic infiltration, whereas in acute exacerbations of atopic dermatitis, numerous CD4+ T cells but few CD8+ T cells, neutrophils, or CXCL8+ cells were detected. In contrast, a pronounced infiltration of neutrophils and of predominantly CD4+ T cells was observed in skin biopsies from pustular psoriasis, Behcet's disease, and acute generalized exanthematous pustulosis, with infiltrating T cells strongly positive for CXCL8 and the chemokine receptor CCR6. Skin-derived T cell clones from pustular skin reactions were positive for CCR6 but negative for CCR8 and secreted high amounts of CXCL8 and GM-CSF, often together with IFN-gamma and TNF-alpha after in vitro stimulation. Moreover, some skin-derived T cell clones from Behcet's disease and from pustular psoriasis predominantly produced CXCL8 and GM-CSF, but failed to secrete IL-5 and IFN-gamma. These cells might represent a particular subset as they differ from both Th1 as well as Th2 T cells and are associated with a unique, neutrophil-rich sterile inflammation. Our findings suggest that CXCL8/GM-CSF-producing T cells may orchestrate neutrophil-rich pathologies of chronic autoinflammatory diseases like pustular psoriasis and Behcet's disease.


(44) Serum and erythrocyte adenosine deaminase activities in patients with Behcet's disease.

Canpolat FUnver MEskioglu FKosebalaban SDurmazlar SP.
Int J Dermatol. 2006 Sep;45(9):1153-6.

Objectives Adenosine deaminase (ADA) is a non-specific marker of the activation of the T cell, which has an important role in the etiology of Behcet's disease (BD). The purpose of this study was to investigate the determination of ADA activity as an index of T-lymphocyte function in BD, which is known to have an T-cell-mediated immune response. Materials and Methods Adenosine deaminase activities in both serum and erythrocytes were measured in 23 untreated patients with BD and in 20 healthy controls. The patients with BD were divided into two groups: active (n = 10) and inactive (n = 13). Results When compared with the control group, serum ADA activity was high (P < 0.01) and erythrocyte ADA activity was significantly low (P < 0.01) in BD. Serum ADA activity of active BD was higher than that of inactive BD (P < 0.01), but erythrocyte ADA activity was found to be lower in active BD than inactive BD (P < 0.01). Comment These findings may provide an additional benefit for the diagnosis of BD and sub-typing of active and inactive BD

(45) Expression of CXCR-1 and CXCR-2 chemokine receptors on synovial neutrophils in inflammatory arthritides: Does persistent or increasing expression of CXCR-2 contribute to the chronic inflammation or erosive changes?

Pay SMusabak USimsek IPekel AErdem HDinc ASengul A.
Joint Bone Spine. 2006 Jul 18; [Epub ahead of print]

OBJECTIVE: To analyze the CXCR-1 and CXCR-2 chemokine receptor expression on peripheral blood neutrophils (PBN) and synovial fluid neutrophils (SFN) of patients with rheumatoid arthritis (RA) and Behcet's disease (BD) (characterized by erosive and non-erosive arthritis, respectively), and to compare them with those of patients with osteoarthritis (OA). METHODS: We used flow cytometry to investigate the expression of CXCR-1 and CXCR-2 chemokine receptors on PBN and SFN of fifty-five (22 RA, 22 BD and 11 OA) age and sex-matched patients. RESULTS: In respect to chemokine receptor expression on neutrophils isolated from patients with RA, mean fluorescein intensity (MFI) of CXCR-1 chemokine receptors on PBN from active and inactive RA patients, and SFN from patients with RA were 151 (90-395), 129 (81-539) and 136 (64-220), respectively, and there were not statistically significant difference each other. But MFI of CXCR-2 chemokine receptors on SFN of patients with RA was 18 (10-32), and significantly higher than PBN of active and inactive RA patients (MFI: 10 (6-15) and 12 (7-16), P=0.002 and 0.037, respectively). In respect to chemokine receptor expression on neutrophils isolated from patients with BD, MFI of CXCR-1 chemokine receptors on PBN of active BD patients was 245 (97-844), and higher than PBN of active RA patients and SFN of BD patients (MFI: 151 (90-395) and 134 (61-231), P=0.047 and 0.017, respectively). MFI of CXCR-2 chemokine receptors on PBN of active and inactive BD patients, and SFN of patients BD were 10 (6-14), 10 (2-16), and 12 (8-24), respectively, there were not statistically significant difference each other. MFI of CXCR-1 chemokine receptors on SFN from patients with RA, BD, and OA were 136 (64-220), 134 (61-231), and 114 (60-180), respectively, and there was no difference between the study groups. MFI of CXCR-2 chemokine receptors on SFN of patients with RA was 18 (10-32), and higher than patients with BD and OA (MFI: 12 (8-24) and 11 (9-18), P=0.037 and 0.005, respectively), though there was no difference between last two groups. CONCLUSION: Our study points that CXCR-1 and CXCR-2 chemokine receptors of SFN may have diverse functions in the course of inflammatory arthritides. These results indicate that CXCR-2 chemokine receptor might play more critical role in long lasting accumulation of neutrophils within the synovial fluid of patients with RA.

(46) LPS-stimulated production of TNF-alpha by peripheral blood monocytes in patients with Behcet's Disease.

Slobodin GToukan YRosner IRozenbaum MBoulman NPavlotzky EKessel AToubi E.
Clin Rheumatol. 2006 Jul 29; [Epub ahead of print]

Tumor necrosis factor alpha (TNF-alpha) is believed to play a significant role in disease pathogenesis of Behcet's disease (BD). High serum levels of TNF-alpha were repeatedly reported in patients with active BD and anti-TNF agents are effective in its treatment. The pathophysiology of TNF-alpha in BD is still unknown and conflicting results regarding TNF-alpha overproduction by peripheral blood monocytes (PBM) from patients with BD were reported. The aim of the study is to compare stimulated production of TNF-alpha by PBM of BD patients with that of healthy volunteers (HV) and to examine correlations between the ability of PBM to produce TNF-alpha and organ/system involvement in patients with BD. Eighteen patients with BD (mean age 38.4+/-12.4 years, 12 males) gave informed consent and completed the European BD Current Activity Form. The PBM were separated and treated with lipopolysaccharide (LPS) overnight. TNF-alpha levels in the supernatants were assayed by ELISA and values were expressed in terms of cell protein contents. The control group included 15 HV (mean age 34.2+/-9.9 years, seven males). The mean production of TNF-alpha/cell protein (ng/mg) and in-group dispersion were similar in both groups (p=0.98). In the subgroup analysis, TNF-alpha production by PBM in BD patients who reported "bad" or "very bad" global well-being over the last month (n=4) was higher compared to other patients with better self-rating (p=0.03). PBM of BD patients in the present study did not overproduce TNF-alpha upon stimulation with LPS. However, BD patients with a higher TNF-alpha-producing capacity had worse sense of well-being.

(47) Activation markers in Behcet's disease.

Coskun BSaral YGodekmerdan AErden ICoskun N.
Skinmed. 2005 Sep-Oct;4(5):282-6.

INTRODUCTION: One of the main problems in Behcet's disease is the lack of an original laboratory marker that can reflect clinical activity. In this study, laboratory parameters that could be used as indicators of active disease are investigated. MATERIALS AND METHODS: The study included a total of 40 patients with Behcet's disease, 25 of whom were active and 15 inactive, who applied to Firat University, Firat Medical Center Dermatology, Rheumatology, Physiotherapy, and Ophthalmology outpatient clinics and a control group composed of 30 healthy volunteers. Serum neopterin, C-reactive protein (CRP), and sedimentation rate (ESR) levels were determined in all patients and healthy controls. RESULTS: Serum neopterin, CRP, and ESR levels in active Behcet's disease patients were significantly higher than those in both the inactive group and healthy controls (p<0.001). CONCLUSIONS: It was contemplated that together with serum CRP and ESR, neopterin could be a useful laboratory parameter in patients in whom disease activation could not be determined.

(48) Possibility of inducing anterior chamber-associated immune deviation by TGF-beta2 treatment of monocytes isolated from Behcet's patients.

Takeuchi MKeino HSuzuki JUsui YHattori TTakeuchi AOh-I KOkunuki YKezuka T,Usui M.
Exp Eye Res. 2006 Oct;83(4):981-8. Epub 2006 Jul 5.

Murine macrophages treated with TGF-beta2 are capable of inducing anterior chamber-associated immune deviation (ACAID), and these macrophages are characterized by impaired IL-12 production and CD40 expression, consequently failing to promote Th1 cell differentiation. In this study, we investigated whether human monocytes can also acquire the specific functions by TGF-beta2 treatment, even when the monocytes are isolated from patients with Behcet's disease (BD). Adherent monocytes isolated from peripheral blood mononuclear cells (PBMC) of 16 BD patients and 16 healthy controls, were cultured overnight with or without 5ng/ml of TGF-beta2. Then, TGF-beta2-treated or untreated adherent cells were co-cultured with allogeneic CD4(+) T cells obtained from healthy subjects. TGF-beta2 treatment inhibited the abilities of adherent monocytes obtained from BD patients to stimulate the proliferation and IFN-gamma production of allogeneic CD4(+) T cells. The reduced IFN-gamma production was also confirmed by IFN-gamma mRNA expression in the co-cultured T cells. IL-12 production and CD40 molecule expression by adherent monocytes obtained from BD patients were strikingly reduced by TGF-beta2 treatment. These results suggest a possibility that adherent monocytes isolated from BD patients may acquire a property to induce ACAID by treatment with TGF-beta2.

(49) Skewed Th1 responses caused by excessive expression of Txk, a member of the Tec family of tyrosine kinases, in patients with Behcet's disease.

Suzuki NNara KSuzuki T.
Clin Med Res. 2006 Jun;4(2):147-51.

Behcet's disease (BD) is characterized by recurrent attacks of uveitis, oral aphtha, genital ulcers and skin lesions. The etiology and pathogenesis of BD are largely unknown. It has been reported that excessive Th1 cell function is involved in the pathogenesis of BD. Previously, we found that Txk, a member of the Tec family of tyrosine kinases, acts as a Th1 cell-specific transcription factor that is involved in the effector function of Th1 cells. Thus, we studied Th1 cytokine production and Txk expression of T-lymphocytes in patients with BD. Peripheral blood lymphocytes produced excessive Th1-associated cytokines including interferon-gamma (IFN-gamma) and interleukin (IL)-12 in patients with BD. Circulating CD3+ and purified CD4+ T cells expressed excessive Txk protein. The extent of IFN-gamma production by the lymphocytes correlated with the expression of Txk protein in the immunoblotting analysis. The majority of cells infiltrating into the skin lesions of patients with BD expressed IFN-gamma. IL-12 and IL-18 were found in the mononuclear cell aggregates in the skin and intestinal lesions of those with BD. Lymphocytes accumulating in the skin and intestinal lesions expressed higher levels of Txk as compared with other Th2-associated diseases. IFN-gamma, IL-18 and IL-12 detected in skin lesions may induce preferential development of Th1 cells in patients with BD. Collectively, Th1 cells expressing Txk and Th1-associated cytokines may play a critical role in the development of skin and intestinal lesions in patients with BD. This review may serve as a reminder of the importance of excessive Th1 cell function in the pathogenesis of BD and may contribute to the discovery of new molecular targets for the development of a specific therapeutic strategy for BD.
(50) Oxidative burst response to monosodium urate crystals in patients with Behcet's syndrome.

Gogus FFresko IElbir YEksioglu-Demiralp EDireskeneli H.

Clin Exp Rheumatol. 2005 Jul-Aug;23(4 Suppl 38):S81-5.

OBJECTIVE: An erythematous response to intradermal injection of monosodium urate crystals (MSU) has been demonstrated in Behcet's syndrome (BS). To further elucidate the pathogenesis of this response, the effects of MSU on in vitro oxidative burst reaction of neutrophils and monocytes were investigated. METHODS: Peripheral blood mononuclear cells from patients with Behcet's syndrome (BS), rheumatoid arthritis (RA), familial Mediterranean fever (FMF) and healthy controls (HC) were incubated with 100 ng/ml phorbol myristate acetate (PMA) and MSU at different dosages (25-500 microg/ml). Oxidative burst reaction was evaluated in neutrophils and monocytes by flow cytometry. RESULTS: In patients with BS, oxidative burst of neutrophils was significantly increased compared to HC at 125 microg/ml and 250 microg/ml dosages of MSU (p < or = 0.001 and 0.004 respectively). In patients with FMF; there was also an increased oxidative burst reaction at 75 microg/ml, 250 g/ml and 500 microg/ml (p < or = 0.007; 0.001 and 0.004 respectively). In patients with BS, oxidative burst of monocytes was increased only at 125 g/ml dosage of MSU (p < or = 0.002). However, in patients with FMF monocyte burst response was increased at 25 microg/ml, 75 microg/ml and 125 g/ml (p < or = 0.004; < 0.0001; < 0.0001 and 0.002 respectively). In RA group, stimulation with PMA resulted in a higher oxidative burst reaction than FMF and BS (p < or = 0.000 and p < or = 0.008). No correlation was observed between oxidative burst of neutrophils or monocytes and intradermal responses to MSU crystals. CONCLUSION: Oxidative burst reaction with MSU is augmented in neutrophils and monocytes of BS. However, the response is not specific and is unassociated with skin dermal test which has a high specificity for BS.

(51) Anti-Saccharomyces cerevisiae antibodies (ASCA) in Behcet's syndrome.

Fresko IUgurlu SOzbakir FCelik AYurdakul SHamuryudan VYazici H.
Clin Exp Rheumatol. 2005 Jul-Aug;23(4 Suppl 38):S67-70

OBJECTIVES: Anti-Saccharomyces cerevisiae antibodies (ASCA) are found in 50-60% of patients with Crohn's disease. Increased as well as normal levels have been reported in Behcet's syndrome (BS). We reassessed the level of IgG and IgA ASCA antibodies in BS and in a group of diseased and healthy controls. METHODS: Eighty-five patients with BS were studied along with 20 patients with ankylosing spondylitis (AS), 24 with Crohn's disease (CD), 25 with ulcerative colitis (UC) and 21 healthy volunteers. A commercial ELISA kit was used (Inova Diagnostics). RESULTS: It was only the patients with CD who had significantly higher levels of antibodies compared with the rest of the group (ANOVA: ASCA IgG, p = 0.0001; ASCA IgA, p = 0.0001). 42% of CD, 4% of BS, 4% of UC and 15% of AS patients had a positive IgG+IgA ASCA. There was a significant trend for patients with gastrointestinal (GI) involvement with BS (n = 8) to be more positive for IgG and IgG+IgA ASCA compared to the rest of the patients with BS (n = 77) (Chi-square, IgG, p = 0.02, IgG+IgA, p = 0.001). CONCLUSION: The rate of positivity of ASCA in BS is comparable to that observed among patients with UC and AS. Patients with BS who have GI involvement may have higher levels of ASCA and this needs to be further studied.

(52) Immunoglobulin E: a new diagnostic clue for Behcet's disease? : IgE and Behcet's disease.

Onat AMBuyukhatipoglu HYilmaz MGeyik RCelik AOzturk MA.
Clin Rheumatol. 2006 May 31; [Epub ahead of print]

Behcet's disease (BD) is a multisystemic inflammatory disorder of unknown etiology. Hyperimmunoglobulinemia has been demonstrated in BD; however, its clinical importance has not yet been discovered. In a few reports, an association between BD and plasma immunoglobulin E (IgE) has been noted. In this study, we had three objectives: (1) to investigate plasma levels of IgE and their association with levels of acute phase reactants, (2) to determine whether treatment has any effect upon IgE levels, and (3) to assess whether higher serum levels of IgE provide a clue for the diagnosis of BD. Fifty-two patients with BD, without any accompanying disease or condition that might lead to a rise in IgE, were compared with 51 age-matched healthy controls. Plasma levels of IgE, IgA, IgG, and IgM were analyzed by means of nephelometric analysis. Results showed that among the 52 patients, 23 (44%) had IgE levels that were higher than the upper limits of normal. IgE was not correlated with age, erythrocyte sedimentation rate, or C-reactive protein (p=0.59, p=0.57, and p=0.757, respectively). These relationships remained nonsignificant when multiple regression analysis was performed, with R (2) of 0.187 and p=0.057. Moreover, treatment of patients with elevated IgE did not produce any predictable IgE response. We conclude that Behcet's patients commonly exhibit elevated plasma IgE levels. However, elevated IgE levels are not correlated with levels of acute phase reactants or disease activity. We suggest that IgE levels might be an independent diagnostic clue in Behcet's patients.

(53) Diversity of gammadelta T cells in patients with Behcet's disease is indicative of polyclonal activation.

Freysdottir JHussain LFarmer ILau SHFortune F.
Oral Dis. 2006 May;12(3):271-7.

OBJECTIVE: Behcet's disease (BD) is a multisystemic disease, with vasculitic lesions in the oral and genital mucosa, eyes, joints, skin and brain. We have previously found that gammadelta T cells are increased in peripheral blood of BD patients. The aim of this study was to investigate the extent of gammadelta T cells in oral biopsies from BD patients with special emphasis on the restriction of Vgamma and Vdelta usage. PATIENTS AND METHODS: Expression of Vgamma and Vdelta chains on peripheral blood gammadelta T cells from 31 BD patients and 19 healthy controls was analysed by flow cytometry and the expression of Vgamma and Vdelta chains in nine ulcerated and eight non-ulcerated oral mucosa from BD patients and non-ulcerated oral mucosa from three healthy controls was analysed by immunohistochemistry. RESULTS: Vgamma9 and Vdelta2 were the predominant chains expressed in peripheral blood of BD patients, although other Vgamma and Vdelta chains were also expressed. The presence of gammadelta T cells was only observed in the ulcerated oral mucosa but not in the non-ulcerated mucosa from the BD patients, and not in the non-ulcerated mucosa from the healthy controls. These gammadelta T cells showed no preferential expression of any of the Vgamma or Vdelta chains. CONCLUSION: These data suggest a polyclonal rather than oligoclonal activation of the gammadelta T cells. This may indicate that during repeated inflammation of the oral mucosa, the gammadelta T cells are responding to a wide variety of antigenic stimuli with consequent expansion of gammadelta T cells expressing various Vgamma and Vdelta chains and that different antigenic stimuli or responses may be responsible for the clinical heterogeneity of the disease.

(54) Discrepancies of NKT cells expression in peripheral blood and in cerebrospinal fluid from Behcet's disease.

Hamzaoui KKamoun MHouman HHentati FHamza MAyed KHamzaoui A.
J Neuroimmunol. 2006 Jun;175(1-2):160-8. Epub 2006 Apr 19.

The precise role of natural killer T (NKT) cells in the pathogenesis of Behcet's disease (BD) remains unknown. The frequency, cytokine profile and heterogeneity of NKT cells were studied in peripheral blood mononuclear cells (PBMC) from 42BD patients and in cerebrospinal fluid (CSF) samples from 9 neuro-BD patients. Flow cytometry revealed a decreased frequency of NKT cells in PBMC from BD patients (median: 0.06%; range: 0%-0.3%) when compared to healthy controls (median: 0.23%; range: 0.1%-0.7%; P<0.01). NKT cells were biased toward a Th(1)-like phenotype, with a significant decrease of IL-4/IFN-gamma ratio in BD (median: 0.049; range: 0.01-0.13) vs. healthy controls (median: 0.82; range: 0.4-1.33; P<0.01). NKT cells were increased in CSF-BD samples (median: 0.18%; range: 0.1%-0.4%), when compared to CSF-NIND patients (median: 0.05%; range: 0.01%-0.09%; P<0.01). Based on the reactivity of PBMC-derived NKT cells toward alpha-galactosylceramide (alpha-GalCer), 80% of BD patients were non-responsive. At the opposite, the reactivity of NKT cells in CSF from BD patients was not impaired. BD-CSF NKT cells exhibited an increased expression of IFN-gamma-producing cells, demonstrating that CSF-NKT cells were functional, and biased toward a Th(1)-like phenotype. These data suggest that functional NKT cells are recruited into BD inflammatory sites contributing to BD pathogenesis.

(55) Identification and characterization of the carboxy-terminal region of Sip-1, a novel autoantigen in Behcet's disease.

Delunardo FConti FMargutti PAlessandri CPriori RSiracusano ARigano RProfumo E,Valesini GSorice MOrtona E.
Arthritis Res Ther. 2006;8(3):R71. Epub 2006 Apr 12.

Given the lack of a serological test specific for Behcet's disease, its diagnosis rests upon clinical criteria. The clinical diagnosis is nevertheless difficult because the disease manifestations vary widely, especially at the onset of disease. The aim of this study was to identify molecules specifically recognized by serum autoantibodies in patients with Behcet's disease and to evaluate their diagnostic value. We screened a cDNA library from human microvascular endothelial cells with serum IgG from two patients with Behcet's disease and isolated a reactive clone specific to the carboxy-terminal subunit of Sip1 (Sip1 C-ter). Using ELISA, we measured IgG, IgM and IgA specific to Sip1 C-ter in patients with various autoimmune diseases characterized by the presence of serum anti-endothelial cell antibodies, such as Behcet's disease, systemic lupus erythematosus, systemic sclerosis and various forms of primary vasculitis, as well as in patients with diseases that share clinical features with Behcet's disease, such as inflammatory bowel disease and uveitis. IgM immunoreactivity to Sip1 C-ter was significantly higher in patients with Behcet's disease and in patients with primary vasculitis than in the other groups of patients and healthy subjects tested (P < 10-4 by Mann-Whitney test). ELISA detected IgG specific to Sip1 C-ter in sera from 11/56 (20%) patients with Behcet's disease, IgM in 23/56 (41%) and IgA in 9/54 (17%). No sera from patients with systemic lupus erythematosus, systemic sclerosis, inflammatory bowel disease, uveitis or healthy subjects but 45% of sera from patients with primary vasculitis contained IgM specific to Sip1 C-ter. Serum levels of soluble E-selectin, a marker of endothelial activation and inflammation, correlated with levels of serum IgM anti Sip-1 C-ter in patients with Behcet's disease (r = 0.36, P = 0.023). In conclusion, Sip1 C-ter is a novel autoantigen in Behcet's disease. IgM specific to Sip1 C-ter might be useful in clinical practice as an immunological marker of endothelial dysfunction in vasculitis.

(56) The levels of serum neopterin in Behcet's disease--objective marker of disease activity.

Kose OArca EAkgul OErbil K.
J Dermatol Sci. 2006 May;42(2):128-30.

(57) Production of Th1/Th2 cytokines and nitric oxide in Behcet's uveitis and idiopathic uveitis.]

Guenane HHartani DChachoua LLahlou-Boukoffa OSMazari FTouil-Boukoffa C.
J Fr Ophtalmol. 2006 Feb;29(2):146-52

Introduction: The aim of this study was to investigate the role of Th1 (IFN-gamma and IL-12), Th2 (IL-10) cytokines and nitric oxide (NO) in the immunopathologic mechanisms of uveitis related to Behcet's disease and isolated idiopathic uveitis. PATIENTS: and method: This study was conducted on 24 patients with Behcet's syndrome who had active uveitis, ten of whom showed isolated uveitis classified as idiopathic uveitis, and 13 healthy controls. The levels of IFN-gamma, IL-12 and IL-10 in sera and supernatants of PBMC cultures stimulated by PHA were estimated using immunoenzymatic dosage (ELISA sandwich according to the methods recommended by Immunotech France). The production of NO was measured in vivo and in vitro for the same patients using the modified Griess method. RESULTS: The induction of IFN-gamma and IL-12 was higher in the two groups of patients than in the controls (P<0.001). Significant IL-10 levels were recorded in 56.5% of patients with Behcet's disease presenting uveitis versus 30% of patients with idiopathic uveitis. NO production was more pronounced in idiopathic uveitis than in Behcet's syndrome (P<0.02). CONCLUSION: The predominance of the Th1 profile was associated with high production of NO in idiopathic uveitis. A Th1/Th2 profile with a moderated increase in NO production was observed in Behcet's disease. Our data have a clinical impact. The observation of combined Th1/Th2 cytokines and NO elevation in both in vivo an in vitro experiments could have a predictive value in characterizing uveitis associated with Behcet's disease.


(58) Capacity of ocular infiltrating T helper type 1 cells of patients with non-infectious uveitis to produce chemokines.

Takase HSugita STaguchi CImai YMochizuki M.
Br J Ophthalmol. 2006 Jun;90(6):765-8. Epub 2006 Feb 7.

BACKGROUND/AIMS: Chemokines are key molecules that initiate leucocyte infiltration to the inflammatory site. The involvement of chemokines in uveitis is well studied, yet the source of this molecule in the inflamed eye is not clearly identified. The possible sources of chemokines are ocular resident cells or the inflammatory cells infiltrated to the eye. Here the authors examined whether ocular infiltrating T cells of uveitis patients do produce chemokines. METHODS: T cell clones (TCCs) were established from ocular infiltrating cells of patients with non-infectious uveitis. TCCs were characterised using flow cytometry. Spontaneous production of chemokines by TCCs was evaluated by ELISA. RESULTS: TCCs from ocular infiltrating cells were revealed to be memory activated Th1 type CD4 positive cells. Those TCCs produced larger amounts of chemokines than TCCs from peripheral blood mononuclear cells of uveitis or healthy donors. CONCLUSIONS: The present data indicate that ocular infiltrating T cells of patients with non-infectious uveitis produce chemokines and recruit further infiltrating lymphoid cells. Such T cells may have roles in the prolonged/chronic state of non-infectious uveitis.

(59) CD8brightCD56+ T cells are cytotoxic effectors in patients with active Behcet's uveitis.

Ahn JKChung HLee DSYu YSYu HG.
J Immunol. 2005 Nov 1;175(9):6133-42.

Behcet's uveitis, characterized by chronic recurrent uveitis and obliterating retinal vasculitis, frequently causes bilateral blindness. Intraocular infiltration of TCRalphabeta+CD8brightCD56+ cells was a distinct feature in Behcet's uveitis. However, phenotypic natures and effector functions of the cells have remained elusive. This study was conducted to determine phenotypic and functional characteristics and cytotoxic mechanisms of CD8brightCD56+ T cells in Behcet's uveitis. CD11b+CD27-CD62L- phenotypes of CD8brightCD56+ T cells were increased in patients with active Behcet's uveitis compared with inactive Behcet's patients and normal controls. Interestingly, CD45RAdimCD45RO- phenotypes were expanded, and CD94 expression was markedly up-regulated in contrast to the down-regulation of NKG2D. Furthermore, these subsets were polarized to produce IFN-gamma and contained high amounts of preformed intracellular perforin while exclusively expressing surface FasL upon PI stimulation. Moreover, the cytolytic functions of freshly isolated CD8brightCD56+ T cells were up-regulated against both K562 (NK-sensitive) and Raji (NK-resistant) cells, which were effectively inhibited by perforin inhibitor (concanamycin A). Their cytolytic activity against HUVECs was also increased and was effectively suppressed by Fas ligand inhibitor (brefeldin A) and partly by perforin inhibitor. Furthermore, cytolytic functions of PMA and ionomycin-stimulated CD8brightCD56+ T cells against HUVECs were greatly enhanced, by pretreatment of recombinant human IFN-gamma on HUVECs. Therefore, CD8brightCD56+ T cells in Behcet's uveitis are characterized by cytotoxic effector phenotypes with functional NK receptors and function as strong cytotoxic effectors through both Fas ligand-dependent and perforin-dependent pathways.

(60) Serum interleukin-18 levels in patients with Behcet's disease. Is its expression associated with disease activity or clinical presentations?

Musabak UPay SErdem HSimsek IPekel ADinc ASengul A.
Rheumatol Int. 2006 Apr;26(6):545-50

Interleukin (IL)-18 is a proinflammatory cytokine which plays a crucial role in T helper (Th)1 type immune response. The aim of this study is to investigate the relationship of serum levels of IL-18 with disease activity and clinical presentations in patients with Behcet's disease (BD). Sixty patients with BD and 20 healthy controls were included in the study. Patients were grouped as having active or inactive disease according to the Leeds activity score. They were also separated as a systemic involvement or mucocutaneous symptoms only. Patients with systemic involvement were further grouped according to the presence of ocular, articular and vascular involvement. IL-18 levels were significantly higher in all patient subgroups as compared to healthy controls and found to be correlated with the activity score in patients having active disease. In conclusion, this cytokine participates in the pathogenesis of BD and its levels are correlated with the disease activity. Detection of increased levels of IL-18 in patients with inactive disease implies that Th1 activation and subclinical inflammation persist during the inactive period of the disease.
(61) Serum interleukin 18 and tumour necrosis factor-alpha levels are increased in Behcet's disease.
Oztas MO. Onder M. Gurer MA. Bukan N. Sancak B.
Clinical & Experimental Dermatology. 30(1):61-3, 2005 Jan.

Inflammation in Behcet's disease is thought to be mediated by cytokines derived from T-helper type 1 (Th1) lymphocytes. In this study, we tried to determine serum interleukin (IL)-18 and tumour necrosis factor (TNF)-alpha levels of patients with Behcet's disease. Twenty-seven patients with active Behcet's disease, and 20 healthy control subjects were included in this study. Differences between mean serum IL-18 and TNF-alpha level of patients with Behcet's disease were significantly increased when compared with the control group. A significant correlation was found between serum IL-18 and TNF-alpha levels of Behcet patients (rs = 0.627, P < 0.0001). IL-18 and TNF-alpha levels may be related to disease pathogenesis. Increased levels of IL-18 also support Th1 predominance in Behcet's disease.

(62) Synovial proinflammatory cytokines and their correlation with matrix metalloproteinase-3 expression in Behcet's disease. Does interleukin-1beta play a major role in Behcet's synovitis?

Pay SErdem HPekel ASimsek IMusabak USengul ADinc A.
Rheumatol Int. 2006 May;26(7):608-13.

The objective of this study has been the well established fact that proinflammatory cytokines and metalloproteinases play a crucial role in the pathogenesis of chronic arthritis as well as the development of pannus, with the eventual erosive changes. Among the proinflammatory cytokines, interleukin-18 (IL-18) has been shown to contribute to the pathogenesis of chronic synovitis by increasing the secretion of interleukin-1beta (IL-1beta) and the tumor necrosis factor-alpha (TNF-alpha) and also stimulating angiogenesis. The aim of this study is to investigate the synovial IL-18, IL-1beta, TNF-alpha and matrix metalloproteinase-3 (MMP-3) levels in patients with Behcet's disease (BD), and compare them with the levels of patients with rheumatoid arthritis (RA) and osteoarthritis (OA). 30 patients with BD, 20 with RA, and 20 with OA were included in the study. The synovial levels of IL-18, IL-1beta, TNF-alpha and MMP-3 were detected using the two-step sandwich ELISA method. The synovial IL-18, TNF-alpha and MMP-3 levels were significantly higher in RA patients than patients with BD (P=0.004, 0.019, 0.025, respectively) and with OA (P=0.004, 0.045, 0.032, respectively). There were no differences, with respect to the cytokine levels, when patients with BD were compared with those with OA. Patients with RA and BD had higher IL-1beta levels than patients with OA (P=0.017, 0.013, respectively). However, no such difference was found for IL-1beta between BD and RA patients. Among patients with RA, positive correlations were found between TNF-alpha and MMP-3 (r=0.683, P=0.001). Our results showed that MMP-3 and proinflammatory cytokines, except IL-1beta, were expressed in relatively small quantities in Behcet's synovitis. Detection of the lower levels of these cytokines and metalloproteinases might explain the non-erosive character of Behcet's arthritis. We suggest that IL-1beta may be involved in the pathogenesis of Behcet's synovitis.

(63) Different ELR (+) angiogenic CXC chemokine profiles in synovial fluid of patients with Behcet's disease, familial Mediterranean fever, rheumatoid arthritis, and osteoarthritis.

Erdem HPay SSerdar MSimsek IDinc AMusabak UPekel ATuran M.
Rheumatol Int. 2005 Dec;26(2):162-7.

The aim of the present study was to determine synovial levels of ELR (+) CXC chemokines, known to attract mainly neutrophils to inflamed tissues by binding the neutrophil chemokine receptors CXCR1 and CXCR2 and promoting neovascularization in patients with various inflammatory disorders. The study group consisted of 14 patients with Behcet's disease and nine with familial Mediterranean fever. Fourteen patients with rheumatoid arthritis and 16 with osteoarthritis served as controls. Synovial chemokine levels were measured by two-step sandwich enzyme-linked immunosorbent assay, and significant differences were found in the various chemokines studied. In addition to its angiogenic properties, increased synovial levels of interleukin-8 by attraction of more neutrophils to synovial fluids might also be responsible for the acute synovitis in patients with Behcet's disease. However, the absence of chronic changes with the eventual development of pannus and erosions might result from relatively lower expression of interleukin-8 and the transient, short-lived nature of the arthritis observed in these patients.

(64) Neutrophil and lymphocyte responses to oral Streptococcus in Adamantiades-Behcet's disease.
Kurauchi T. Yokota K. Matsuo T. Fujinami Y. Isogai E. Isogai H. Ohtsuki H. Oguma K.
FEMS Immunology & Medical Microbiology. 43(2):125-31, 2005

Immune reactions against microorganisms play an important pathogenic role in Adamantiades-Behcet's disease. We had previously obtained Streptococcus sanguinis (strain BD113-20), isolated from the oral cavity of patients with Adamantiades-Behcet's syndrome. To investigate the pathogenesis of this isolate, we examined neutrophil reactions and levels of cytokine production by lymphocytes after stimulation with the strain. The reactions of neutrophils were examined by chemiluminescence assay using whole blood. The amounts of interferon gamma (IFN-gamma) and interleukin (IL)-4, IL-8, IL-10 and IL-12, produced by peripheral blood mononuclear cells, were measured by ELISA. Strain BD113-20 activated neutrophils from Adamantiades-Behcet's patients and healthy volunteers, and, in addition it increased the IFN-gamma production by lymphocytes. Lymphocytes from Adamantiades-Behcet's patients showed a dominant T helper-1 immune response. Results indicated that both bacterial stimulation!
and host hypersensitivity might be involved in the symptoms and pathogenesis of Adamantiades-Behcet's disease.
(65) Neutrophil CD64 expression in Behcet's disease.
Ureten K. Ertenli I. Ozturk MA. Kiraz S. Onat AM. Tuncer M. Okur H. Akdogan A. Apras S. Calguneri M.
Journal of Rheumatology. 32(5):849-52, 2005.

OBJECTIVE: Hyperfunction of neutrophils is a characteristic finding in Behcet's disease (BD). Microbial agents have been proposed as causative agents in the disease flares. Fc gamma receptor 1 (CD64) is not normally expressed by neutrophils of healthy individuals, but is upregulated by these cells in response to microbial wall components and proinflammatory cytokines. The degree of polymorphonuclear leukocyte (PMN) CD64 expression is different in autoimmune diseases and systemic infectious diseases. We investigated PMN CD64 expression in patients with BD. METHODS: Thirty-seven patients with active BD (M/F: 18/19, mean age: 34.4 +/- 9.7 yrs), 35 patients with inactive BD (M/F: 11/24, mean age: 35.9 +/- 11.6 yrs), 27 patients with culture proven infections (M/F: 19/8, mean age: 54.4 +/- 15.2 yrs), 31 healthy controls (M/F: 14/17, mean age: 37.7 +/- 8.7 yrs), and 42 patients with active inflammatory disease (M/F: 13/29, mean age: 39.3 +/- 14.9 yrs) were enrolled in this study!
. Flow cytometry was used to assess the prevalence of CD64-bearing PMN in whole blood samples. RESULTS: The prevalence of CD64-bearing PMN was significantly higher in patients with infectious disease (77.1 +/- 18.4), inflammatory disease (37.1 +/- 27.5), and active BD (48.9 +/- 22.5) than in healthy controls (9.5 +/- 7.8) or patients with inactive BD (12.9 +/- 9.5). CD64 expression was similar in controls and patients with inactive BD. In the infectious disease group, expression of CD64 was significantly higher than in the active BD and active inflammatory disease groups, while there was no significant difference between the groups of patients with active BD and inflammatory disorders. CONCLUSION: Neutrophil CD64 expression increases during exacerbation of BD. This increase appears to be a non-specific inflammatory response and does not reflect PMN activation triggered by a living microorganism.

(66) Down-regulation of IFN-gamma-producing CD56+ T cells after combined low-dose cyclosporine/prednisone treatment in patients with Behcet's uveitis.
Ahn JK. Seo JM. Yu J. Oh FS. Chung H. Yu HG.
Investigative Ophthalmology & Visual Science. 46(7):2458-64, 2005.

PURPOSE: To investigate the effects of combined low-dose cyclosporine and prednisone (Cs/Pd) treatment on circulating CD56+ T cells in patients with Behcet's uveitis. METHODS: Ten patients with Behcet's uveitis and 10 healthy control subjects were prospectively recruited. The patients were treated with Cs/Pd for 2 months. Phenotypic and functional changes in circulating CD56+ T cells were assayed before and after treatment. CD56+ T-cell subsets were determined by flow cytometric analysis with monoclonal antibodies for CD3, CD4, CD8, CD56, pan gammadelta TCR, and Valpha24. The absolute numbers of cells in the lymphocyte subsets were calculated. Cytokine (IFN-gamma, IL-4, and IL-10) expressions were measured by ELISA and by intracellular cytokine staining. RESULTS: The proportions of CD56+ T cells, specifically CD8highCD56+ and CD56+gammadelta T-cell subsets, were significantly higher in active Behcet's uveitis but normalized after treatment, whereas the total T-lymphocyte c!
ount and the absolute numbers of CD56- T cells were unaffected by treatment. The levels of IFN-gamma and IL-4 were elevated in aqueous humor and serum in Behcet's uveitis (P < 0.001), whereas IL-10 was not detected. After treatment, serum IL-4 levels markedly increased (P < 0.001), and IFN-gamma production by circulating CD56+ T cells was then suppressed. IL-4 and -10 production by CD56+ T cells was increased by treatment, but in contrast, minimal changes were found in CD56- T cells. CONCLUSIONS: The results imply that Cs/Pd treatment for Behcet's uveitis selectively affects the population of and the cytokine expression in CD56+ T cells, but without significant changes in CD56- T cells, and that IFN-gamma-producing CD56+ T cells are the central pathogenic immune cells in Behcet's uveitis.

(67) NF-kappaB protects Behcet's disease T cells against CD95-induced apoptosis up-regulating antiapoptotic proteins.

Todaro M. Zerilli M. Triolo G. Iovino F. Patti M. Accardo-Palumbo A. di Gaudio F. Turco MC. Petrella A. de Maria R. Stassi G.
Arthritis & Rheumatism. 52(7):2179-91, 2005.

OBJECTIVE: To determine whether prolongation of the inflammatory reaction in patients with Behcet's disease (BD) is related to apoptosis resistance and is associated with the up-regulation of antiapoptotic factors. METHODS: The percentage of cell death was evaluated by flow cytometry in peripheral blood mononuclear cells from 35 patients with BD and 30 healthy volunteers. The expression levels of antiapoptotic factors and NF-kappaB regulatory proteins were measured using Western blotting and immunohistochemical analyses. To down-regulate NF-kappaB nuclear translocation, BD T lymphocytes were exposed in vitro to thalidomide and subjected to transfection with NF-kappaB small interfering RNA. RESULTS: Although CD95 is highly expressed in BD T cells, the absence of sensitivity to CD95-induced apoptosis observed may be attributable to the inhibitory action of antiapoptotic genes. Immunoblot analysis for major antiapoptotic proteins showed considerable up-regulation of the short!
form of cellular FLIP (cFLIP) and Bcl-x(L) in BD activated T cells, while levels of Bcl-2, caspase 3, and caspase 8 in activated T cells from patients with BD were comparable with those in activated T cells from normal donors. Moreover, expression of IKK and IkappaB was up-regulated, whereas NF-kappaB translocated to the nucleus in BD T cells, suggesting that NF-kappaB activation may modulate the expression of antiapoptotic genes. Interestingly, thalidomide and NF-kappaB small interfering RNA down-regulated cFLIP and Bcl-x(L) expression levels and sensitized BD activated T cells to CD95-induced apoptosis. CONCLUSION: Taken together, these results indicate that NF-kappaB contributes to the regulation of the apoptosis-related factors and death receptors leading to apoptosis resistance in BD T cell subsets. Our results suggest that NF-kappaB plays a crucial role in the pathogenesis of BD, and that its pharmacologic control could represent a key strategy in modulating specific immune-mediated disease.

Thrombophilia
(68) Fibrinolytic activity and d-dimer levels in Behcet's syndrome.

Yurdakul SHekim NSoysal TFresko IBavunoglu IOzbakir FTabak FMelikoglu M,Hamuryudan VYazici H.
Clin Exp Rheumatol. 2005 Jul-Aug;23(4 Suppl 38):S53-8.

OBJECTIVE: Thrombophlebitis occurs in a third of patients with Behcet's syndrome (BS). The thrombotic tendency in BS has been studied with inconclusive results perhaps due to the inadequate numbers of patients studied during the acute phase of the thrombosis as well as the lack of appropriate diseased controls. We have studied tissue-type plasminogen activator (t-PA) and its inhibitor (PAI-1), and d-dimer levels in BS patients with and without thrombosis both in the acute and chronic phases along with suitable diseased and healthy controls. METHODS: t-PA and PAI-1 were studied by ELISA and d-dimer by semiquantitative latex agglutination slide test in 30 BS patients without deep vein thrombosis (DVT), 10 BS with acute DVT (ADVT), 25 BS with chronic DVT, 27 with ankylosing spondylitis, 26 diffuse systemic sclerosis, 15 patients with ADVT due to other causes, 10 patients with sepsis, and 23 healthy controls. RESULTS: The t-PA levels in BS with ADVT were significantly lower than those in patients with ADVT due to other causes (7.4 +/- 6.2 vs. 13.4 +/- 6.3, P = 0.027) while PAI-1 levels did not show significant differences between the groups (P = 0.60). The numbers of patients with d-dimer levels of > or = 0.5 microg/ml in BS with ADVT were similar to those found in patients with ADVT due to other causes (9/10 vs. 14/14). CONCLUSION: The relatively low t-PA levels point to a defect in fibrinolysis in BS. d-dimer levels are increased in the acute phase of thrombosis in BS.

(69) Circulated Activated Platelets and Increased Platelet Reactivity in Patients With Behcet's Disease.

Akar SOzcan MAAtes HGurler OAlacacioglu IOzsan GHAkkoc NOzkan SDemirkan FOnen F.
Clin Appl Thromb Hemost. 2006 Oct;12(4):451-7

Behcet's disease (BD) is a multisystem disorder. Venous as well as arterial thrombosis is a common complication of BD but exact pathogenetic mechanism of the thrombotic tendency is not well known. This study aimed to evaluate circulating activated platelets and platelet reactivity in Behcet's patients. Twenty-two Behcet's patients (4 female, 18 male; mean age 38.6 +/- 10.9 years) and 20 control subjects (8 female, 12 male; mean age 38.8 +/- 9.4 years) were included. Those patients who had hypertension, hyperlipidemia, peripheral or coronary artery disease, hepatic or renal function abnormality, and who were using aspirin and other platelet-active drugs were excluded. Platelet activity and reactivity to adenosine diphosphate (ADP) were measured by whole blood flow cytometry. We assessed markers of platelet degranulation (P-selectin; CD62P) and the activated glycoprotein IIb/IIIa receptor (PAC1 binding to fibrinogen binding site) before and after stimulation with ADP. Platelet P-selectin expression was not significantly different between patients and control subjects both at baseline (p=0.420) and after stimulation (p=0.56). Baseline (p=0.001) and ADP-stimulated (p=0.003) PAC1 binding was significantly higher in Behcet's patients than in the control group. Clinical activity has no effect on P-selectin expression and PAC1 binding. There is evidence of platelet activity and hyperreactivity in patients with BD and this may contribute to a prothrombotic state. In addition to aspirin, other antiplatelet drugs may be useful in the prevention and treatment of thrombosis in Behcet's patients.

(70) Decreased protein S activity is related to the disease activity of Behcet's disease.

Kwon SRLim MJPark SGMoon YSPark W.
Rheumatol Int. 2006 Sep 13; [Epub ahead of print]

We wanted to see whether the active inflammation in Behcet's disease (BD) can cause a thrombotic disorder by decreasing the protein S (PS) activity, and we evaluated the relationship between the decreased PS activity and the disease activity of BD. We included 122 patients with BD whose PS activity levels were measured. In 51 patients, the PS activity was measured again when there were changes in the number of items of "The Behcet's Disease Current Activity Form (BDCAF)". The thrombosis rate was 2.5% (3/122), and the PS activity was low in all three of the patients with thrombosis. The incidence of low PS activity in the total 122 BD patients was 27% (33/122). The incidence of the low PS activity in the active BD patients was 33.7% (31/92), and this was significantly more frequent than in the inactive BD patients, (6.7%, 2/30) (chi(2)-test, P value = 0.0038). The decrease of PS activity had good correlation with the increase of the number of BDCAF items (r = -0.351, P value = 0.012). The PS activity decrease is related to the BD activity. The low PS activity can be the risk factor for thrombotic disorder and also the activity marker for BD and other inflammatory diseases.

(71) Lipid peroxidation and homocysteine levels in Behcet's disease.

Mungan AGCan MAcikgoz SEsturk EAltinyazar C.
Clin Chem Lab Med. 2006;44(9):1115-8.

Background: The aim of this study was to investigate serum paraoxonase (PON1) activity in relation to homocysteine, malondialdehyde (MDA) and lipid parameters in active and inactive Behcet's disease (BD). Methods: A total of 46 consecutive BD patients and 25 healthy control subjects were included in the present study. Results: Serum PON1 activity in both active and inactive BD was significantly lower compared with healthy subjects (p<0.05). When compared to the control group, serum MDA levels were significantly higher in both active and inactive BD (p<0.05). Serum C-reactive protein (CRP) and homocysteine concentrations were significantly higher in active BD than those in inactive BD and control subjects (p<0.05). In addition, there was significant negative correlation between serum PON1 and MDA levels (r=-0.697, p<0.05) and serum PON1 activity was also negatively correlated with homocysteine levels (r=-0.428, p<0.05) in BD patients. Conclusions: Decreased PON1 could explain the increased lipid peroxidation and oxidative stress observed in BD. Also, according to our results, we suggest that homocysteine may contribute to decreased serum PON1 activity.

(72) Thrombophilic risk factors and homocysteine levels in Behcet's disease in eastern Spain and their association with thrombotic events.

Ricart JMVaya ATodoli JCalvo JVilla PEstelles AEspana FSantaolaria MCorella D,Aznar J.
Thromb Haemost. 2006 Apr;95(4):618-24.

Behcet's disease (BD) is a chronic inflammatory disorder in which thrombosis occurs in about 30% of patients. The prothrombotic mechanisms are unknown. Thrombophilic defects and hyperhomocysteinaemia may be involved in the pathogenesis of thrombotic events, although results have been controversial. Moreover, no information is available on this issue for eastern Spain. We studied the prevalence of inherited and acquired thrombophilic risk factors in 79 patients with BD (43 men, 36 women) who had (n = 23) or did not have (n = 56) thrombosis, and in 84 healthy control subjects (42 men, 42 women). Risk factors examined were antithrombin, protein C and protein S levels, factor V Leiden, the prothrombin G20210A mutation, the methylenetetrahydrofolate reductase C677T polymorphism, and acquired thrombophilic risk factors, including anticardiolipin antibodies, lupus anticoagulant, and serum homocysteine levels. There were no differences between patients and controls in any of the parameters studied. When we studied BD patients with and without thrombotic events, the only thrombophilic defect that differed was the prothrombin G20210A mutation: Three out of 23 patients with thrombosis were carriers, compared with none of 56 patients without thrombosis (p = 0.022). Two of the three carriers developed catastrophic or recurrent thrombotic episodes; one was a homozygous carrier of the G20210A prothrombin mutation and the other was doubly heterozygous for the G20210A prothrombin mutation and factor V Leiden. A meta-analysis demonstrated an association of factor V Leiden and prothrombin mutation with thrombosis in BD. When studies from Turkey were excluded from the meta-analysis, only the prothrombin G20210A mutation was associated with thrombosis.

(73) Platelet-activating factor and P-selectin activities in thrombotic and nonthrombotic Behcet's patients.
Tunc SE. Aksu K. Keser G. Oksel F. Doganavsargil E. Pirildar T. Turk T. Terzioglu E. Huseyinov A.
Rheumatology International. 25(5):326-31, 2005.

OBJECTIVE: The aim of this study was to compare plasma Platelet-activating factor (PAF) and P-selectin (CD62P) activities in Behcet's disease patients with and without thrombosis. METHODS: In this cross-sectional and descriptive study, 30 consecutive Behcet's patients were included, 15 of them with venous thrombosis. All patients were also divided into two subgroups according to the presence or absence of clinical activity. Plasma PAF levels, basal and Ca++ ionophore (A23187)-induced leukocyte (cellular) PAF activities, and platelet-rich plasma DeltaCD62P activity (the mean fluorescent density difference between CD62P phycoerythrin-positive and -negative stains) were evaluated. RESULTS: In the thrombotic group, plasma PAF (P=0.001), basal leukocyte PAF (P=0.017), induced leukocyte PAF (P=0.024), and DeltaCD62P (P=0.023) levels were significantly higher than in the nonthrombotic group. In the whole group of Behcet's patients, there was a positive correlation between plasma !
PAF and DeltaCD62P levels (r=0.533, P=0.002). When we compared clinically active and inactive patients with respect to the above parameters, there was no significant difference, irrespective of thrombosis. Plasma PAF (P=0.001), basal leukocyte PAF (P=0.004), and DeltaCD62P (P=0.038) levels were significantly higher in the presence of both clinical activity and thrombosis than of clinical activity alone. CONCLUSION: Platelet-activating factor and CD62P may contribute to endothelial injury and thrombosis development in Behcet's disease. These two parameters seem related to the presence of thrombosis rather than clinical activity.


(74) Impaired endothelium-dependent flow-mediated dilation in Behcet's disease: more prominent endothelial dysfunction in patients with vascular involvement.
Oflaz H. Mercanoglu F. Karaman O. Kamali S. Erer B. Genchellac H. Pamukcu B. Umman S.Inanc M. Gul A.
International Journal of Clinical Practice. 59(7):777-81, 2005.

Brachial artery endothelial dysfunction was shown previously in a small group of Behcet's disease (BD) patients. This study aimed to compare the endothelial function in BD patients with and without vascular involvement. The study group consisted of 25 BD patients with vascular involvement, 25 BD patients without any vascular disease and 46 healthy controls. Brachial artery flow-mediated (endothelium-dependent) dilation (FMD), nitroglycerine-induced dilation and carotid artery intima-media thickness were measured. FMD was impaired in patients with BD (10.41 +/- 3.85%) compared to healthy controls (14.41 +/- 3.39%, p < 0.001). FMD was significantly lower in BD patients with vascular involvement (8.80 +/- 3.63%) than those without any vascular disease (12.02 +/- 3.43%, p = 0.003). This study reveals that endothelial dysfunction documented by brachial artery FMD is a feature of BD, and it is more prominent in patients with vascular involvement.

Metabolism

(75) The relationship between serum prolactin levels and disease activity in patients with Behcet's disease.

Atasoy MKaratay SYildirim KKadi MErdem TSenel K.
Cell Biochem Funct. 2006 Jul-Aug;24(4):353-6.

The aim of this study was to determine the serum levels of prolactin in patients with Behcet's disease and to evaluate its correlation with disease activity. Serum prolactin levels were measured by a chemiluminescence method in 32 patients with Behcet's disease and compared with 20 age-and sex-matched healthy controls. The patients with Behcet's disease were subdivided into two groups according to disease activity: active (18 patients; 13 men and five women, average age 34.0 +/- 6.5 (28-48) years), and inactive (14 patients; 10 men and four women, average age 32.7 +/- 3.1 (22-49 years). Patients with active Behcet's disease had higher serum prolactin levels than the inactive and control groups. Prolactin levels in patients with active Behcet's disease differed significantly from the healthy control subjects (p < 0.05) only, but not the inactive group. Four patients out of 32 (12.5%) Behcet's disease patients showed mild hyperprolactinemia. All four of these cases were from the active Behcet's disease group. Prolactin levels were correlated with ESR (p < 0.05) and CRP (p < 0.05) levels in the active BD group, but not in the inactive BD and control groups. Our results suggest a possible role for this immunoregulatory hormone in the disease expression and pathogenesis of Behcet's disease.

(76) Serum substance P and calcitonin gene-related peptide levels in Behcet's disease and their association with disease activity.

Aki TKarincaoglu YSeyhan MBatcioglu K.
Clin Exp Dermatol. 2006 Jul;31(4):583-7.

BACKGROUND: Substance P (SP) and calcitonin gene-related peptide (CGRP) are neuropeptides that have a role in several cutaneous diseases and inflammations. Aim. To evaluate SP, CGRP and serum interleukin (IL)-8 levels in Behcet's disease (BD) and to explore the relationship of these peptides with BD activity. METHODS: The study group comprised 30 patients with BD, and 30 healthy individuals acted as controls. Serum levels of SP, CGRP and IL-8 were determined by micro-ELISA test during the active and inactive disease periods of patients with BD. These data were compared with each other and controls. Active and inactive periods of BD were established. RESULTS: The mean +/- SD serum CGRP (ng/ml) and IL-8 levels (pg/ml) in inactive BD (5.87 +/- 2.49 and 0.62 +/- 0.24, respectively) were significantly higher than the control group (4.74 +/- 1.17 and 0.46 +/- 0.11) (P < 0.05 for both). The difference between serum CGRP and IL-8 levels in active BD were also significantly higher than in inactive BD (P < 0.05 for both). Serum SP values (ng/ml) in active BD (18.27 +/- 5.38) were significantly higher than in inactive BD (15.26 +/- 5.74) and controls (12.6 +/- 4.45) (P < 0.05 for all), whereas the difference between the serum SP values in inactive BD and the control group was not statistically significant (P > 0.05). CONCLUSION: Serum SP and CGRP may have a role in the pathogenesis of BD. In addition, serum IL-8, SP and CGRP levels can be used as laboratory parameters indicating activity in BD.


(77) Evaluation of allantoin levels as a new marker of oxidative stress in Behcet's disease.

Yardim-Akaydin SSepici AOzkan YSimsek BSepici V.
Scand J Rheumatol. 2006 Jan-Feb;35(1):61-4.

The increased production of reactive oxygen species (ROS) from activated neutrophils in Behcet's disease (BD) and recurrent aphthous stomatitis (RAS) may result in increased oxidative stress. Uric acid can react rapidly with neutrophil-derived ROS to form allantoin. The purpose of the study was to evaluate the serum levels of allantoin as a new marker of oxidative stress in BD compared with malondialdehyde (MDA) levels as a well-known marker. Blood samples were obtained from 23 BD patients, 22 RAS patients as positive controls, and 21 healthy controls. When compared to the healthy controls, we found higher allantoin and MDA levels in the BD patients and higher MDA levels in the RAS patients. Serum ascorbic acid levels in the BD patients were significantly lower than in the controls. Increased allantoin and MDA levels suggest the possible involvement of free radicals in BD. As allantoin is only a product of uric acid oxidation by reactive oxygen and nitrogen species, it may also be used as a marker of oxidative stress in BD.


(78) Lipoprotein (a) and nitrites in Behcet's disease: relationship with disease activity and vascular complications.

Esmat SEl Sherif HAnwar SFahmy IElmenyawi MShaker O.
Eur J Dermatol. 2006 Jan-Feb;16(1):67-71

Our objective was the assessment of serum lipoprotein(a) {Lp(a)} and nitrites in Behcet's disease (BD) patients and their relation to vascular events and disease activity. Thirty cases of BD and 14 healthy volunteers were included. Serum levels of Lp(a) were estimated using enzyme-linked immunosorbent assays. Serum nitrites were measured according to the method of Benjamin and Vallence. Compared to controls, BD patients had significantly lower concentrations of serum nitrites, and significantly higher concentrations of Serum Lp(a). Significantly higher levels of serum Lp(a) were observed in patients with vascular complications, while significantly lower levels of serum nitrites were found during disease activity and in patients with erythema nodosum like lesions. Increased serum lipoprotein (a) may contribute to the increased incidence of vascular complications in Behcet's disease. Decreased nitrites can be considered as a marker of disease activity that may be related to endothelial dysfunction. 

(79) Urinary 8-isoprostaglandin F(2alpha) level in Behcet's disease.

Ozdol NCAtes AAydintug OTMelli M.
Prostaglandins Other Lipid Mediat. 2005 Dec;78(1-4):96-106.

Although its etiology remains unknown, the increased production of reactive oxygen species in Behcet's disease (BD) have been reported. Furthermore, it has been suggested that vascular and endothelial tissue damage seen in BD is related to elevated reactive oxygen species generated by activated neutrophils from BD patients. To investigate the formation of lipid peroxidation in BD patients in vivo, urinary level of 8-isoprostaglandin F(2alpha) was quantitated by enzyme immunoassay after solid phase extraction in different clinical forms of BD patients. There was no difference in urinary level of 8-isoprostaglandin F(2alpha) between BD patient and healthy control group. There was also no difference in urinary levels of 8-isoprostaglandin F(2alpha) in subgroup analyses of BD patients, i.e. in mucocutaneous and vascular type BD patients; active and inactive BD patients. Contrary to the findings in literature, we found no difference in urinary level of 8-isoprostaglandin F(2alpha) between patients with systemic lupus erythematosus and healthy control group. These findings show no increase in lipid peroxidation despite the augmented formation of reactive oxygen species in BD patients. It may be interesting to assess formation of urinary level of 8-isoprostaglandin F(2alpha) in BD patients who do not take any medication.

(80) Evaluation of serum leptin concentration in Behcet's disease with ocular involvement.

Kavuncu SKoc FKurt MEryuksel BOrtac SOzdal PFirat E.

Graefes Arch Clin Exp Ophthalmol. 2005 Nov;243(11):1158-60.

PURPOSE: To assess the correlation between the serum leptin concentration and ocular involvement in patients with Behcet's disease. METHODS: The study included 28 male consecutive patients with Behcet's disease ( group A, aged 19-59, median 35.5 years) and 15 male healthy control subjects ( group B, aged 25-45, median 35 years). The body mass index (BMI) was calculated for each subject at the study enrollment stage. We measured serum leptin, neutrophil count and erythrocyte sedimentation rate (ESR). Kruskal-Wallis variance analysis and the Mann-Whitney U-test were used for statistical analysis. RESULTS: The age and BMI between the patients with ocular Behcet's disease and the control group were not different. White cell count and ESR values were found to be significantly higher among patients with Behcet's disease and ocular involvement (p<0.001). The median serum leptin concentrations were as follows: group A: 2.66 (0.57-7.02 ng/ml) and in group B: 2.55 (1.55-7.82 ng/ml). There was no statistically significant difference between the groups. CONCLUSION: Serum leptin level does not correlate with ocular involvement in patients with Behcet's disease.

(81) Autoantibodies to peroxiredoxin I and IV in patients with systemic autoimmune diseases.
Karasawa R. Ozaki S. Nishioka K. Kato T
Microbiology & Immunology. 49(1):57-65, 2005.

Anti-oxidative enzymes protect living bodies from various oxidative stresses. In the systemic autoimmune diseases, autoantibodies to oxidized molecules and to anti-oxidative enzymes have been reported. To promote understanding of the relationships between autoimmunity and oxidative stress, we here investigate whether autoimmunity to the anti-oxidative peroxiredoxin (Prxs) enzymes exists in patients with systemic autoimmune diseases. Specifically, we detected autoantibodies to recombinant Prx I and Prx IV respectively by ELISA and western blotting. Next, clinical parameters were compared between the anti-Prx I or IV-positive and-negative patients. We found that 33% of the 92 patients with autoimmune diseases tested possessed autoantibodies to Prx I (57% in systemic lupus erythematosus (SLE), 19% in rheumatoid arthritis (RA), 5% in Behcet disease, and 46% in primary vasculitis syndrome). In contrast, autoantibodies to Prx IV were detected in only 17% of the same patients. No!
significant correlation was found between occurrence of the two autoantibodies. Clinically, possession of anti-Prx I autoantibodies correlated with lower serum levels of CH50, C3, and C4. Taken together, our data demonstrate the existence of autoantibodies to Prxs for the first time. The autoantibodies to Prx I may be involved in the pathophysiology of systemic autoimmune diseases such as SLE and vasculitis.

(82) Hypothalamic proline-rich polypeptide is an oxidative burst regulator.
Davtyan TK. Manukyan HM. Hakopyan GS. Mkrtchyan NR. Avetisyan SA. Galoyan AA.
Neurochemical Research. 30(3):297-309, 2005 Mar.

The AGAPEPAEPAQPGVY proline-rich polypeptide (PRP) was isolated from neurosecretory granules of the bovine neurohypophysis; it is produced by N. supraopticus and N. paraventricularis. PRP possesses immune-modulating activity, preventing the death of Gram-negative bacteria-infected mice. Here we show that PRP does not affect human peripheral blood neutrophlis and monocytes phagocytosis but dramatically enhances spontaneous or fMLP- and PMA-induced, and also phagocytosis-dependent, oxidative burst. We demonstrated the regulatory role of PRP on the oxidative burst induction of normal and relapsing inflammatory disease (Behcet's disease and familial Mediterranean fever) neutrophils and monocytes. Our results suggest a previously undescribed role for the hypothalamic peptide within primary activated neutrophils and monocytes, since we provide evidence that PRP can differentially regulate both chemotaxis- and phagocytosis-dependent oxidative burst in normal and inflammatory disease effector cells.

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