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Ana Sayfa : Recent BD News : Review of published papers : Nonclinical - Scientific : Listed during August 2004 – April 2005

Listed during August 2004 – April 2005

REVIEW OF PUBLISHED PAPERS: NONCLINICAL SCIENTIFIC
Prepared by: G. Wallace (UK)
 
 
1-3 Reviews
4-16 Immunology
17-23 Vascular/Thrombophilia
24-25 Effects of treatment on immune response
26-34 Gene polymorphisms
35-37 Letters
 
REVIEWS
 
(1) Behcet's disease.
Al-Mutawa SA, Hegab SM.
P.O. Box 1287, Hawalli, 32013 Kuwait. hegab10@hotmail.com
Clin Exp Med. 2004 Dec;4(3):103-31.
Behcet's disease is a recurrent multisystem vasculitis that can affect any organ or system, but was originally described as orogenital ulcerations and uveitis. Specific criteria have been proposed for diagnosis and identification of affected organs by different national authorities. Behcet's disease is proposed to be due to an antigen/antibody reaction. The antigen can be external (microbial or other) or self-antigen. Self-antigens include HLA-B, S and interphotoreceptor retinoid binding protein, the oral mucosal antigens, and alphatropomycin. The antibody reaction manifests as changes common to any inflammatory process. Circulating immune complexes and neutrophil hyperactivity are present with the expression of adhesion molecules related to disease activity associated with phenotypic and functional aberrations affecting both Th1 and Th2 activity. The results in an increase of interleukin-4, -10, and -1B and interleukin-2 receptors with deficient interleukin-12, interferon-gamma, and expression of cell adhesion CDII/CD18, accompanied by increased B cells secreting IgG. The clinical picture varies according to the organ affected; emphasis is placed on those of diagnostic importance and those affecting morbidity and mortality. The histopathology demonstrates vasculitis with inflammatory cell infiltration, the endothelium expressing ICAM-1 and E-selectin, vascular occlusion with sequences. Treatment includes corticosteroids. Other immunosuppressant and biological agents include anti-tumor necrosis factor, interferon-alpha, Campath-1, and the S antigen. Colchicine and other miscellaneous therapies are included.

(2) Behcet's disease.
 
Suzuki Kurokawa M, Suzuki N.
Department of Immunology, St. Marianna University School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-8511, Japan. n3suzuki@marianna-u.ac.jp
Clin Exp Med. 2004 Sep;4(1):10-20.
 
Behcet's disease (BD) is a systemic disorder of recurrent acute inflammation, characterized by major symptoms of oral aphthous ulcers, uveitis, skin lesions and genital ulcers. Involvement of intestines, vessels, and central nervous system (CNS) sometimes leads to a poor prognosis. Patients with BD are known to distribute along the ancient Silk Road. The incidence is relatively higher from eastern Asia to the Mediterranean area as roughly 1-10 patients in 10,000 people, whereas only 1-2 patients in 1,000,000 people in UK and North America. Although etiology of the disease is still unknown, high prevalence of HLA-B51, increased expression of heat shock protein 60 and Th1 dominant immune responses in the patients are considered important in its pathogenesis. Non-infectious neutrophil activation and infection with Streptococcus sanguis and herpes simplex virus would also be associated. Because BD lacks any pathognomonic symptoms and laboratory findings, the diagnosis relies largely upon the criteria proposed by the International Study Group for Behcet's disease in 1990. In Japan, the diagnosis was also made according to the Japanese criteria revised in 1987. Recently, the Behcet's Disease Research Committee of Japan again revised the Japanese criteria in 2003 to avoid overdiagnosis. The new Japanese criteria are introduced in this review. Differential diagnosis excluding Sweet's disease, pemphigus, erythema nodosum and Crohn's disease is important, and positive laboratory data for pathergy test, prick test for dead Streptococci and HLA-B51 are emphasized to make appropriate diagnosis in these criteria. Pathological findings of the disease-affected site such as erythematous nodosum is also stressed. Treatment for the disease has been chosen according to the clinical symptoms. Non-steroidal anti-inflammatory drugs, immunosuppressants, corticosteroids and colchicine are basically introduced. Recently, effects of interferon-alpha/beta, anti-tumor necrosis factor antibody and thalidomide are encouraging, specifically in treatment for the cases with poor prognosis including eye, intestine, vessel and CNS involvement. Low dose weekly administration of methotraxate looks effective for the cases with CNS involvement. Further studies for elucidation of the etiology, improvement of the diagnostic criteria and development of new therapy are needed to conquer the disease.
 
(3) Behcet's disease: a review.
 
Al-Otaibi LM, Porter SR, Poate TW.
Oral Medicine, Division of Maxillofacial Diagnostic, Medical & Surgical Sciences, Eastman Dental Institute for Oral Health Care Sciences, UCL, University of London, 256 Gray's Inn Road, London WC1X 8LD, UK.
J Dent Res. 2005 Mar;84(3):209-22.
 
Behcet's disease (BD) is a multi-system inflammatory disorder dominated clinically by recurrent oral and genital ulceration, uveitis, and erythema nodosum. Behcet's disease runs a chronic course, with unpredictable exacerbations and remissions whose frequency and severity may diminish with time. Behcet's disease typically arises in young adults, although childhood-onset BD has also been reported. The disease can affect both genders and has a worldwide distribution, although it is more prevalent in countries of the ancient Silk Route. The cause of BD remains unknown, although an autoimmune reaction triggered by an infectious agent in a genetically predisposed individual has been suggested. The treatment of BD is symptomatic and empirical, but generally specific to the clinical features of each patient. The majority of affected individuals do not have life-threatening disease, although mortality can be associated with vascular-thrombotic and neurological disease.
 
IMMUNOLOGY
 
(4) Different ELR (+) angiogenic CXC chemokine profiles in synovial fluid of patients with Behcet's disease, familial Mediterranean fever, rheumatoid arthritis, and osteoarthritis.
 
Erdem H, Pay S, Serdar M, Simsek I, Dinc A, Musabak U, Pekel A, Turan M.
Department of Rheumatology, Gulhane Military School of Medicine, Etlik, Ankara 06018, Turkey, herdem67@gata.edu.tr. Rheumatol Int. 2004 Nov 3; [Epub ahead of print]
 
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.
 
(5) 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.
Department of Dermatology, Gazi University Faculty of Medicine, Besevler, Ankara, Turkey. moztas@gazi.edu.tr Clin Exp Dermatol. 2005 Jan;30(1):61-3.
 
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.
 
(6) Serum mannose-binding lectin levels are decreased in Behcet's disease and associated with disease severity.
 
Inanc N, Mumcu G, Birtas E, Elbir Y, Yavuz S, Ergun T, Fresko I, Direskeneli H.
Division of Rheumatology and Hematology, Faculty of Medicine, University of Marmara, Istanbul, Turkey. nevsun@superonline.com J Rheumatol. 2005 Feb;32(2):287-91.
 
OBJECTIVE: To investigate serum levels of mannose-binding lectin (MBL), a complement-like protein of collectin family, in patients with Behcet's disease (BD). METHODS: MBL levels were measured in sera of 130 patients with BD, 64 patients with recurrent oral ulcerations (ROU), and 105 healthy controls (HC) with ELISA. RESULTS: Patients with BD had significantly lower median serum MBL levels compared to HC (1857 vs 3136 ng/ml, p = 0.001). No significant difference was observed in median serum MBL levels between BD and ROU (2309 ng/ml, p = 0.252). Low MBL levels (</= 500 ng/ml) were present in a higher proportion of BD patients compared to HC (29% vs 16%, p = 0.021). A severe disease course (total clinical severity score >/= 4) was more frequently observed in BD patients with very low serum MBL levels (</= 100 ng/ml) (19% vs 6%, p = 0.046). When serum MBL levels were analyzed separately according to gender, the frequency of vascular disease was higher in men with very low serum MBL levels (80% vs 42%, p = 0.042). CONCLUSIONS: MBL deficiency might contribute to the pathogenesis of BD and affect its clinical course.
 
(7) The significance of serum nitric oxide levels in Behcet's disease and recurrent aphthous stomatitis.
 
Yildirim M, Baysal V, Inaloz HS, Doguc D.
University of Suleyman Demirel, School of Medicine, Department of Dermatology, Isparta, Turkey. J Dermatol. 2004 Dec;31(12):983-8
 
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 serum 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.
 
(8) HLA class I and class II genotyping in patients with Behcet's disease: a regional study of eastern part of Turkey.
 
Pirim I, Atasoy M, Ikbal M, Erdem T, Aliagaoglu C.
Ataturk University, Medical School, Department of Medical Biology, 25240-Erzurum, Turkey.ipirim@hotmail.com
Tissue Antigens. 2004 Sep;64(3):293-7.
 
Class I human leucocyte antigen (HLA)-B51 is well known to be associated with Behcet's disease in many ethnic groups. However, there has been no published paper with respect to its association with HLA class I and class II among the Turkish people who live in the eastern region of Turkey. Moreover, as it is known that B51 antigen is encoded by 21 alleles, B*5101-5121, HLA-B51 allele typing was performed, as well as HLA class I and class II genotyping of 75 patients with the disease and the 54 individuals in the matched control group. The result shows that the HLA-B51 frequency was significantly higher (58.66%) in the patient group, compared to that in the control group (18.51%) (OR = 6.245). In the subtyping of B51 alleles, 44 B51-positive patients possessed B*5101 (45.5%), B*5108 (25%), B*5105 (9.1%) and B*5104 (4.5%). There was no significant difference in the HLA-B51 allelic distribution between the patient group and the control group. However, homozygous carriers of HLA-B51 showed considerably high risk (OR = 2.647) in the patient group, compared to that in the control group. In the genotyping of class II HLA alleles, while HLA-DRB1*04 (45.3%) and HLA-DRB1*07 (24%) were the predominant alleles in the patient group, DRB1*11 (50%) appeared to be more common in the control group.
 
(9) Involvement of Th1 cells and heat shock protein 60 in the pathogenesis of intestinal Behcet's disease.
 
Imamura Y, Kurokawa MS, Yoshikawa H, Nara K, Takada E, Masuda C, Tsukikawa S, Ozaki S, Matsuda T, Suzuki N.
Department of Medicine, St Marianna University School of Medicine, Kawasaki, Kanagawa, Japan. Clin Exp Immunol. 2005 Feb;139(2):371-8.
 
Involvement of excessive Th1 cell functions and heat shock protein expression in the pathogenesis of Behcet's disease (BD) has been reported. In this study we have characterized immune responses in intestinal lesions of BD. Peripheral blood lymphocytes (PBL) of BD and healthy controls (HC) and tissue specimens of intestinal Behcet's disease (intestinal BD), Crohn's disease (CD) and ulcerative colitis (UC) were analysed for mRNA and protein expression by reverse transcriptase-polymerase chain reaction (PCR) and immunohistochemistry, respectively. PBL of BD patients expressed the Th1-related chemokine receptor, CCR5 and CXCR3 preferentially compared with those of healthy controls. Intestinal lesions of BD expressed interferon (IFN)-gamma, tumour necrosis factor (TNF)-alpha and interleukin (IL)-12 mRNA, indicating Th1 skewed responses in vivo. mRNA of Txk, a Tec family tyrosine kinase specific to Th1 cells, was expressed in the lesions, suggesting its contribution to the Th1-dominant responses. In the intestinal samples, CCR5 was detected in all the cases with BD, whereas Th2-related CCR3 and CCR4 were detected randomly, mainly in the cases with inactive BD and those receiving large amounts of prednisolone, indicating the Th1-dominant immune responses in the intestinal lesions. As the ligands of CCR5, MIP1alpha and MIP1beta were detected, whereas RANTES was not. Heat shock protein (HSP) 60 was expressed in PBL and intestinal tissues of BD. Th1-dominant immune responses and HSP60 expression may induce the inflammatory responses and thus be associated with the pathogenesis of intestinal BD.
 
(10) Excessive expression of Txk, a member of the Tec family of tyrosine kinases, contributes to excessive Th1 cytokine production by T lymphocytes in patients with Behcet's disease.
 
Nagafuchi H, Takeno M, Yoshikawa H, Kurokawa MS, Nara K, Takada E, Masuda C, Mizoguchi M, Suzuki N.
Department of Immunology and Medicine, St Marianna University School of Medicine, Kawasaki, Kanagawa, Japan. Clin Exp Immunol. 2005 Feb;139(2):363-70.
 
Excessive Th1 cell function is importantly involved in the pathogenesis of Behcet's disease (BD). We previously found that Txk, a member of the Tec family of tyrosine kinases, acts as a Th1 cell specific transcription factor. To investigate immune aberration in the pathogenesis of BD, we studied the expression of Txk and Th1 cytokines in peripheral blood lymphocytes (PBL) and skin lesions in patients with BD. Cytokine production by the lymphocytes was assessed using ELISA. PBL produced excessive Th1 associated cytokines including IFN-gamma and IL-12 spontaneously and in response to exogenous HSP60-derived peptide stimulation, which was shown to induce proliferation of PBL, in patients with BD. Circulating CD4+ T cells expressed excessive Txk protein. A majority of cells infiltrating into skin lesions expressed IFN-gamma in the BD specimens. IL-12 and IL-18 were also expressed in the mononuclear cell aggregates. Lymphocytes accumulating in the skin lesion expressed higher levels of Txk as compared with atopic dermatitis lesions, a typical Th2 disease. IFN-gamma, IL-18 and Il-12 were detected in the BD skin lesions, which may induce preferential development of Th1 cells in patients with BD. The mononuclear cell aggregates contained Txk expressing cells in such skin lesions. Collectively, Txk expressing Th1 cells and the Th1 associated cytokines may play a critical role in the development of skin lesions in BD.
 
(11) Tc1/Tc2 ratio in the inflammatory process in patients with Behcet's disease.
 
Houman H, Hamzaoui A, Ben Ghorbal I, Khanfir MS, Feki M, Hamzaoui K.
Department of Internal Medicine, La Rabta Hospital, Tunis, Tunisia.
Mediators Inflamm. 2004 Aug;13(4):247-53.
 
BACKGROUND: Peripheral blood CD8+ T cells expressing interferon gamma and interleukin-4 (IL-4), and lacking CD28 molecules, were responsible for the dynamic interplay between peripheral blood and inflammatory sites. INTRODUCTION: The aim of the current study was to define in Behcet's disease (BD), CD8+ T-cell subsets using CD28 and CD11b monoclonal antibodies, and the characterization of the Tc1/Tc2 ratio and perforin expression. METHODS: Flow cytometry was used for intracytoplasmic cytokines and perforin expression. Effector cells were investigated by adhesion of CD8+ T cells to human microvascular endothelial cells and by chemotaxis using beta-chemokine. RESULTS: Interferon-gamma-producing CD8+ T cells in active and remission BD patients were increased, which induce a significant increase of the Tc1:Tc2 ratio in BD. CD8(+)CD28(-)CD11b+ T cells were found to be more expanded in BD patients than in age-matched healthy controls. The expression of CD11b molecules in active BD allowed to CD8(+)CD28+/CD8(+)CD28- subsets to adhere to human microvascular endothelial cells, with more efficiency in BD. Using MIP-1alpha, we observed that the migratory process of CD28(-)CD11b(+) is more important in BD. CD28(-)CD11b+ exhibited an increased perforin expression in BD patients. CONCLUSION: Taken together these results suggest the presence of immune activation, probably in response to a profound inflammation affecting BD patients. The physiopathological significance of these results were toward autoimmune diseases and/or infectious process.
 
(12) Serum interleukin-2, interleukin-6, tumour necrosis factor-alpha and nitric oxide levels in patients with Behcet's disease.
 
Akdeniz N, Esrefoglu M, Keles MS, Karakuzu A, Atasoy M.
Department of Dermatology, Yuzuncu Yil University, Faculty of Medicine, Turkey.nakdeniz71@hotmail.com
Ann Acad Med Singapore. 2004 Sep;33(5):596-9.
 
INTRODUCTION: Behcet's disease (BD) is a chronic systemic disorder characterised by oral and genital ulcerative lesions, ocular and cutaneous manifestations. Cytokines are the major mediators of immunologic and inflammatory reactions. Nitric oxide is reactive nitrogen intermediate which plays a key role in pathogenesis of many inflammatory and autoimmune skin diseases. The study was conducted to determine serum interleukin-2 (IL-2), interleukin-6 (IL-6), tumour necrosis factor (TNF)-alpha and nitric oxide levels in relation to the pathogenesis of Behcet's disease. MATERIALS AND METHODS: Serum IL-2, IL-6, and TNF-alpha levels were measured with test kits by enzyme-linked immunosorbent assay (ELISA) method, while serum nitric oxide levels were determined with a test kit by colorimetric method. Serum IL-2, IL-6, TNF-alpha and nitric oxide concentrations in 27 patients with Behcet's disease and in 16 healthy controls were determined by extrapolation from their standard curves. The significance of the mean differences between the 2 groups was assessed by the Mann-Whitney U test. RESULTS: The serum levels of IL-2, IL-6, TNF-alpha, and nitric oxide concentrations in patients with BD were significantly higher than those of the controls (P <0.001). CONCLUSION: Our results suggest that elevated levels of IL-2, IL-6, TNF-alpha, and nitric oxide in Behcet's disease appear to be related to the disease.
 
(13) Autoreactive CD8+ cytotoxic T lymphocytes to major histocompatibility complex class I chain-related gene A in patients with Behcet's disease.
 
Yasuoka H, Okazaki Y, Kawakami Y, Hirakata M, Inoko H, Ikeda Y, Kuwana M.
Institute for Advanced Medical Research, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Arthritis Rheum. 2004 Nov;50(11):3658-62.
 
OBJECTIVE: To detect and characterize the autoreactive CD8+ T cells to major histocompatibility complex class I chain-related gene A (MICA), a stress-inducible antigen preferentially expressed on the epithelium and endothelium, in patients with Behcet's disease (BD). METHODS: A candidate for the antigenic MICA peptide was selected based on its predicted binding affinity for HLA-B51 and proteasomal cleavage sites. Peripheral blood T cells from 14 patients with BD and 15 healthy controls were repeatedly stimulated with the MICA peptide, and the specific T cell response was measured by peptide-induced interferon-gamma. Cytotoxic T lymphocyte activity was examined by chromium-51 release from an HLA-B51-transfected B cell line in the presence of the MICA peptide. RESULTS: A 9-mer peptide AAAAAIFVI (termed MICA transmembrane [MICA-TM]) was selected as a candidate for the antigenic peptide presented by HLA-B51. A specific T cell response to MICA-TM was detected in 4 patients with BD (29%) but in none of the 15 healthy donors. All 4 responders had HLA-B51 and active disease, and the specific T cell response was lost after the BD-related symptoms disappeared. The MICA-induced T cell response was specifically inhibited by anti-HLA class I antibody or by CD8+ cell depletion. MICA-reactive T cells recognized an HLA-B51-transfected B cell line pulsed with MICA-TM or a B cell line transfected with both HLA-B51 and MICA in the absence of exogenous peptides. Finally, MICA-stimulated T cell lines lysed the HLA-B51-expressing B cell line in the presence of MICA-TM. CONCLUSION: HLA-B51-restricted cytotoxic T lymphocytes autoreactive to MICA may be involved in the pathogenesis of BD.
 
(14) 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.
Department of Internal Medicine, La Rabta Hospital, Tunis, Tunisia.
J Autoimmun. 2004 Nov;23(3):267-73.
 
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 clinical 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.
 
(15) The number of CD8+ T cells and NKT cells increases in the aqueous humor of patients with Behcet's uveitis.
 
Yu HG, Lee DS, Seo JM, Ahn JK, Yu YS, Lee WJ, Chung H.
Department of Ophthalmology, Seoul Artificial Eye Centre, Seoul National University Hospital Clinical Research Institute, Seoul, Korea.
Clin Exp Immunol. 2004 Aug;137(2):437-43.
 
To determine whether there are differences in the immunopathogenesis of different endogenous uveitis syndromes, the phenotypic characteristics of immune cells were analysed among patients with endogenous uveitis. The aetiology of the uveitis included idiopathic recurrent acute anterior uveitis (18 patients), idiopathic intermediate uveitis (13 patients), Behcet's uveitis (17 patients), Vogt-Koyanagi-Harada syndrome (7 patients), and so on. Flow cytometric analysis was performed using immune cells of the aqueous humor and the peripheral blood during the active phase of intraocular inflammation, and monoclonal antibodies to CD3, CD4, CD8, CD14, CD19, CD56, TCR gammadelta, pan TCR alphabeta and Valpha24. CD8+ T cells were predominant in the aqueous humor of the patients with Behcet's uveitis, whereas CD4+ T cells were mainly found in the aqueous humor of patients other than those with Behcet's uveitis. The number of NKT (CD3+CD56+) cells was significantly higher both in the aqueous humor and the peripheral blood of the patients with Behcet's uveitis compared with the other groups (P < 0.05). CD8+CD56+ cells were the predominant subtype of the increased NKT cells in patients with Behcet's uveitis. In addition, intraocular infiltration of CD14+ cells significantly differed among the uveitis patients (P < 0.05). These results suggest that the immunopathogenesis of endogenous uveitis can vary between syndromes, and that CD8+CD56+ NKT cells may play an important role in the immunopathogenesis of Behcet's uveitis.
 
(16) 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.
Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
Rheumatol Int. 2005 Jan;25(1):33-6.
 
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.
 
VASCULAR-THROMBOPHILIA
 
(17) Thrombophilic factors are not the leading cause of thrombosis in Behcet's disease.
 
Leiba M, Seligsohn U, Sidi Y, Harats D, Sela BA, Griffin JH, Livneh A, Rosenberg N, Gelernter I, Gur H, Ehrenfeld M.
Department of Medicine C, Sheba Medical Centre, Tel-Hashomer 52621, Israel.
Ann Rheum Dis. 2004 Nov;63(11):1445-9.
 
BACKGROUND: Venous and arterial thromboses occur in patients with Behcet's disease and are associated with significant morbidity and mortality. Studies on a possible association between the occurrence of thrombosis and thrombophilia in patients with this disease have been controversial. OBJECTIVE: To determine the prevalence of the most common thrombophilias and dyslipidaemia in patients with Behcet's disease with and without thrombosis. METHODS: Blood samples from 107 patients with Behcet's disease who had or did not have thrombosis were analysed for factor V Leiden, prothrombin G20210A polymorphism, methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, factor VIII level, homocysteine and C reactive protein concentrations, dyslipidaemia, and plasma glucosylceramide. RESULTS: There was no difference between patients with and without thrombosis in the prevalence of prothrombin G20210A polymorphism, factor V Leiden, homozygous MTHFR C677T, or plasma concentrations of homocysteine, C reactive protein, or glucosylceramide. In contrast, patients with thrombosis were found to have significantly higher mean levels of factor VIII, total cholesterol, triglycerides, VLDL cholesterol, and apolipoproteins B-100, C-II, and C-III than those without thrombosis. Multistepwise logistic regression analysis showed that triglyceride concentration was the best marker associated with thrombosis (p = 0.008), with an estimated odds ratio of 1.58 (95% confidence interval, 1.09 to 2.30) for a difference of 40 mg/dl. CONCLUSIONS: Thrombophilia does not seem to play a major role in the tendency to thrombosis in Behcet's disease. However, dyslipidaemia, predominantly hypertriglyceridaemia, might be a risk factor.
 
(18) Thrombin activatable fibrinolysis inhibitor in Behcet's disease.
 
Donmez A, Aksu K, Celik HA, Keser G, Cagirgan S, Omay SB, Inal V, Aydin HH, Tombuloglu M, Doganavsargil E.
Ege University Medical School Hospital, Department of Internal Medicine, Division of Hematology, 35100 Bornova, Izmir, Turkey. adonmez@med.ege.edu.tr Thromb Res. 2005;115(4):287-92.
 
INTRODUCTION: Thrombin activatable fibrinolysis inhibitor (TAFI) is a procarboxypeptidase downregulating plasmin formation, thereby causing a tendency for thrombosis development. Since, Behcet's disease (BD) is a systemic vasculitis, which is commonly complicated by arterial and venous thrombosis, we aimed to find out plasma TAFI levels in BD, compared with healthy controls. We also searched whether plasma TAFI levels were significantly different between Behcet's subgroups with and without thrombosis. MATERIALS AND METHODS: In this study, 105 BD patients (M/F: 64/41; mean age 36+/-1 years), followed up by Ege University Rheumatology Department were enrolled. The exclusion criteria were hemophilia, hyperlipidemia, diabetes mellitus, hepatic diseases renal failure, antiphospholipid positivity, oral contraceptive use and pregnancy. Age-and sex-matched healthy controls (n=53) were also included. Plasma TAFI levels were measured by ELISA. Since TAFI is also an acute-phase reactant, we also measured other inflammatory markers such as C-reactive protein (CRP). RESULTS: Plasma TAFI levels were significantly higher in Behcet's patients (91.1+/-7.4 ng/ml) compared with healthy controls (14.3+/-4.5 ng/ml) (P<0.001), but there were no significant difference between the subgroups with and without thrombosis. In BD, there was no correlation between plasma TAFI levels and CRP. CONCLUSIONS: Regardless of manifest thrombosis, plasma TAFI levels in BD were significantly higher than in healthy controls. High TAFI levels might possibly contribute to the thrombotic tendency in BD. Future studies investigating TAFI gene polymorphism and functional activity are clearly needed, to clarify the exact role of TAFI in Behcet's thrombosis.
 
(19) Serum paraoxonase activity is decreased in the active stage of Behcet's disease.
 
Karakucuk S, Baskol G, Oner AO, Baskol M, Mirza E, Ustdal M.
Department of Ophthalmology, Erciyes University Faculty of Medicine, Kayseri 38039, Turkey.sarper2002@yahoo.com
Br J Ophthalmol. 2004 Oct;88(10):1256-8.
 
AIMS: To evaluate paraoxonase1 (PON1) activities and malondialdehyde (MDA) levels, one of the end products of lipid peroxidation induced by reactive oxygen species in patients with Behcet's disease (BD) in the active stage. METHODS: Serum MDA levels and PON1 levels were measured spectrophotometrically in 16 patients with BD in the active stage of the disease and in 15 healthy subjects who constituted the control group. RESULTS: In the BD group, median (range) serum PON1 and MDA levels were 149.64 U/l (88.02-281.68) and 1.21 nmol/ml (0.90-3.42), respectively. In the control group, median (range) serum PON1 and MDA levels were 206.86 U/l (114.43-422.52) and 0.72 nmol/ml (0.50-1.12), respectively. There was a statistically significant decrease in serum PON1 levels (p = 0.02) and an increase in serum MDA levels (p<0.001) in patients with BD in the active stage when compared to controls. CONCLUSION: Endothelial damage and increased polymorph nuclear leucocyte activity in the active stage of BD could result in a pro-oxidation environment which, in turn, results in decreased antioxidant PON activity and increased lipid peroxidation as evidenced by increased MDA levels.
 
(20) Levels of soluble E-selectin in patients with active Behcet's disease.
 
Sari RA, Kiziltunc A, Taysi S, Akdemir S, Gundogdu M.
Department of Immunology/Rheumatology, Ataturk University Medical School, 25240 Erzurum, Turkey.refikali@yahoo.com
Clin Rheumatol. 2005 Feb;24(1):55-9.
 
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.
 
(21) Vascular endothelial function and plasma homocysteine levels in Behcet's disease.
 
Ozdemir R, Barutcu I, Sezgin AT, Acikgoz N, Ermis N, Esen AM, Topal E, Bariskaner E, Ozerol I.
Department of Cardiology, Faculty of Medicine, Inonu University, Turgut Ozal Medical Center, Malatya, Turkey. rozdemir@inonu.edu.tr
Am J Cardiol. 2004 Aug 15;94(4):522-5.
 
The purpose of the present study was to test endothelial function and to determine if plasma homocysteine levels are associated with endothelial injury in patients with Behcet's disease (BD). Flow-mediated dilation in patients with BD was smaller than that of control subjects (p = 0.001), and mean plasma homocysteine levels in patients with BD were significantly higher (p = 0.0001). On regression analysis, only mean plasma homocysteine concentration was independently related to flow-mediated dilation (F = 5.7, p = 0.001).
 
(22) Activated protein C levels in Behcet's disease and risk of venous thrombosis.
 
Navarro S, Ricart JM, Medina P, Vaya A, Villa P, Todoli J, Estelles A, Mico ML, Aznar J, Espana F.
Research Centre, Hospital Universitario La Fe, Valencia, Spain.
Br J Haematol. 2004 Aug;126(4):550-6.
 
Behcet's disease is a multi-systemic inflammatory disorder of unknown cause. Most abnormalities have been associated with endothelial injury caused by vasculitis. Thrombosis occurs in about 25% of patients, although the mechanism is unknown. The objective of this study was to evaluate the protein C activation system in Behcet's disease and its correlation with venous thromboembolism (VTE). Thirty-nine patients (12 with VTE) and 78 age- and sex-matched controls were included in the study, and levels of protein C, protein S, activated protein C (APC), protein C inhibitor (PCI), soluble thrombomodulin (TM), antithrombin (AT), alpha(1)-antitrypsin, fibrinogen, factor VIII, von Willebrand factor (VWF) and C-reactive protein (CRP) were measured. APC and TM levels were significantly lower in patients than in controls, whereas protein S, AT, alpha(1)-antitrypsin, fibrinogen, factor VIII, VWF and CRP levels were significantly higher in patients than in controls. APC, PCI and TM levels were lower in patients with VTE (0.65 +/- 0.19 ng/ml, 86% +/- 22% and 15.5 +/- 7.1 ng/ml respectively) than in those without VTE (0.78 +/- 0.17 ng/ml, 100% +/- 15% and 22.1 +/- 15.3 ng/ml) (P < 0.05). In patients, APC levels below 0.75 ng/ml (10th percentile of the control group) increased the risk of VTE about fivefold (odds ratio = 5.1; 95% confidence interval = 1.1-23.4). These results show that reduced APC levels are associated with the high incidence of VTE in Behcet's disease.
 
(23) Serum homocysteine level is higher in Behcet's disease with vascular involvement.
 
Ates A, Aydintug O, Olmez U, Duzgun N, Duman M.
Department of Clinical Immunology and Rheumatology, Ankara University Faculty of Medicine, Ankara, Turkey.
Rheumatol Int. 2005 Jan;25(1):42-44.
 
OBJECTIVE: Behcet's disease (BD) is a multisystemic inflammatory disorder of unknown etiology that is sometimes associated with thrombosis. However, the mechanism of hypercoagulability is not known. In this study, we investigated whether hyperhomocysteinemia, being a well-known risk factor for thrombosis, is also a contributing risk factor to venous and arterial thromboses of BD. METHODS: Forty-five patients with BD and 40 healthy subjects were included in the study. Sixteen patients had vascular involvement. Serum homocysteine levels were determined by fluorescence polarization immunoassay. RESULTS: In male patients, the frequency of vascular involvement was significantly higher than in females (46.7% vs 13.3%, P<0.05). Serum homocysteine levels were significantly higher in patients with BD than healthy controls (P<0.01), in patients with vascular involvement than those with mucocutaneous involvement (P<0.01) and healthy controls (P=0.001), and in male patients than in female patients (P<0.001). There was no significant difference in homocysteine levels between the BD patients with mucocutaneous involvement and healthy subjects. In multiple regression analysis, serum homocysteine level was independently associated with thrombosis (odds ratio 1.29, P<0.01), but male sex was not. CONCLUSIONS: This preliminary study suggests that elevated serum homocysteine levels may play some role in the development of venous and arterial thromboses in BD.
 
EFFECTS OF TREATMENT ON IMMUNE RESPONSE
 
(24) 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.
Department of Internal Medicine, Clinical Immunology, and Rheumatology, Medical School of Ankara University, Ankara, Turkey
Rheumatol Int. 2005 Jan;25(1):1-5.
 
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.
 
(25) Influence of human recombinant interferon-alpha2a (rhIFN-alpha2a) on altered lymphocyte subpopulations and monocytes in Behcet's disease.
 
Treusch M, Vonthein R, Baur M, Gunaydin I, Koch S, Stubiger N, Eckstein AK, Peter HH, Ness T, Zierhut M, Kotter I.
Department of Internal Medicine II (Hematology/Oncology/Immunology/Rheumatology), University Hospital, Otfried-Muller Strasse 10, D-72076 Tubingen, Germany.
Rheumatology (Oxford). 2004 Oct;43(10):1275-82.
 
OBJECTIVE: In Behcet's disease (BD), several abnormalities of lymphocyte subpopulations have been described. Standard treatment comprises immunosuppressive drugs. We successfully treated 50 patients with ocular BD with interferon-alpha2a (IFN-alpha2a) (response rate 92%), although this is counterintuitive because IFN-alpha is immunostimulatory and can sometimes even induce autoimmune diseases such as systemic lupus erythematosus or rheumatoid arthritis. The aim of the present study was to elucidate the immunomodulatory effects that IFN-alpha might exert on peripheral blood mononuclear cells (PBMC) in BD by examining changes in the distribution of lymphocyte subpopulations under IFN-alpha2a treatment. METHODS: Fourteen patients with ocular BD were evaluated before and at weeks 4 and 24 of IFN-alpha treatment and compared with 10 healthy controls. PBMC were stained with monoclonal antibodies and measured by flow cytometry. RESULTS: Compared with the controls there is a significant elevation of monocytes (CD14(+)), CD8(+)/gammadelta T cells, CD3(+)/gammadelta T cells, natural killer (NK) cells (CD56(+)/CD16(+)) and activated/regulatory T cells (CD4(+)/CD25(+) and CD8(+)/CD25(+)) in patients with active BD before treatment with IFN-alpha2a. Numbers of naive T cells (CD8(+)/CD45(+)RA(+)/RO(-), CD4(+)/CD45(+)RA(+)/RO(-)) were significantly lower. Under therapy, NK cells, CD8(+)/gammadelta T cells and CD3(+)/gammadelta T cells decreased significantly, whereas B cells increased. The previously reduced expression of HLA class I on monocytes in HLA-B51-positive patients rose to levels comparable to HLA-B51-negative patients. CONCLUSION: These results implicate the participation of NK cells and gammadelta T cells, especially CD8(+)/gammadelta T cells, in the pathogenesis of BD and may explain one mechanism by which IFN-alpha2a exerts therapeutic effects. Alternatively, they may result indirectly from remission induction by IFN-alpha2a. The reduced expression of HLA class I on monocytes in HLA-B*51-positive patients might reflect an impaired expression of and antigen presentation by HLA-B*51.
 
GENE POLYMORPHISMS
 
(26) Vascular endothelial growth factor gene polymorphisms in Behcet's disease.
 
Salvarani C, Boiardi L, Casali B, Olivieri I, Cantini F, Salvi F, Malatesta R, La Corte R, Triolo G, Ferrante A, Filippini D, Paolazzi G, Sarzi-Puttini P, Nicoli D, Farnetti E, Chen Q, Pulsatelli L.
Unita di Reumatologia and Laboratorio di Biologia Molecolare, Ospedale di Reggio Emilia, Bologna, Italy. salvarani.carlo@asmn.re.it
J Rheumatol. 2004 Sep;31(9):1785-9.
 
OBJECTIVE: To evaluate potential associations of vascular endothelial growth factor (VEGF) gene polymorphisms with Behcet's disease (BD) and disease expression. METHODS: Case patients were 122 consecutive Italian patients with BD followed at the Rheumatology, Ophthalmology, and Neurology Units in Bologna, Ferrara, Milano, Palermo, Potenza, Prato, Reggio Emilia, and Trento over a 3-year period (1997-99) and who satisfied the International Study Group criteria for BD. Also selected as a control group were 200 healthy age and sex matched blood donors. All patients with BD and controls were genotyped by polymerase chain reaction and allele-specific oligonucleotide techniques for +936 C/T (rs3025039) and -634 C/G (rs2010963) mutations and for an 18 base pair (bp) insertion/deletion (I/D) polymorphism at -2549 of the the VEGF promoter region. In vitro release of VEGF by peripheral blood mononuclear cells (PBMC) was investigated by ELISA in healthy controls homozygous for the polymorphisms studied. RESULTS: The carriage rates of the alleles I and -634C were significantly more frequent in patients with BD than in healthy controls [p corr = 0.036, OR 1.8 (95% CI 1.1-2.9) and p corr = 0.05, OR 1.8 (95% CI 1.1-3.0), respectively]. While the distribution of allele +936T was similar in patients with BD and healthy controls, its frequency was significantly higher in BD patients with posterior uveitis/retinal vasculitis than in those without (p = 0.022, OR 2.4, 95% CI 1.1-5.0). Lipopolysaccharide-stimulated VEGF production from PBMC of healthy subjects was higher in II homozygous than in DD homozygous. CONCLUSION: Our data indicate that carriers of -634C and I alleles are associated with susceptibility to developing BD.
 
(27) A novel mutation (T61I) in the gene encoding tumour necrosis factor receptor superfamily 1A (TNFRSF1A) in a Japanese patient with tumour necrosis factor receptor-associated periodic syndrome (TRAPS) associated with systemic lupus erythematosus.
 
Ida H, Kawasaki E, Miyashita T, Tanaka F, Kamachi M, Izumi Y, Huang M, Tamai M, Origuchi T, Kawakami A, Migita K, Motomura M, Yoshimura T, Eguchi K.
First Department of Internal Medicine, Nagasaki University Hospital of Medicine and Dentistry, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan. idah@net.nagasaki-u.ac.jp Rheumatology (Oxford). 2004 Oct;43(10):1292-9.
 
OBJECTIVE: To identify potential mutations in the tumour necrosis factor receptor superfamily 1A gene (TNFRSF1A) in a Japanese female patient with recurrent fever complicated by systemic lupus erythematosus (SLE), and in her family members. METHODS: DNA sequencing of exons 1-10 of the TNFRSF1A gene was performed to determine mutations that might be associated with the tumour necrosis factor receptor-associated periodic syndrome (TRAPS). Moreover, the TNFRSF1A gene was examined in Japanese patients with autoimmune diseases, including SLE, rheumatoid arthritis (RA), mixed connective tissue disease (MCTD) and Behcet's disease, and in healthy Japanese controls. Enzyme-amplified sensitivity immunoassay (EASIA) analysis was used to assess serum levels of TNF, the 55-kDa TNF receptor (TNFRSF1A) and the 75-kDa TNF receptor (TNFRSF1B). Membrane TNFRSF1A expression was analysed on the surface of peripheral blood mononuclear cells by flow cytometry. RESULTS: A novel mutation, a heterozygous C to T transition in exon 3 which substitutes an isoleucine for a threonine at position 61 (T61I) was detected in the TNFRSF1A gene derived from the genomic DNA of a Japanese female TRAPS patient. Two nieces and one nephew, all with a similar clinical phenotype, also possessed the same TNFRSF1A mutation. We further demonstrated the same mutation in five of 60 SLE patients (8.3%) and in five of 120 healthy individuals (4.2%), with no significant differences. Although high titres of serum TNF and soluble TNFRSF1B protein were observed in this patient, low titres of soluble TNFRSF1A protein were detected. However, a defect in TNFRSF1A shedding in vitro was not observed in monocytes derived from this patient. CONCLUSION: This is the first report of a TRAPS patient associated with SLE with a novel TNFRSF1A mutation (T61I).
 
(28) 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.
Arthritis Research Campaign Epidemiology Unit, University of Manchester, Manchester, UK. Rheumatology (Oxford). 2005 Feb 10; [Epub ahead of print]
 
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 -7867*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.
 
(29) 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.
Department of Immunology, Institute for Experimental Medical Research, Istanbul University, Istanbul, Turkey. J Rheumatol. 2005 Jan;32(1):93-7.
 
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. Distribution 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.
 
(30) Association of HYPA haplotype in the mannose-binding lectin gene-2 with Behcet's disease.
 
Park KS, Min K, Nam JH, Bang D, Lee ES, Lee S.
Department of Biology, Sungshin Women's University, Seoul, South Korea. kspark@sungshin.ac.kr Tissue Antigens. 2005 Mar;65(3):260-5
 
Behcet's disease (BD) is a multisystemic, recurrent inflammatory disease caused by the combinations of multiple genetic and environmental factors. Moreover, the MBL2 gene single-nucleotide polymorphisms and haplotypes are known to increase the susceptibility to inflammatory disease and to alter the serum levels of mannose-binding lectin (MBL. We postulated that the haplotypes of the MBL2 gene influence therapeutic response in BD, thus affecting the clinical symptoms in 282 BD patients. The promoter region, MBL2-550*C/*C (L/L) homozygote was found to have a lower frequency in BD patients than that in controls. No difference was observed in the allele frequencies of G-221C (Y/X), C+4T (P/Q) or Gly54Asp (A/B) of the MBL2 gene in BD patients and in controls. The HYPA haplotype contributed to BD occurrence, whereas the LYPA haplotype was negatively associated with BD. BD patients with several symptoms and with an earlier disease-onset age had a higher HYPA haplotype frequency. BD patients showing poor response (S) to therapy had a higher HYPA frequency than those showing good response (M). It seems that possessing HYPA increases the risk of BD and that the MBL2 HYPA haplotype plays a role in MBL levels and increases the susceptibility to BD.
 
(31) Association of the R92Q TNFRSF1A mutation and extracranial deep vein thrombosis in patients with Behcet's disease.
 
Amoura Z, Dode C, Hue S, Caillat-Zucman S, Bahram S, Delpech M, Grateau G, Wechsler B, Piette JC.
Hopital Pitie-Salpetriere, Paris, France. zahir.amoura@psl.ap-hop-paris.fr <zahir.amoura@psl.ap-hop-paris.fr> Arthritis Rheum. 2005 Feb;52(2):608-11.
 
OBJECTIVE: Behcet's disease is a chronic, relapsing, multisystemic inflammatory disorder characterized by recurrent oral and genital ulcers and by ocular, articular, vascular, and central nervous system involvement. The tumor necrosis factor alpha (TNFalpha) pathway is likely involved in the pathophysiology of Behcet's disease. One of the 2 TNFalpha receptors is TNF receptor superfamily 1A (TNFRSF1A). We searched for R92Q TNFRSF1A mutations in patients with Behcet's disease. METHODS: A search for TNFRSF1A mutations was performed by polymerase chain reaction amplification of the TNFRSF1A gene, followed by denaturing high-performance liquid chromatography scanning. RESULTS: Among the 74 unrelated European patients with Behcet's disease, 5 (6.8%) carried the R92Q TNFRSF1A mutation. The frequency of the R92Q mutation in patients with Behcet's disease was significantly higher than that in controls (P = 0.006 by Fisher's exact test). Deep vein thrombosis was significantly associated with the R92Q mutation (P = 0.001 [with Bonferroni adjustment for multiple comparisons]). Among the 30 patients with thrombosis, 10 had cerebral thrombophlebitis. None of these patients had the R92Q mutation. Among the 20 patients with Behcet's disease who had extracranial deep vein thrombosis, 6 had the R92Q mutation, whereas 14 did not (P < 0.0001) CONCLUSION: The R92Q mutation in patients with Behcet's disease is associated with an increased risk of extracranial venous thrombosis. This new finding may help in understanding the complex prothrombotic state in patients Behcet’s disease.
 
(32) Specific interleukin-1 gene polymorphisms in Turkish patients with Behcet's disease.
 
Coskun M, Bacanli A, Sallakci N, Alpsoy E, Yavuzer U, Yegin O.
Department of Pediatric Immunology, Akdeniz University School of Medicine, Antalya, Turkey. Exp Dermatol. 2005 Feb;14(2):124-9.
 
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-1beta-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.
 
(33) Apolipoprotein E polymorphism and lipoprotein compositions in patients with Behcet's disease.
 
Tursen U, Eskandari G, Kaya TI, Tamer L, Ikizoglu G, Atik U.
Department of Dermatology, University of Mersin School of Medicine, Mersin, Turkey. utursen@mersin.edu.tr Int J Dermatol. 2004 Dec;43(12):900-3.
 
BACKGROUND: Behcet's disease (BD) is a multisystemic disease of unknown etiology characterized by chronic relapsing oral-genital ulcers and uveitis. Some abnormalities in lipoprotein metabolism have been described in patients with BD. METHODS: In this study, apolipoprotein E (apo E) polymorphism and lipoprotein cholesterol concentrations in 30 patients with BD were compared with those of 27 control subjects. RESULTS: Both patients and controls were found to be normolipidemic. Patients with BD had significantly higher concentrations of high-density lipoprotein (HDL) cholesterol than those of controls (P < 0.05); however, there was no difference in serum triglyceride, low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) cholesterol concentrations. The distribution of apo E genotypes and alleles was the same in both groups. There were slight differences in allele frequency between the groups, but this was not statistically significant. CONCLUSIONS: The high HDL cholesterol levels observed in our patients were not related to abnormalities in apo E alleles.
 
(34) N-acetyltransferase 2 polymorphisms in patients with Behcet's disease.
 
Tamer L, Tursen U, Eskandari G, Ates NA, Ercan B, Yildirim H, Atik U.
Department of Biochemistry, Mersin University, Turkey. lutamer@yahoo.com Clin Exp Dermatol. 2005 Jan;30(1):56-60.
 
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.
 
LETTERS
 
(35) Mannose-binding lectin polymorphisms in patients with Behcet's disease.
Wang H, Nakamura K, Inoue T, Yanagihori H, Kawakami Y, Hashimoto S, Oyama N, Kaneko F, Fujita T, Nishida T, Mizuki N.
J Dermatol Sci. 2004 Nov;36(2):115-7.
 
(36) Association between interleukin 6 gene polymorphisms and Behcet's disease in Korean people.
 
Chang HK, Jang WC, Park SB, Han SM, Nam YH, Lee SS, Kim JU, Lee HS.
Ann Rheum Dis. 2005 Feb;64(2):339-40.
 
(37) Elevated FVIII and FIX level in a Behcet's disease patient with intracardiac thrombosis and pulmonary arterial aneurysms.
Atalay F, Ernam D, Okten F, Akar N.
Thromb Res. 2005;115(1-2):159-61.

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