ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Pathogenesis of Behçet syndrome

Pathogenesis of Behçet syndrome
Authors:
Ellison L Smith, MD
Yusuf Yazici, MD
Section Editor:
Peter A Merkel, MD, MPH
Deputy Editor:
Philip Seo, MD, MHS
Literature review current through: Jan 2024.
This topic last updated: Aug 14, 2023.

INTRODUCTION — Behçet syndrome, also known as Behçet disease, is an inflammatory disease characterized by recurrent oral aphthous ulcers and numerous potential systemic manifestations. These include genital ulcers; skin lesions; and ocular, neurologic, vascular, articular, and gastrointestinal disease.

Many, but not all, clinical manifestations of Behçet syndrome are believed to be due to vasculitis. Among the systemic vasculitides, Behçet syndrome is remarkable for its ability to involve blood vessels of all sizes (small, medium, and large) on both the arterial and venous sides of the circulation.

The etiology and pathogenesis of Behçet syndrome are discussed in this review. The clinical manifestations, epidemiology, diagnosis, and treatment of this disorder are presented separately. (See "Clinical manifestations and diagnosis of Behçet syndrome" and "Treatment of Behçet syndrome".)

ETIOLOGY AND PATHOGENESIS — The underlying cause of Behçet syndrome is unknown. As with other autoimmune diseases, the disorder may represent aberrant immune activity triggered by exposure to an agent, perhaps infectious, in patients with a genetic predisposition to develop the disease. Both autoimmune and autoinflammatory features have been described. Major disease mechanisms in Behçet syndrome include the following [1]:

●Genetic influences, including association with certain human leukocyte antigens (HLA) as well as some non-HLA genes

●Altered host bacteria or bacteria response

●Altered innate immune function

●Altered populations of hematopoietic cells and associated cytokines

●Presence of immune complexes and autoantibodies

●Vascular endothelial activation and hypercoagulability

●Neutrophil activation

●Epigenetic alterations

Behçet syndrome is more common and often more severe along the ancient silk road, which extends from eastern Asia to the Mediterranean. Further discussion of Behçet syndrome epidemiology is presented separately. (See "Clinical manifestations and diagnosis of Behçet syndrome", section on 'Epidemiology'.)

Proposed triggering agents include viral and bacterial antigens or other environmental sources, such as chemicals or heavy metals. Direct infection of affected tissues has not been observed, although it is still a possible contributor. Unlike some other autoimmune diseases, cigarette smoking has not been shown to be a risk factor for the development of Behçet syndrome in most studies [2-4]. There have been case reports of Behçet-type disease manifestations in patients treated with interleukin (IL) 17 inhibitors including secukinumab [5-8].

Proteomics is the evaluation of the structure and function of proteins in an organism in order to better understand biologic systems. A proteomics study of 98 patients with Behçet syndrome and 31 healthy controls identified 220 differentially expressed proteins and in particular identified altered biologic processes involving complement activation, wound healing, angiogenesis, and leucocyte-mediated immunity, as well as identifying several potential biomarkers for vascular disease [9]. Another study identified 43 differentially expressed proteins, particularly involving toll-like receptor 9 and NF-kappaB signaling pathways, and also identified some potential biomarkers [10].

Genetic — Genetic predisposition to the disease is likely polygenic.

HLA genes — Increased risk of developing Behçet syndrome is associated with the presence of certain human leukocyte antigens, particularly HLA-B51 [11]. A meta-analysis of 4800 cases and 16,289 controls has shown a significant increase in the risk of HLA-B51/B5 carriers to develop Behçet syndrome compared with non-carriers (pooled odds ratio of 5.8) [12]. This relationship was consistent across multiple geographic locations, including Eastern Asia, Middle East/North Africa, Southern Europe, and Northern/Eastern Europe, but insufficient data were available for analysis of North American studies.

In individual studies, higher than baseline prevalences of HLA-B51 has been found in patients with Behçet syndrome in Italy (odds ratio of 5.9), in Germany, and in Middle Eastern and Far Eastern countries along the silk road (63 versus 9 percent in controls), of HLA-B52 (21 versus 9 percent) in Israel, and of HLA-B57 in the United Kingdom [13-19]. HLA-B5101 and, to a lesser extent, HLA-5108 alleles have been most closely linked in patients along the silk road [20]. Other HLA alleles may increase (HLA-B15, HLA-B27, HLA-B57, HLA-A26) or decrease (HLA-B49, HLA-A03) the risk for Behçet syndrome in various populations and in males and females [21-24]. However, the HLA contribution is estimated to be less than 20 percent [25].

There may also be a genetic contribution to disease severity. Presence of a HLA-B51 allele has been associated with worse disease in several studies [13,26-30].

Several possible mechanisms for the genetic linkage to HLA-B51 have been suggested:

●Alterations in the B pocket of the antigen-binding groove conformed by HLA-B51 may determine whether Behçet syndrome associated peptides bind and contribute to Behçet syndrome activity [31,32].

●Cross-reactivity between HLA-B51 and organ-specific antigens may exist [33].

●Linkage disequilibrium with other disease-associated genes has been reported on chromosome 6, including a tumor necrosis factor (TNF) promoter polymorphism in proximity to the HLA B gene locus, to the major histocompatibility complex class I chain-related gene A (MICA), a locus telomeric to the HLA-B site, and other nearby loci [17,19,34-39]. Several meta-analyses have demonstrated that the MICA A6 allele is associated with increased susceptibility to Behçet syndrome [40-42].

●HLA-B51 positivity is associated in patients with Behçet syndrome with HAP10, a low activity variant of endoplasmic reticulum aminopeptidase 1 (ERAP1). Endoplasmic reticulum aminopeptidases trim peptides in the endoplasmic reticulum to facilitate loading of these peptides onto the class I major histocompatibility complex. Cellular studies with HAP10 have demonstrated the production of longer peptides, with resultant changes to the peptidome, which may act to stimulate immune activity [43-45]. A study of ERAP1 and ERAP2 knockout transfectant HLAB51:01 cells demonstrated alterations in the HLA-B51 peptidome [46]. Other polymorphisms of the ERAP1 gene have also been described in association with Behçet syndrome [47-49].

Though most cases of Behçet syndrome are sporadic, families with multiple affected members, known as familial clustering, have been reported, and having a first-degree relative with Behçet syndrome does increase risk for the disease [50-52]. HLA-B51 rates are higher in familial than in sporadic cases. Affected children of patients with Behçet syndrome may have an earlier age of onset, a property termed genetic anticipation [53]; this characteristic has been linked, in many genetic disorders, to an increased number of nucleotide repeats within each successive generation. In Behçet syndrome, for example, a triplet repeat microsatellite polymorphism of (GCT)n found within a major histocompatibility complex (MHC) Class I related gene was found to be associated with the disorder in one study of 77 affected patients in Japan [54].

Non-HLA genes — Non-HLA genes also play a role in determining susceptibility to disease. Genome-wide screening of affected families with more than one affected member has identified additional, non-HLA regions of potential interest [55]. Examples include associations between Behçet syndrome and:

●Polymorphisms of the intercellular adhesion molecule (ICAM) 1 gene, the endothelial nitric oxide synthase gene, TNF genes, the vascular endothelial growth factor (VEGF) gene, manganese superoxide dismutase gene, cytochrome P450 gene, the interleukin (IL) 10 gene, the IL-23 receptor gene, and many other genes [17,26,56-83]

●Missense mutations of the familial Mediterranean fever (MEFV) gene, encoding the protein pyrin that is expressed of the surface of neutrophils [84-87]

Altered bacteria and bacteria response — Altered host bacteria or response to bacteria may play a role in the pathogenesis of Behçet syndrome.

Molecular mimicry may play a role, and studies suggest a possible pathogenic role of certain bacterial antigens that have cross-reactivity with human peptides. The cross-reactive self-antigens may include the heat shock proteins, a family of 60 to 90 kDa proteins produced by many cells in response to stress. These proteins have significant sequence homology between humans and bacteria. T cells and/or antibodies may recognize epitopes shared by both host and infectious organism heat shock proteins, thereby initiating and/or perpetuating Behçet syndrome.

Elevated levels of antibodies against epitopes of mycobacterial heat shock protein, some of which have significant homology to human heat shock proteins, have been observed among patients with Behçet syndrome. One study evaluated the antigenicity of 47 synthetic peptides (each 15 amino acids in length) derived from the sequence of the mycobacterial 65 kD heat shock protein [88]. Increased levels of IgG and IgA antibodies against three of these synthetic peptides was observed, two of which had significant homology to two areas of a human mitochondrial 60 kD heat shock protein. Exacerbations of ocular disease coincided with enhanced levels of these autoimmune antibodies [89]. Furthermore, these peptides can induce uveitis when injected into Lewis rats.

A response to mycobacterial heat shock proteins by gamma-delta T cells may play a role in the pathogenesis of Behçet syndrome. One study found that 25 of 33 patients with Behçet syndrome showed significant increases in gamma-delta T cells in response to exposure to mycobacterial heat shock proteins; by comparison, only 2 of 55 control individuals exhibited such an increase [90].

Specific bacteria, particularly streptococci, may also be important contributors to the immune response among patients with Behçet syndrome:

●Skin testing to streptococcal antigens often induces hypersensitivity reactions and sometimes results in systemic exacerbations of Behçet syndrome [91].

●A study of 106 patients with Behçet syndrome from Turkey showed a higher rate of Streptococcal mutans salivary colonization compared with controls, and colonization was associated with low levels of serum mannose-binding lectin compared with controls [92]. Another study of 54 patients with Behçet syndrome compared with 25 healthy controls and 8 patients with recurrent aphthous stomatitis found variations in oral mucosal and salivary microbial communities between the groups [93].

●Indirect evidence for cross-reactivity is suggested by the finding that patients with Behçet syndrome are more likely than normals to have significant antibody titers to Streptococcus sanguis [94,95]; this organism, particularly some with uncommon serotypes, is found at increased levels in the oral cavities of patients with the disorder. Circulating antibodies have been detected to streptococcal heat shock proteins [96]. Patients with Behçet syndrome demonstrate increased reactivity to lipoteichoic acid, a streptococcal antigen.

●Streptococcal antigens have been shown to increase IL-6 and interferon gamma secretion from the T lymphocytes of patients with Behçet syndrome and to upregulate their gamma delta T cells, which secrete IL-6, IL-8, and TNF-alpha [97-99].

●The importance of streptococcal infection was indirectly assessed by a prospective study which compared the efficacy of benzathine G penicillin plus colchicine in 94 patients with Behçet syndrome with that of colchicine alone in 60 patients [100]. Compared with colchicine alone, penicillin plus colchicine resulted in a significantly greater degree of improvement in mucocutaneous lesions.

●Studies have reported alterations in the microbiome in patients with Behçet syndrome [101-105]. An evaluation of the fecal microbiota of 22 patients with Behçet syndrome compared with 16 healthy cohabitating controls found significant differences in the microbiome signature of the patients with Behçet syndrome [101]. A study of 32 patients with active Behçet syndrome compared with 74 healthy controls found significant gut microbiome changes [102].

●Host response to Helicobacter pylori infection may play a role. This was illustrated in a study that found similar rates of serum H. pylori IgG levels between patients and controls but found a higher rate of H. pylori cytotoxin-associated gene-A antibodies in Behçet patients [106]. These antibodies have been postulated to be mediators of vascular damage in other conditions via cross-reaction with endothelin antigens. Helicobacter eradication in these patients decreased Behçet syndrome activity. A meta-analysis of six studies found a 1.39 times greater rate of H. pylori in patients with Behçet syndrome and improved mucocutaneous symptoms in treated patients [107].

Herpes simplex virus (HSV) has been investigated as a possible infectious trigger in Behçet syndrome. HSV type-1 genome has been isolated from the nuclei of lymphocytes in patients with Behçet syndrome, and immune complexes containing HSV-1 antigen have been reported. Other studies have not shown an association between HSV and Behçet syndrome, including polymerase chain reaction (PCR) testing of saliva and a randomized trial of acyclovir treatment that was not effective [20].

Parvovirus B19 was the subject of an investigation that used a semiquantitative technique to assess the amount of parvovirus B19 deoxyribonucleic acid (DNA) present in 40 patients and controls [18]. There was more B19 DNA present in the nonulcerative skin lesions of patients with Behçet syndrome than in the ulcerative skin lesions or in control patients [18].

Altered innate immune function — Mannose-binding lectin (MBL) is part of the innate immune system and activates the complement cascade after binding to carbohydrate structures on microorganisms. Low serum levels of MBL and MBL gene mutations have been observed in Behçet syndrome as well as in other autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. Very low levels of MBL correlated with increased disease severity. Since MBL deficiencies are associated with increased risk of some infections, and since infectious disease has been associated with Behçet syndrome, MBL deficiencies may lead to impaired immune response against microorganisms and subsequent immune activation in Behçet syndrome [92,108].

Toll-like receptors are receptors on lymphocytes and some solid tissue cells which are directed against pathogenic microbes and which are a part of the innate immune system. Altered patterns of toll-like receptors have been described in Behçet syndrome [109-111]. Monocytes of patients with Behçet syndrome with active disease demonstrate increased activity of toll-like receptors 2 and 4, and, in one study, this was inversely correlated with 25-OH vitamin D levels [112,113]. Intestinal lesions in patients with Behçet syndrome expressed increased toll-like receptor 2 and 4 messenger ribonucleic acid (RNA) compared with healthy controls [114]. Messenger RNA of toll-like receptor 4 but not toll-like receptor 2 in peripheral blood mononuclear cells was elevated in a study of 47 active patients with active Behçet syndrome compared with controls, and methylation rate of toll-like receptor 4 but not toll-like receptor 2 was lower [115].

Cellular immunity and cytokines — In Behçet syndrome, there are alterations in the numbers of T cell subpopulations and evidence of cellular activation [1]. Autoreactive T cells appear to play a critical role in the pathogenesis of Behçet syndrome, and a trial of lymphocyte depletion with an anti-CD52 monoclonal antibody CAMPATH-1H appeared to reduce disease activity in 18 patients with Behçet syndrome [116]. As noted above, heat shock proteins or streptococcal antigens may play a role in stimulating oligoclonal T cell expansion [90]. Adenosine deaminase, an enzyme involved in lymphocyte proliferation, maturation, and differentiation, is activated in Behçet syndrome, particularly during disease exacerbations [117-119].

A T helper (Th) 1 predominant response has been observed in many studies of Behçet syndrome, but some studies have shown evidence for a Th2 response. In reality there may be a mix of Th1 and Th2 activity in Behçet syndrome [20,120-122]. Others have suggested that Th1 and Th17 may be involved in the disease's active phases, while Th2 may have an impact on disease course and severity [123].

Th1 lymphocytes, which produce cytokines IL-2, IL-6, IL-8, IL-12, IL-18, TNF-alpha, and interferon gamma, are increased in many studies in patients with Behçet syndrome [20,120,124-130]. Some studies have shown that serum levels of IL-12, soluble TNF-alpha receptors, and IL-8 may correlate with disease activity [131-135], while others have noted increased production of such cytokines from peripheral blood mononuclear cells of patients with Behçet syndrome regardless of disease activity [136]. Twenty-four patients with active ocular Behçet syndrome demonstrated elevated levels of IgA, C3, C4, IL-6, IL-8, and TNF-alpha compared with controls; a study of 43 patients with active versus inactive Behçet posterior uveitis showed activity correlated with increased serum levels of IL-6, IL-8, TNF-alpha, VEGF, and malondialdehyde (MDA) [128,137]. Elevated cerebrospinal fluid IL-6 levels have been observed in patients with Behçet syndrome with active neurologic disease and may be a marker of disease activity and persistence [138]. Increased IL-8, monocyte chemoattractant protein 1, interferon-gamma, and IL-12 messenger RNA were observed in biopsy specimens from 20 patients with active Behçet syndrome compared with healthy controls; no increase in IL-4 and IL-13 was observed in this study [127]. Increased expression of IL-23 messenger RNA has been described in Behçet erythema nodosum-like lesions [139]. It has been suggested that plasmacytoid dendritic cells and type I interferons play a role in polarizing the immune activity toward Th1 activity [140].

Th2 phenotype associated changes have also been observed. Studies have shown peripheral blood mononuclear cells from patients with Behçet syndrome produce increased amounts of IL-4, IL-10, and IL-13 [50,121,141]. Analysis of T cell subpopulations in patients with Behçet syndrome has shown relative increases in the CD8:CD4 ratio, with relative reductions in percentages of suppressor T cells, particularly in patients with active disease. Levels of serum soluble CD30, which is released from CD4+ Th2 cells and which is a marker of TH2 activity, is elevated in patients with Behçet syndrome with active disease.

T helper 17 (Th17) cells, which produce IL-17 and which are distinct from Th1 and Th2 lymphocytes, have been found to be increased and activated in patients with Behçet syndrome and may explain some of the apparently conflicting findings regarding Th1 and Th2 activity in this disorder [142-150]. A study of serum, bronchoalveolar lavage, and cerebrospinal fluid in 95 patients with active Behçet manifestations compared with 55 controls found elevated IL-26 levels, which have been found to promote the generation of TH17 cytokines [150].

Changes in T cell subsets have been identified in a number of studies, including increased numbers of T cells carrying the activation markers CD29 and CD69 [20,151-154]. Patients with Behçet syndrome have relatively high levels of gamma-delta T cells in the circulation and at inflammatory sites [88,90,151,155,156]; such cells are also present in peripheral blood in higher numbers during active versus quiescent Behçet syndrome (9 versus 2 percent, respectively) [155]. Gamma-delta T cell activation may be polyclonal; the response may be to a variety of antigenic stimuli [157]. Soluble CD28, which may play a role in T cell regulation, is elevated in the serum of patients with active Behçet syndrome, levels may correlate with disease activity, and polymorphisms of CD28 and CTLA-4 (which binds CD28) have been associated with Behçet syndrome [57,74,158]. HLA-B51 restricted CD8+ cytotoxic T lymphocytes autoreactive to MHC class I chain related gene A (MICA), a protein preferentially expressed on epithelial and endothelial cells in a stress-dependent manner, have been described in patients with Behçet syndrome [159].

Flow cytometric analysis of immune cells from the aqueous humor of patients with active Behçet uveitis showed elevated levels of CD8+ T cells and CD3+CD56+ NK T cells [160]. Other studies have also shown T lymphocyte infiltration into the eye in Behçet syndrome by CD4+ Th1 cells [161-163]. Th1 cytokines are elevated in the aqueous humor and serum of patients with Behçet uveitis [164,165]. Ocular fluid from patients with Behçet syndrome with active uveitis demonstrated inflammatory cytokines, including interferon, IL-2, TNF, IL-6, and IL-17, and activated ocular CD4+ T cells produced large amounts of TNF and IL-17, which were blocked in the presence of the TNF inhibitor infliximab [142].

Synovial fluid in Behçet syndrome demonstrates lower levels of inflammatory cytokines than that in patients with rheumatoid arthritis, a more erosive disease. One study showed elevated levels of IL-8 and soluble IL-2 receptor but relatively lower levels of TNF-alpha, IL-1 beta, IL-1 receptor antagonist, and transforming growth factor (TGF) beta than the synovial fluid from patients with rheumatoid arthritis. Another study showed elevated levels of IL-1 beta but lower levels of IL-18, TNF-alpha, and matrix metalloproteinase (MMP)-3 compared with rheumatoid arthritis [166]. Bronchoalveolar lavage from patients with Behçet pulmonary disease shows higher levels of IL-18 and interferon-gamma before and after LPS stimulation than in controls.

The inflammatory response in Behçet syndrome may be accentuated by refractoriness of activated T cells and neutrophils to apoptosis. T cells from patients with Behçet syndrome demonstrate resistance to spontaneous and CD95-induced apoptosis, and this may be mediated by NF-kappaB via regulation of apoptosis-related factors and death receptors [167]. Circulating neutrophils are resistant to apoptosis in the remission stage of Behçet uveitis [168].

Neopterin is secreted by monocytes and macrophages as a result of interferon-gamma secretion by activated T lymphocytes and may, therefore, be an indicator of cellular immune activation. Elevated serum and urine neopterin levels have been observed in patients with Behçet syndrome compared with controls [169,170].

Alterations in cellular signaling pathways in Behçet syndrome has been described. One study showed activation of the JAK1/STAT3 pathway in CD14(+) monocytes and CD4(+) T cells in nine patients with Behçet syndrome compared with nine healthy controls [171].

Autoantibody and immune complex formation — In addition to cellular immune activation, there is also evidence of humoral immune activation in Behçet syndrome. Increased numbers of circulating B lymphocytes have been observed; this appears to be antigen driven, not simply a polyclonal increase [20,172,173].

Autoantibodies appear to play a role in the pathogenesis of Behçet syndrome. Autoantibodies have been described against a number of targets including oral mucosal antigens, endothelial cells, T cell costimulatory molecule CTLA-4, killer immunoglobulin-like receptors, oxidized low-density lipoprotein, and kinectin [174-179]. Anti-Saccharomyces cerevisiae antibodies (ASCA) have been observed in patients with Behçet syndrome [180,181].

Autoimmune activity against retinal self-antigens appears to be important in the pathogenesis of Behçet uveitis [182]. Retinal-S antigen is localized to the photoreceptor of the retina, and has been shown to be a potent uveitic autoantigen [183]. Peripheral blood S-antigen responsive lymphocytes are elevated during exacerbations of ocular inflammation in patients with Behçet syndrome [184,185]. Other suspected Behçet syndrome retinal autoantigens are alpha tropomyosin, selenium binding protein, and interphotoreceptor retinoid binding protein [186-188]. Alpha-tropomyosin or kinectin is a membrane protein predominantly confined to the endoplasmic reticulum [186,189,190]. Immunization of rodents with alpha-tropomyosin can cause inflammation of the uveal tract and the skin, reminiscent of lesions seen in Behçet syndrome. Antikinectin antibodies are present at modestly higher rates and titers in patients with Behçet syndrome than in patients with other autoimmune connective tissue diseases [179].

Endothelial activation and altered coagulation — Endothelial dysfunction is a characteristic finding in Behçet syndrome [191]. Endothelium-dependent flow-mediated dilation is reduced [192,193]. Endothelial activation in affected blood vessels is a mediator of vascular inflammation as well as thrombosis in Behçet syndrome [174,175,194,195].

A number of molecules have been identified that interact to mediate endothelial dysfunction in Behçet syndrome. Nitric oxide (NO) is a highly reactive molecule associated with inflammatory activity and endothelial function. A number of lines of research have documented the role of NO in endothelial activation in Behçet syndrome, including increased serum, erythrocyte, synovial, and aqueous humor NO concentrations in Behçet syndrome, and elevated levels of NO metabolites compared with controls [175,196-200]. Polymorphisms of endothelial NO synthase genes and related genes have been associated with susceptibility to Behçet syndrome in some populations [56,58,60,64]. Elevated levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase, have been observed in Behçet syndrome [201].

Increased oxidative stress has been observed in patients with Behçet syndrome. Findings have included increased plasma MDA, reduced glutathione:oxidized glutathione ratio, reduced superoxide dismutase, and elevated catalase [192,202].

Elevated mean plasma homocysteine levels have been observed in Behçet syndrome, and this has been found to be associated with NO concentrations and decreased flow-mediated vessel dilatation [203,204]. A number of studies have shown an association between Behçet syndrome and elevated homocysteine levels; hyperhomocysteinemia may be an acquired and potentially reversible risk factor for Behçet syndrome, may be a clinical marker of disease activity, and may be associated with thrombosis [20,169,205-207]. Increased rates of vitamin B12 and folate deficiency in patients with Behçet syndrome may contribute to hyperhomocysteinemia [208].

Vascular endothelial growth factor levels are higher in patients with Behçet syndrome and have been associated with increased disease activity and NO concentrations [73,209-211]. Cerebrospinal fluid VEGF levels were higher in a group of patients with Behçet syndrome with neurologic involvement compared with patients with noninflammatory neurologic diseases [212]. Polymorphisms of the VEGF gene are associated with Behçet syndrome, but not in all populations [56,58,59,213].

IgM-antiendothelial antibodies were found to be reactive with alpha enolase in some Korean patients with Behçet syndrome [214]. A follow-up study demonstrated IgM-antiendothelial antibodies in patients with Behçet syndrome (56 percent), systemic sclerosis (71.4 percent), rheumatoid arthritis (65 percent), Takayasu (50 percent), dermatomyositis (52.9 percent), and mixed connective tissue disease (45.5 percent); these antibodies were associated with the presence of vascular lesions in patients with Behçet syndrome [215]. Leptin is expressed by endothelial cells, and increased levels in Behçet syndrome may correlate with disease activity [216]. Endothelial cell activation and a generalized hypercoagulable state were observed in 24 patients with ocular Behçet syndrome characterized by increased mean levels of factor VIII, factor XI, von Willebrand factor antigen and ristocetin, antithrombin III, and fibrinogen [217].

A generalized hypercoagulable state appears to exist in many patients with Behçet syndrome. Thrombin formation is increased, and fibrinolysis is decreased [20,218,219]. Lower activated protein C (APC) and soluble thrombomodulin concentrations in the plasma of patients with Behçet syndrome have been observed. Thrombomodulin, present on the endothelial cell surface, binds thrombin, and the substrate specificity of thrombin thus bound is changed so that it preferentially activates protein C rather than cleaving fibrinogen. The APC generated at the endothelial surface is an important inhibitor of coagulation. (See "Overview of hemostasis".)

The findings of significantly decreased mean concentrations of plasma APC among 39 Spanish patients with Behçet syndrome versus healthy controls, and of lower levels of APC among patients with Behçet syndrome who had a prior thromboembolic episode versus those who had not, suggest that an acquired deficiency of APC in Behçet syndrome may contribute to the risk of thrombosis [220]. Platelet activity is increased in patients with Behçet syndrome [221]. Studies have shown decreased erythrocyte deformability in Behçet syndrome [222,223]. Tissue-type plasminogen activator levels are lower in patients with deep venous thrombosis who have Behçet syndrome than in those who do not have Behçet syndrome; this suggests a defect in fibrinolysis in Behçet syndrome [224].

A study of 98 patients with Behçet syndrome and 70 controls demonstrated in the patients with Behçet syndrome impaired thrombin-catalyzed fibrin formation and fibrin susceptibility to plasmin-induced lysis, associated with increased plasma oxidative stress markers, and increased neutrophil NADPH oxidase activity and reactive oxygen species production, which supports the role of neutrophil activation in thrombus formation in Behçet syndrome [225].

Thrombophilic factors such as factor V Leiden and prothrombin G20210A gene have not been linked to Behçet syndrome, although patients with Behçet syndrome with coexisting thrombophilic factors may be at higher risk for thrombosis [226,227]. Levels of the fibrinolytic inhibitors thrombin-activatable fibrinolysis inhibitor (TAFI) and plasminogen activator inhibitor-1 (PAI-1) were higher in patients with Behçet syndrome than in controls, particularly in those patients with thrombosis [228].

However, the majority of available evidence suggests that the pathogenesis of thrombosis in Behçet syndrome is not due to a hypercoagulable state as much as it is due to vascular damage induced by inflammation or intrinsic endothelial dysfunction that, by itself, serves as a source of thrombogenic stimuli [229-232].

Patients with Behçet syndrome have increased intima-media thickness and decreased arterial distensibility compared with controls [233].

Neutrophil activation — Polymorphonuclear leukocytes (PMNs) are activated in Behçet syndrome.

In Behçet syndrome, PMN motility is increased. Increased circulating levels of cytokines such as IL-8 and TNF-alpha lead to activation of PMNs and the endothelial surface [234,235]. Cell surface markers indicative of activation, such as CD64, are increased in patients with active disease to levels similar to those of patients with sepsis [236]. PMNs exhibit increased motility and enhanced adhesion to endothelial cells in vitro, a property due, in part, to increased expression of cell surface receptors including CD11a, CD18, and ICAM-1 [237]. Neutrophil binding to the endothelium is also facilitated by upregulated surface expression of adhesion molecules such as E-selectin. Increased E-selectin on the luminal surface favors neutrophil adhesion and facilitates neutrophil migration into the wall of the affected vessel and beyond [194].

Measurements of serum-soluble levels of this activity have been observed. Serum-soluble ICAM-1 is increased in patients with Behçet syndrome, and the concentration may correlate with disease activity [118,238]. The serum of patients with active Behçet syndrome may promote increased E-selectin presentation [121]. Some of this may be due to anti-endothelial antibodies [194]. Serum-soluble levels of selectin have been shown to be elevated in patients with active untreated disease but not if it is treated or inactive [239,240]. A study of patients with Behçet retinal vasculitis showed elevated levels of soluble E-selectin, s-ICAM-1, and Interferon-beta. In vitro studies showed that these were produced by activated retinal vascular endothelial cells and that this could be inhibited by pretreatment with anti-Toll-like receptor 3 [241].

The protein actin is required for PMN mobility. The presence of high levels of a truncated actin with an N-terminus of Met-44 has been observed in neutrophils from patients with Behçet syndrome; PMN-elastase responsible for this cleavage has been isolated. Resulting altered PMN activity has been described [242,243].

Increased amount of reactive oxygen species suggest neutrophil mediated immunity [20,244,245]. Endogenous free radical scavenging enzymes appear to be reduced in Behçet syndrome, creating an imbalance in the oxidant antioxidant equilibrium [20,117].

Serum granulocyte colony-stimulating factor (G-CSF) levels and neutrophil apoptosis are increased in active patients with Behçet syndrome compared with controls [246].

Markers of neutrophil activity have been proposed as possible indicators of disease activity and severity. These include polymorphonuclear elastase, plasma myeloperoxidase, and advanced oxidation protein products [118,247,248].

Neutrophil extracellular traps (NETs) are networks of extracellular fibers generated by neutrophils and that bind pathogens. A series of studies has demonstrated that circulating neutrophils from patients with Behçet syndrome versus controls more readily release NETs, and this was inhibited by colchicine and dexamethasone. The study also showed that serum from patients with Behçet syndrome stimulated neutrophils from healthy volunteers to release more NETs, endothelial cells from healthy volunteers were inhibited when cultured with NETs from patients with Behçet syndrome, and NETs were identified around blood vessels in specimens from patients with Behçet syndrome and vasculitis [249]. Another study found that circulating NETs and neutrophil-derived NETs were higher in Behçet syndrome patients, and the NETs promoted macrophage activation and facilitated T cell differentiation [250].

Matrix metalloproteinases play a role in leucocyte invasion of the central nervous system. Elevated levels of matrix metalloprotein-9 have been described in patients with Behçet syndrome compared with controls, and levels correlated with CSF neutrophil and mononuclear cells in a study of patients with Behçet syndrome with neurologic disease [251].

Behçet arthritis is characterized by synovial inflammation with significant neutrophilic greater than lymphocytic inflammation [252].

Monocytes from patients with Behçet syndrome have enhanced activity, with increased differentiation and expression of adhesion molecules and cytokines, which, in turn, leads to neutrophil activation [20,253,254].

Epigenetic alterations — Epigenetic changes may contribute to the pathophysiology of Behçet syndrome [255]. Epigenetics is the study of phenotypic cellular changes that occur due to changes in how genes are read or utilized by the cell and not due to changes in the gene sequences themselves.

Alterations of DNA methylation of immune cells in Behçet syndrome has been described. DNA methylation, addition of a methyl group to a carbon in cytosine rings within CpG dinucleotides, results in gene transcription repression. Hypomethylation allows ongoing transcription activity, and alterations in DNA methylation have been described in a number of immune diseases. A study of DNA methylation of monocytes and CD4+ T cells from 16 patients with Behçet syndrome compared with 12 healthy controls showed altered methylation patterns in genes involved in cytoskeletal dynamics, and these alterations were changed by disease treatment [256]. Other studies have also described alterations in DNA methylation in patients with Behçet syndrome [257].

PATHOLOGY — Histologic examination of involved tissue in patients with Behçet syndrome frequently reveals a vasculitis, although this finding may not be demonstrated in all lesions [1,258]. The classic Behçet lesion is necrotizing leukocytoclastic obliterative perivasculitis and venous thrombosis with lymphocytic infiltration of capillaries, veins, and arteries of all sizes. Cellular infiltration is often in a perivascular distribution; neutrophils and CD4+ T lymphocytes are present around the vasa vasorum and perivascular area. When a frank leukocytoclastic vasculitis is present, there may be endothelial swelling, extravasation of erythrocytes, and fibrinoid necrosis of blood vessel walls. Thrombosis is often present [20].

Mucocutaneous lesions demonstrate lymphocytic infiltration, immunoglobulin and complement deposition, and liquefaction-degeneration at the dermal-epidermal junction in association with necrosis and ulcer formation [259,260].

Neutrophilic and mononuclear infiltrates are frequently observed in spontaneous acute lesions and following testing for pathergy [1,261]. Histopathologic evaluation of 23 positive pathergy responses revealed mixed type inflammatory cell infiltrate in 39.1 percent, lobular panniculitis without vasculitis in 8.7 percent, neutrophilic infiltrate in 8.7 percent, and lymphocytic infiltration in 21.7 percent, with endothelial swelling and thickening in 17.3 percent, erythrocyte extravasation in 26 percent, perivascular cell infiltrate in 13 percent, lymphocytic vascular reaction in 8.6 percent, lymphocytic vasculitis in 13 percent, and leukocytoclastic vasculitis in 21.7 percent [262].

Papulopustular lesions may show leukocytoclastic vasculitis with IgM, IgG, C3, and fibrin deposits, consistent with an immune complex vasculitis [263,264]. Pustular skin lesions are often not sterile and may contain Staphylococcus aureus and Prevotella species [265].

Erythema nodosum type lesions in Behçet syndrome demonstrate lobular or mixed lobular and septal panniculitis; demonstrate variable numbers of neutrophils, lymphocytes, and histiocytes; and often show leukocytoclastic vasculitis.

Ocular Behçet lesions may show leukocyte infiltration around blood vessels, occlusive retinal perivasculitis, and thrombosis. Nongranulomatous panuveitis is characteristic. During active disease, neutrophils may be present in the anterior chamber of the eye, as well as the corneal epithelium, iris, ciliary body, and choroids [20].

Central nervous system lesions in Behçet syndrome demonstrate perivascular cuffing of T lymphocytes and monocytes, as well as apoptosis of affected neurons [266]. Involved areas include the spinal cord, brainstem (including the pons, medulla oblongata, and midbrain), cerebellum, basal ganglia, thalamus, internal capsule, and periventricular white matter.

Although renal involvement is infrequent and usually mild, when present, renal histology may show mesangial proliferation, proliferative glomerulonephritis, crescent formation, and deposits of immunoglobulin, complement, and immune complex in the glomeruli [267].

Behçet arthritis is characterized by synovial inflammation with significant neutrophilic greater than lymphocytic inflammation [252].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Behçet syndrome" and "Society guideline links: Vasculitis".)

SUMMARY

●Pathogenesis – Many, but not all, clinical manifestations of Behçet syndrome are believed to be due to vasculitis. Among the systemic vasculitides, Behçet syndrome is remarkable for its ability to involve blood vessels of all sizes (small, medium, and large) on both the arterial and venous sides of the circulation. (See 'Etiology and pathogenesis' above.)

●Pathology – Histologic examination of involved tissue in patients with Behçet syndrome frequently reveals a vasculitis, although this finding may not be demonstrated in all lesions. The classic Behçet lesion is necrotizing leukocytoclastic obliterative perivasculitis and venous thrombosis with lymphocytic infiltration of capillaries, veins, and arteries of all sizes. Cellular infiltration is often in a perivascular distribution; neutrophils and CD4+ T lymphocytes are present around the vasa vasorum and perivascular area. Other histologic findings may include panniculitis in erythema nodosum-like lesions and neutrophilic and mononuclear infiltrates in spontaneous acute lesions and following testing for pathergy. (See 'Pathology' above.)

●Etiology – The underlying cause of Behçet syndrome is unknown. As with autoimmune diseases, the disorder may represent aberrant immune activity triggered by exposure to an agent, perhaps infectious, in patients with a genetic predisposition to develop the disease. (See 'Etiology and pathogenesis' above.)

●Genetics – Genetic predisposition to the disease is likely polygenic. Genetic influences include association with certain human leukocyte antigens (HLA), including HLA-B51, but both HLA and non-HLA genes may play a role. (See 'Genetic' above and 'HLA genes' above and 'Non-HLA genes' above.)

●Bacterial antigens – Studies suggest a possible pathogenic role of certain bacterial antigens that have cross-reactivity with human peptides. Different studies have implicated various antigens and organisms, including heat shock proteins, streptococcal antigens, Helicobacter pylori, Herpes simplex virus, and parvovirus B19. (See 'Altered bacteria and bacteria response' above.)

●Innate immunity – Altered innate immune function has been suggested by some studies. These include investigations suggesting deficiencies in mannose-binding lectin and alterations in the expression of toll-like receptors. (See 'Altered bacteria and bacteria response' above and 'Altered innate immune function' above.)

●T-cell autoreactivity – There are alterations in the numbers of T cell subpopulations and evidence of cellular activation. Autoreactive T cells appear to play a critical role in the pathogenesis of Behçet syndrome. A T helper (Th) 1 predominant response has been observed in many studies of Behçet syndrome, but some studies have shown evidence for a Th2 response. There may be a mix of Th1 and Th2 activity in Behçet syndrome and increased activity of Th17 cells. (See 'Cellular immunity and cytokines' above.)

●Humoral immunity – In addition to cellular immune activation, there is also evidence of humoral immune activation in Behçet syndrome, and autoantibodies have been described against a number of targets. Immune complexes may also play a role. (See 'Autoantibody and immune complex formation' above.)

●Endothelial dysfunction – Endothelial dysfunction is a characteristic finding in Behçet syndrome. Endothelium-dependent flow-mediated dilation is reduced, and endothelial activation in affected blood vessels is a mediator of vascular inflammation as well as thrombosis in Behçet syndrome. (See 'Endothelial activation and altered coagulation' above.)

●Polymorphonuclear leukocytes – Polymorphonuclear leukocytes (PMNs) are activated in Behçet syndrome; PMNs exhibit increased motility and enhanced adhesion to endothelial cells in vitro. (See 'Endothelial activation and altered coagulation' above and 'Neutrophil activation' above.)

●Epigenetics – Epigenetic changes may contribute to the pathophysiology of Behçet syndrome. Alterations of DNA methylation of immune cells in Behçet syndrome has been described. (See 'Epigenetic alterations' above.)

  1. Direskeneli H. Behçet's disease: infectious aetiology, new autoantigens, and HLA-B51. Ann Rheum Dis 2001; 60:996.
  2. Bilgin AB, Turkoglu EB, Ilhan HD, et al. Is Smoking a Risk Factor in Ocular Behçet Disease? Ocul Immunol Inflamm 2015; 23:283.
  3. Malek Mahdavi A, Khabbazi A, Yaaghoobian B, et al. Cigarette smoking and risk of Behcet's disease: a propensity score matching analysis. Mod Rheumatol 2019; 29:633.
  4. Lee YB, Lee JH, Lee SY, et al. Association between smoking and Behçet's disease: a nationwide population-based study in Korea. J Eur Acad Dermatol Venereol 2019; 33:2114.
  5. Dincses E, Yurttas B, Esatoglu SN, et al. Secukinumab induced Behçet's syndrome: a report of two cases. Oxf Med Case Reports 2019; 2019:omz041.
  6. Barrado-Solís N, Rodrigo-Nicolás B, De la Morena-Barrio I, et al. Report of two cases of Behçet's disease developed during treatment with secukinumab. J Eur Acad Dermatol Venereol 2020; 34:e587.
  7. Calleja Algarra A, Aragón Miguel R, Andrés Lencina JJ, et al. Behçet's-like disease during secukinumab treatment: new paradoxical reaction? J Dtsch Dermatol Ges 2021; 19:116.
  8. Ward M, Maliyar K, Gooderham M. A case report of recalcitrant aphthous ulcers in two patients treated with interleukin-17 inhibitors. SAGE Open Med Case Rep 2021; 9:2050313X211034925.
  9. Cheng L, Wang D, Wang Z, et al. Proteomics Landscape Mapping of Organ-Resolved Behçet's Disease Using In-Depth Plasma Proteomics for Identifying Hyaluronic Binding Protein 2 Expression Associated With Vascular Involvement. Arthritis Rheumatol 2023; 75:424.
  10. Liu H, Zhang P, Li F, et al. Identification of the immune-related biomarkers in Behcet's disease by plasma proteomic analysis. Arthritis Res Ther 2023; 25:92.
  11. Takeno M. The association of Behçet's syndrome with HLA-B51 as understood in 2021. Curr Opin Rheumatol 2022; 34:4.
  12. de Menthon M, Lavalley MP, Maldini C, et al. HLA-B51/B5 and the risk of Behçet's disease: a systematic review and meta-analysis of case-control genetic association studies. Arthritis Rheum 2009; 61:1287.
  13. Sakane T, Takeno M, Suzuki N, Inaba G. Behçet's disease. N Engl J Med 1999; 341:1284.
  14. Arber N, Klein T, Meiner Z, et al. Close association of HLA-B51 and B52 in Israeli patients with Behçet's syndrome. Ann Rheum Dis 1991; 50:351.
  15. Salvarani C, Boiardi L, Mantovani V, et al. Association of MICA alleles and HLA-B51 in Italian patients with Behçet's disease. J Rheumatol 2001; 28:1867.
  16. Kötter I, Günaydin I, Stübiger N, et al. Comparative analysis of the association of HLA-B*51 suballeles with Behçet's disease in patients of German and Turkish origin. Tissue Antigens 2001; 58:166.
  17. Ahmad T, Wallace GR, James T, et al. Mapping the HLA association in Behçet's disease: a role for tumor necrosis factor polymorphisms? Arthritis Rheum 2003; 48:807.
  18. Baskan EB, Yilmaz E, Saricaoglu H, et al. Detection of parvovirus B19 DNA in the lesional skin of patients with Behçet's disease. Clin Exp Dermatol 2007; 32:186.
  19. Mizuki N, Meguro A, Tohnai I, et al. Association of Major Histocompatibility Complex Class I Chain-Related Gene A and HLA-B Alleles with Behçet's Disease in Turkey. Jpn J Ophthalmol 2007; 51:431.
  20. Evereklioglu C. Current concepts in the etiology and treatment of Behçet disease. Surv Ophthalmol 2005; 50:297.
  21. Bennani N, Atouf O, Benseffaj N, et al. [HLA polymorphism and Behçet's disease in Moroccan population]. Pathol Biol (Paris) 2009; 57:403.
  22. Kamiishi T, Itoh Y, Meguro A, et al. [Four-digit allele genotyping of HLA-A and HLA-B genes in Japanese patients with Behçet's disease (BD) by a PCR-SSOP-luminex method and stratification analysis according to each major symptom of BD]. Nippon Ganka Gakkai Zasshi 2008; 112:451.
  23. Meguro A, Inoko H, Ota M, et al. Genetics of Behçet disease inside and outside the MHC. Ann Rheum Dis 2010; 69:747.
  24. Takeuchi M, Kastner DL, Remmers EF. The immunogenetics of Behçet's disease: A comprehensive review. J Autoimmun 2015; 64:137.
  25. Gül A, Hajeer AH, Worthington J, et al. Evidence for linkage of the HLA-B locus in Behçet's disease, obtained using the transmission disequilibrium test. Arthritis Rheum 2001; 44:239.
  26. Sakane T, Takeno M. Novel approaches to Behçet's disease. Expert Opin Investig Drugs 2000; 9:1993.
  27. Ermakova NA, Alekberova ZS, Prokaeva TB, Poljanskaja IB. Frequency of HLA in patients with Behçet's disease and association with occlusive retinal vasculitis. Adv Exp Med Biol 2003; 528:231.
  28. Choukri F, Chakib A, Himmich H, et al. HLA-B phenotype modifies the course of Behçet's disease in Moroccan patients. Tissue Antigens 2003; 61:92.
  29. Gül A, Uyar FA, Inanc M, et al. Lack of association of HLA-B*51 with a severe disease course in Behçet's disease. Rheumatology (Oxford) 2001; 40:668.
  30. Pamukcu M, Duran TI, Demirag MD. HLA-B51 Impact on Clinical Symptoms in Behcet's Disease. J Coll Physicians Surg Pak 2022; 32:904.
  31. Mizuki N, Inoko H, Ohno S. Pathogenic gene responsible for the predisposition of Behçet's disease. Int Rev Immunol 1997; 14:33.
  32. Gebreselassie D, Spiegel H, Vukmanovic S. Sampling of major histocompatibility complex class I-associated peptidome suggests relatively looser global association of HLA-B*5101 with peptides. Hum Immunol 2006; 67:894.
  33. Wildner G, Thurau SR. Cross-reactivity between an HLA-B27-derived peptide and a retinal autoantigen peptide: a clue to major histocompatibility complex association with autoimmune disease. Eur J Immunol 1994; 24:2579.
  34. Ota M, Mizuki N, Katsuyama Y, et al. The critical region for Behçet disease in the human major histocompatibility complex is reduced to a 46-kb segment centromeric of HLA-B, by association analysis using refined microsatellite mapping. Am J Hum Genet 1999; 64:1406.
  35. Muñoz-Saá I, Cambra A, Pallarés L, et al. Allelic diversity and affinity variants of MICA are imbalanced in Spanish patients with Behçet's disease. Scand J Immunol 2006; 64:77.
  36. Hughes EH, Collins RW, Kondeatis E, et al. Associations of major histocompatibility complex class I chain-related molecule polymorphisms with Behcet's disease in Caucasian patients. Tissue Antigens 2005; 66:195.
  37. Gül A, Hajeer AH, Worthington J, et al. Linkage mapping of a novel susceptibility locus for Behçet's disease to chromosome 6p22-23. Arthritis Rheum 2001; 44:2693.
  38. Hughes T, Coit P, Adler A, et al. Identification of multiple independent susceptibility loci in the HLA region in Behçet's disease. Nat Genet 2013; 45:319.
  39. Kirino Y, Bertsias G, Ishigatsubo Y, et al. Genome-wide association analysis identifies new susceptibility loci for Behçet's disease and epistasis between HLA-B*51 and ERAP1. Nat Genet 2013; 45:202.
  40. Wei F, Zhang YU, Li W. A meta-analysis of the association between Behçet's disease and MICA-A6. Biomed Rep 2016; 4:741.
  41. Zhang J, Liao D, Yang L, Hou S. Association between Functional MICA-TM and Behcet's Disease: A Systematic Review and Meta-analysis. Sci Rep 2016; 6:21033.
  42. Lee YH, Song GG. Associations between major histocompatibility complex class I chain-related gene A polymorphisms and susceptibility to Behcet's disease. A meta-analysis. Z Rheumatol 2015; 74:714.
  43. Guasp P, Barnea E, González-Escribano MF, et al. The Behçet's disease-associated variant of the aminopeptidase ERAP1 shapes a low-affinity HLA-B*51 peptidome by differential subpeptidome processing. J Biol Chem 2017; 292:9680.
  44. Guasp P, Alvarez-Navarro C, Gomez-Molina P, et al. The Peptidome of Behçet's Disease-Associated HLA-B*51:01 Includes Two Subpeptidomes Differentially Shaped by Endoplasmic Reticulum Aminopeptidase 1. Arthritis Rheumatol 2016; 68:505.
  45. Cavers A, Kugler MC, Ozguler Y, et al. Behçet's disease risk-variant HLA-B51/ERAP1-Hap10 alters human CD8 T cell immunity. Ann Rheum Dis 2022; 81:1603.
  46. Guasp P, Lorente E, Martín-Esteban A, et al. Redundancy and Complementarity between ERAP1 and ERAP2 Revealed by their Effects on the Behcet's Disease-associated HLA-B*51 Peptidome. Mol Cell Proteomics 2019; 18:1491.
  47. Padula MC, Leccese P, Lascaro N, et al. From structure to function for the characterization of ERAP1 active site in Behçet syndrome. A novel polymorphism associated with known gene variations. Mol Immunol 2020; 117:155.
  48. Riahi P, Kazemnejad A, Mostafaei S, et al. ERAP1 polymorphisms interactions and their association with Behçet's disease susceptibly: Application of Model-Based Multifactor Dimension Reduction Algorithm (MB-MDR). PLoS One 2020; 15:e0227997.
  49. Mahmoudi M, Aslani S, Meguro A, et al. A comprehensive overview on the genetics of Behçet's disease. Int Rev Immunol 2022; 41:84.
  50. Akpolat T, Koç Y, Yeniay I, et al. Familial Behçet's disease. Eur J Med 1992; 1:391.
  51. Koné-Paut I, Geisler I, Wechsler B, et al. Familial aggregation in Behçet's disease: high frequency in siblings and parents of pediatric probands. J Pediatr 1999; 135:89.
  52. Ahn HS, Kim HJ, Kazmi SZ, et al. Familial risk of Behçet's disease among first-degree relatives: a population-based aggregation study in Korea. Rheumatology (Oxford) 2021; 60:2697.
  53. Fresko I, Soy M, Hamuryudan V, et al. Genetic anticipation in Behçet's syndrome. Ann Rheum Dis 1998; 57:45.
  54. Mizuki N, Ota M, Kimura M, et al. Triplet repeat polymorphism in the transmembrane region of the MICA gene: a strong association of six GCT repetitions with Behçet disease. Proc Natl Acad Sci U S A 1997; 94:1298.
  55. Karasneh J, Gül A, Ollier WE, et al. Whole-genome screening for susceptibility genes in multicase families with Behçet's disease. Arthritis Rheum 2005; 52:1836.
  56. Salvarani C, Boiardi L, Casali B, et al. Endothelial nitric oxide synthase gene polymorphisms in Behçet's disease. J Rheumatol 2002; 29:535.
  57. Gunesacar R, Erken E, Bozkurt B, et al. Analysis of CD28 and CTLA-4 gene polymorphisms in Turkish patients with Behcet's disease. Int J Immunogenet 2007; 34:45.
  58. Karasneh JA, Hajeer AH, Silman A, et al. Polymorphisms in the endothelial nitric oxide synthase gene are associated with Behçet's disease. Rheumatology (Oxford) 2005; 44:614.
  59. Salvarani C, Boiardi L, Casali B, et al. Vascular endothelial growth factor gene polymorphisms in Behçet's disease. J Rheumatol 2004; 31:1785.
  60. Kim JU, Chang HK, Lee SS, et al. Endothelial nitric oxide synthase gene polymorphisms in Behçet's disease and rheumatic diseases with vasculitis. Ann Rheum Dis 2003; 62:1083.
  61. Verity DH, Wallace GR, Vaughan RW, et al. HLA and tumour necrosis factor (TNF) polymorphisms in ocular Behçet's disease. Tissue Antigens 1999; 54:264.
  62. Lee EB, Kim JY, Lee YJ, et al. TNF and TNF receptor polymorphisms in Korean Behcet's disease patients. Hum Immunol 2003; 64:614.
  63. Kamoun M, Chelbi H, Houman MH, et al. Tumor necrosis factor gene polymorphisms in Tunisian patients with Behcet's disease. Hum Immunol 2007; 68:201.
  64. Nakao K, Isashiki Y, Sonoda S, et al. Nitric oxide synthase and superoxide dismutase gene polymorphisms in Behçet disease. Arch Ophthalmol 2007; 125:246.
  65. Tursen U, Tamer L, Api H, et al. Cytochrome P450 polymorphisms in patients with Behcet's disease. Int J Dermatol 2007; 46:153.
  66. Alayli G, Aydin F, Coban AY, et al. T helper 1 type cytokines polymorphisms: association with susceptibility to Behçet's disease. Clin Rheumatol 2007; 26:1299.
  67. Lee YJ, Kang SW, Park JJ, et al. Interleukin-18 promoter polymorphisms in patients with Behçet's disease. Hum Immunol 2006; 67:812.
  68. Akman A, Sallakci N, Coskun M, et al. TNF-alpha gene 1031 T/C polymorphism in Turkish patients with Behçet's disease. Br J Dermatol 2006; 155:350.
  69. Chmaisse HN, Fakhoury HA, Salti NN, Makki RF. The ICAM-1 469 T/C gene polymorphism but not 241 G/A is associated with Behçets disease in the Lebanese population. Saudi Med J 2006; 27:604.
  70. Fei Y, Webb R, Cobb BL, et al. Identification of novel genetic susceptibility loci for Behçet's disease using a genome-wide association study. Arthritis Res Ther 2009; 11:R66.
  71. Touma Z, Farra C, Hamdan A, et al. TNF polymorphisms in patients with Behçet disease: a meta-analysis. Arch Med Res 2010; 41:142.
  72. Dilek K, Ozçimen AA, Saricaoğlu H, et al. Cytokine gene polymorphisms in Behçet's disease and their association with clinical and laboratory findings. Clin Exp Rheumatol 2009; 27:S73.
  73. Kamoun M, Houman MH, Hamzaoui A, Hamzaoui K. Vascular endothelial growth factor gene polymorphisms and serum levels in Behçet's disease. Tissue Antigens 2008; 72:581.
  74. Park KS, Baek JA, Do JE, et al. CTLA4 gene polymorphisms and soluble CTLA4 protein in Behcet's disease. Tissue Antigens 2009; 74:222.
  75. Horie Y, Meguro A, Ota M, et al. Association of TLR4 polymorphisms with Behcet's disease in a Korean population. Rheumatology (Oxford) 2009; 48:638.
  76. Sousa I, Shahram F, Francisco D, et al. Brief report: association of CCR1, KLRC4, IL12A-AS1, STAT4, and ERAP1 With Behçet's disease in Iranians. Arthritis Rheumatol 2015; 67:2742.
  77. Gül A. Pathogenesis of Behçet's disease: autoinflammatory features and beyond. Semin Immunopathol 2015; 37:413.
  78. Hu J, Hou S, Zhu X, et al. Interleukin-10 gene polymorphisms are associated with Behcet's disease but not with Vogt-Koyanagi-Harada syndrome in the Chinese Han population. Mol Vis 2015; 21:589.
  79. Ombrello MJ, Kastner DL, Remmers EF. Endoplasmic reticulum-associated amino-peptidase 1 and rheumatic disease: genetics. Curr Opin Rheumatol 2015; 27:349.
  80. Yalçin B, Atakan N, Dogan S. Association of interleukin-23 receptor gene polymorphism with Behçet disease. Clin Exp Dermatol 2014; 39:881.
  81. Ortiz Fernández L, Coit P, Yilmaz V, et al. Genetic Association of a Gain-of-Function IFNGR1 Polymorphism and the Intergenic Region LNCAROD/DKK1 With Behçet's Disease. Arthritis Rheumatol 2021; 73:1244.
  82. Su G, Zhong Z, Zhou Q, et al. Identification of Novel Risk Loci for Behçet's Disease-Related Uveitis in a Chinese Population in a Genome-Wide Association Study. Arthritis Rheumatol 2022; 74:671.
  83. Shan J, Zhou P, Liu Z, et al. Association of miRNA-146a Gene Polymorphism Rs2910164 with Behcet's Disease: A Meta-analysis. Ocul Immunol Inflamm 2022; 30:1883.
  84. Livneh A, Aksentijevich I, Langevitz P, et al. A single mutated MEFV allele in Israeli patients suffering from familial Mediterranean fever and Behçet's disease (FMF-BD). Eur J Hum Genet 2001; 9:191.
  85. Kogan A, Shinar Y, Lidar M, et al. Common MEFV mutations among Jewish ethnic groups in Israel: high frequency of carrier and phenotype III states and absence of a perceptible biological advantage for the carrier state. Am J Med Genet 2001; 102:272.
  86. Rabinovich E, Shinar Y, Leiba M, et al. Common FMF alleles may predispose to development of Behcet's disease with increased risk for venous thrombosis. Scand J Rheumatol 2007; 36:48.
  87. Dursun A, Durakbasi-Dursun HG, Zamani AG, et al. Genetic analysis of MEFV gene pyrin domain in patients with Behçet's disease. Mediators Inflamm 2006; 2006:41783.
  88. Direskeneli H, Hasan A, Shinnick T, et al. Recognition of B-cell epitopes of the 65 kDa HSP in Behçet's disease. Scand J Immunol 1996; 43:464.
  89. de Smet MD, Ramadan A. Circulating antibodies to inducible heat shock protein 70 in patients with uveitis. Ocul Immunol Inflamm 2001; 9:85.
  90. Suzuki Y, Hoshi K, Matsuda T, Mizushima Y. Increased peripheral blood gamma delta+ T cells and natural killer cells in Behçet's disease. J Rheumatol 1992; 19:588.
  91. Skin hypersensitivity to streptococcal antigens and the induction of systemic symptoms by the antigens in Behçet's disease--a multicenter study. The Behcet's Disease Research Committee of Japan. J Rheumatol 1989; 16:506.
  92. Mumcu G, Inanc N, Aydin SZ, et al. Association of salivary S. mutans colonisation and mannose-binding lectin deficiency with gender in Behçet's disease. Clin Exp Rheumatol 2009; 27:S32.
  93. Seoudi N, Bergmeier LA, Drobniewski F, et al. The oral mucosal and salivary microbial community of Behçet's syndrome and recurrent aphthous stomatitis. J Oral Microbiol 2015; 7:27150.
  94. Yokota K, Hayashi S, Fujii N, et al. Antibody response to oral streptococci in Behçet's disease. Microbiol Immunol 1992; 36:815.
  95. Isogai E, Ohno S, Kotake S, et al. Chemiluminescence of neutrophils from patients with Behçet's disease and its correlation with an increased proportion of uncommon serotypes of Streptococcus sanguis in the oral flora. Arch Oral Biol 1990; 35:43.
  96. Calgüneri M, Ertenli I, Kiraz S, et al. Effect of prophylactic benzathine penicillin on mucocutaneous symptoms of Behçet's disease. Dermatology 1996; 192:125.
  97. Hirohata S, Oka H, Mizushima Y. Streptococcal-related antigens stimulate production of IL6 and interferon-gamma by T cells from patients with Behcet's disease. Cell Immunol 1992; 140:410.
  98. Mochizuki M, Suzuki N, Takeno M, et al. Fine antigen specificity of human gamma delta T cell lines (V gamma 9+) established by repetitive stimulation with a serotype (KTH-1) of a gram-positive bacterium, Streptococcus sanguis. Eur J Immunol 1994; 24:1536.
  99. Evereklioglu C, Er H, Türköz Y, Cekmen M. Serum levels of TNF-alpha, sIL-2R, IL-6, and IL-8 are increased and associated with elevated lipid peroxidation in patients with Behçet's disease. Mediators Inflamm 2002; 11:87.
  100. Calgüneri M, Kiraz S, Ertenli I, et al. The effect of prophylactic penicillin treatment on the course of arthritis episodes in patients with Behçet's disease. A randomized clinical trial. Arthritis Rheum 1996; 39:2062.
  101. Consolandi C, Turroni S, Emmi G, et al. Behçet's syndrome patients exhibit specific microbiome signature. Autoimmun Rev 2015; 14:269.
  102. Ye Z, Zhang N, Wu C, et al. A metagenomic study of the gut microbiome in Behcet's disease. Microbiome 2018; 6:135.
  103. van der Houwen TB, van Laar JAM, Kappen JH, et al. Behçet's Disease Under Microbiotic Surveillance? A Combined Analysis of Two Cohorts of Behçet's Disease Patients. Front Immunol 2020; 11:1192.
  104. Yasar Bilge NS, Pérez Brocal V, Kasifoglu T, et al. Intestinal microbiota composition of patients with Behçet's disease: differences between eye, mucocutaneous and vascular involvement. The Rheuma-BIOTA study. Clin Exp Rheumatol 2020; 38 Suppl 127:60.
  105. Joubert M, André M, Barnich N, Billard E. Microbiome and Behçet's disease: a systematic review. Clin Exp Rheumatol 2023; 41:2093.
  106. Apan TZ, Gürsel R, Dolgun A. Increased seropositivity of Helicobacter pylori cytotoxin-associated gene-A in Behçet's disease. Clin Rheumatol 2007; 26:885.
  107. Yu Y, Yao X, Liang J, et al. Is Helicobacter pylori associated with Behçet's syndrome? A meta-analysis. Helicobacter 2019; 24:e12663.
  108. Inanc N, Mumcu G, Birtas E, et al. Serum mannose-binding lectin levels are decreased in behcet's disease and associated with disease severity. J Rheumatol 2005; 32:287.
  109. Yavuz S, Elbir Y, Tulunay A, et al. Differential expression of toll-like receptor 6 on granulocytes and monocytes implicates the role of microorganisms in Behcet's disease etiopathogenesis. Rheumatol Int 2008; 28:401.
  110. Seoudi N, Bergmeier LA, Hagi-Pavli E, et al. The role of TLR2 and 4 in Behçet's disease pathogenesis. Innate Immun 2014; 20:412.
  111. Liu X, Wang C, Ye Z, et al. Higher expression of Toll-like receptors 2, 3, 4, and 8 in ocular Behcet's disease. Invest Ophthalmol Vis Sci 2013; 54:6012.
  112. Do JE, Kwon SY, Park S, Lee ES. Effects of vitamin D on expression of Toll-like receptors of monocytes from patients with Behcet's disease. Rheumatology (Oxford) 2008; 47:840.
  113. Liang L, Tan X, Zhou Q, et al. IL-1β triggered by peptidoglycan and lipopolysaccharide through TLR2/4 and ROS-NLRP3 inflammasome-dependent pathways is involved in ocular Behçet's disease. Invest Ophthalmol Vis Sci 2013; 54:402.
  114. Nara K, Kurokawa MS, Chiba S, et al. Involvement of innate immunity in the pathogenesis of intestinal Behçet's disease. Clin Exp Immunol 2008; 152:245.
  115. Kolahi S, Rashtchizadeh N, Mahdavi AM, et al. Evaluation of DNA methylation status of toll-like receptors 2 and 4 promoters in Behcet's disease. J Gene Med 2020; 22:e3234.
  116. Lockwood CM, Hale G, Waldman H, Jayne DR. Remission induction in Behçet's disease following lymphocyte depletion by the anti-CD52 antibody CAMPATH 1-H. Rheumatology (Oxford) 2003; 42:1539.
  117. Erkiliç K, Evereklioglu C, Cekmen M, et al. Adenosine deaminase enzyme activity is increased and negatively correlates with catalase, superoxide dismutase and glutathione peroxidase in patients with Behçet's disease: original contributions/clinical and laboratory investigations. Mediators Inflamm 2003; 12:107.
  118. Calis M, Ates F, Yazici C, et al. Adenosine deaminase enzyme levels, their relation with disease activity, and the effect of colchicine on adenosine deaminase levels in patients with Behçet's disease. Rheumatol Int 2005; 25:452.
  119. Canpolat F, Unver M, Eskioğlu F, et al. Serum and erythrocyte adenosine deaminase activities in patients with Behçet's disease. Int J Dermatol 2006; 45:1053.
  120. Hamzaoui K, Hamzaoui A, Guemira F, et al. Cytokine profile in Behçet's disease patients. Relationship with disease activity. Scand J Rheumatol 2002; 31:205.
  121. Raziuddin S, al-Dalaan A, Bahabri S, et al. Divergent cytokine production profile in Behçet's disease. Altered Th1/Th2 cell cytokine pattern. J Rheumatol 1998; 25:329.
  122. Dalghous AM, Freysdottir J, Fortune F. Expression of cytokines, chemokines, and chemokine receptors in oral ulcers of patients with Behcet's disease (BD) and recurrent aphthous stomatitis is Th1-associated, although Th2-association is also observed in patients with BD. Scand J Rheumatol 2006; 35:472.
  123. Vaccarino L, Triolo G, Accardo-Palombo A, et al. Pathological implications of Th1/Th2 cytokine genetic variants in Behçet's disease: Data from a pilot study in a Sicilian population. Biochem Genet 2013; 51:967.
  124. Sugi-Ikai N, Nakazawa M, Nakamura S, et al. Increased frequencies of interleukin-2- and interferon-gamma-producing T cells in patients with active Behçet's disease. Invest Ophthalmol Vis Sci 1998; 39:996.
  125. Frassanito MA, Dammacco R, Cafforio P, Dammacco F. Th1 polarization of the immune response in Behçet's disease: a putative pathogenetic role of interleukin-12. Arthritis Rheum 1999; 42:1967.
  126. Boiardi L, Salvarani C, Casali B, et al. Intercellular adhesion molecule-1 gene polymorphisms in Behçet's Disease. J Rheumatol 2001; 28:1283.
  127. Ben Ahmed M, Houman H, Miled M, et al. Involvement of chemokines and Th1 cytokines in the pathogenesis of mucocutaneous lesions of Behçet's disease. Arthritis Rheum 2004; 50:2291.
  128. Bardak Y, Aridoğan BC. The demonstration of serum interleukin 6-8, tumor necrosis factor-alpha, complement, and immunoglobulin levels in Behçet's disease with ocular involvement. Ocul Immunol Inflamm 2004; 12:53.
  129. Suzuki N, Nara K, Suzuki T. Skewed Th1 responses caused by excessive expression of Txk, a member of the Tec family of tyrosine kinases, in patients with Behcet's disease. Clin Med Res 2006; 4:147.
  130. Imamura Y, Kurokawa MS, Yoshikawa H, et al. Involvement of Th1 cells and heat shock protein 60 in the pathogenesis of intestinal Behcet's disease. Clin Exp Immunol 2005; 139:371.
  131. Turan B, Gallati H, Erdi H, et al. Systemic levels of the T cell regulatory cytokines IL-10 and IL-12 in Bechçet's disease; soluble TNFR-75 as a biological marker of disease activity. J Rheumatol 1997; 24:128.
  132. Katsantonis J, Adler Y, Orfanos CE, Zouboulis CC. Adamantiades-Behçet's disease: serum IL-8 is a more reliable marker for disease activity than C-reactive protein and erythrocyte sedimentation rate. Dermatology 2000; 201:37.
  133. Musabak U, Pay S, Erdem H, et al. Serum interleukin-18 levels in patients with Behçet's disease. Is its expression associated with disease activity or clinical presentations? Rheumatol Int 2006; 26:545.
  134. Turan B, Pfister K, Diener PA, et al. Soluble tumour necrosis factor receptors sTNFR1 and sTNFR2 are produced at sites of inflammation and are markers of arthritis activity in Behçet's disease. Scand J Rheumatol 2008; 37:135.
  135. Durmazlar SP, Ulkar GB, Eskioglu F, et al. Significance of serum interleukin-8 levels in patients with Behcet's disease: high levels may indicate vascular involvement. Int J Dermatol 2009; 48:259.
  136. Mege JL, Dilsen N, Sanguedolce V, et al. Overproduction of monocyte derived tumor necrosis factor alpha, interleukin (IL) 6, IL-8 and increased neutrophil superoxide generation in Behçet's disease. A comparative study with familial Mediterranean fever and healthy subjects. J Rheumatol 1993; 20:1544.
  137. Ozdamar Y, Berker N, Bahar G, et al. Inflammatory mediators and posterior segment involvement in ocular Behcet disease. Eur J Ophthalmol 2009; 19:998.
  138. Akman-Demir G, Tüzün E, Içöz S, et al. Interleukin-6 in neuro-Behçet's disease: association with disease subsets and long-term outcome. Cytokine 2008; 44:373.
  139. Lew W, Chang JY, Jung JY, Bang D. Increased expression of interleukin-23 p19 mRNA in erythema nodosum-like lesions of Behçet's disease. Br J Dermatol 2008; 158:505.
  140. Pay S, Simsek I, Erdem H, et al. Dendritic cell subsets and type I interferon system in Behçet's disease: does functional abnormality in plasmacytoid dendritic cells contribute to Th1 polarization? Clin Exp Rheumatol 2007; 25:S34.
  141. Mantaş C, Direskeneli H, Ekşioglu-Demiralp E, Akoglu T. Serum levels of Th2 cytokines IL-4 and IL-10 in Behçet's disease. J Rheumatol 1999; 26:510.
  142. Sugita S, Kawazoe Y, Imai A, et al. Inhibition of Th17 differentiation by anti-TNF-alpha therapy in uveitis patients with Behçet's disease. Arthritis Res Ther 2012; 14:R99.
  143. Shimizu J, Takai K, Fujiwara N, et al. Excessive CD4+ T cells co-expressing interleukin-17 and interferon-γ in patients with Behçet's disease. Clin Exp Immunol 2012; 168:68.
  144. Hamzaoui K. Th17 cells in Behçet's disease: a new immunoregulatory axis. Clin Exp Rheumatol 2011; 29:S71.
  145. Geri G, Terrier B, Rosenzwajg M, et al. Critical role of IL-21 in modulating TH17 and regulatory T cells in Behçet disease. J Allergy Clin Immunol 2011; 128:655.
  146. Liang L, Wang H, Peng XY, Zhao M. [The changes of Th lymphocyte subsets in patients with Behcet disease]. Zhonghua Yan Ke Za Zhi 2011; 47:393.
  147. Lee YJ, Horie Y, Wallace GR, et al. Genome-wide association study identifies GIMAP as a novel susceptibility locus for Behcet's disease. Ann Rheum Dis 2013; 72:1510.
  148. Nanke Y, Yago T, Kotake S. The Role of Th17 Cells in the Pathogenesis of Behcet's Disease. J Clin Med 2017; 6.
  149. Deniz R, Tulunay-Virlan A, Ture Ozdemir F, et al. Th17-Inducing Conditions Lead to in vitro Activation of Both Th17 and Th1 Responses in Behcet's Disease. Immunol Invest 2017; 46:518.
  150. Kaabachi W, Bouali E, Berraïes A, et al. Interleukin-26 is overexpressed in Behçet's disease and enhances Th17 related -cytokines. Immunol Lett 2017; 190:177.
  151. Freysdottir J, Lau S, Fortune F. Gammadelta T cells in Behçet's disease (BD) and recurrent aphthous stomatitis (RAS). Clin Exp Immunol 1999; 118:451.
  152. Yato H, Matsumoto Y. CD56+ T cells in the peripheral blood of uveitis patients. Br J Ophthalmol 1999; 83:1386.
  153. Eksioglu-Demiralp E, Direskeneli H, Ergun T, et al. Increased CD4+CD16+ and CD4+CD56+ T cell subsets in Behçet's disease. Rheumatol Int 1999; 19:23.
  154. Kim TW, Chung H, Yu HG. Chemokine expression of intraocular lymphocytes in patients with Behçet uveitis. Ophthalmic Res 2011; 45:5.
  155. Bank I, Duvdevani M, Livneh A. Expansion of gammadelta T-cells in Behçet's disease: role of disease activity and microbial flora in oral ulcers. J Lab Clin Med 2003; 141:33.
  156. Clemente A, Cambra A, Munoz-Saá I, et al. Phenotype markers and cytokine intracellular production by CD8+ gammadelta T lymphocytes do not support a regulatory T profile in Behçet's disease patients and healthy controls. Immunol Lett 2010; 129:57.
  157. Freysdottir J, Hussain L, Farmer I, et al. Diversity of gammadelta T cells in patients with Behcet's disease is indicative of polyclonal activation. Oral Dis 2006; 12:271.
  158. Ben Dhifallah I, Chelbi H, Braham A, et al. CTLA-4 +49A/G polymorphism is associated with Behçet's disease in a Tunisian population. Tissue Antigens 2009; 73:213.
  159. Yasuoka H, Okazaki Y, Kawakami Y, et al. Autoreactive CD8+ cytotoxic T lymphocytes to major histocompatibility complex class I chain-related gene A in patients with Behçet's disease. Arthritis Rheum 2004; 50:3658.
  160. Yu HG, Lee DS, Seo JM, et al. The number of CD8+ T cells and NKT cells increases in the aqueous humor of patients with Behçet's uveitis. Clin Exp Immunol 2004; 137:437.
  161. Keino H, Sakai J, Nishioka K, et al. Clonally accumulating T cells in the anterior chamber of Behçet disease. Am J Ophthalmol 2000; 130:243.
  162. Takase H, Sugita S, Taguchi C, et al. Capacity of ocular infiltrating T helper type 1 cells of patients with non-infectious uveitis to produce chemokines. Br J Ophthalmol 2006; 90:765.
  163. Ahn JK, Chung H, Lee DS, et al. CD8brightCD56+ T cells are cytotoxic effectors in patients with active Behcet's uveitis. J Immunol 2005; 175:6133.
  164. Ahn JK, Yu HG, Chung H, Park YG. Intraocular cytokine environment in active Behçet uveitis. Am J Ophthalmol 2006; 142:429.
  165. Guenane H, Hartani D, Chachoua L, et al. [Production of Th1/Th2 cytokines and nitric oxide in Behçet's uveitis and idiopathic uveitis]. J Fr Ophtalmol 2006; 29:146.
  166. Pay S, Erdem H, Pekel A, et al. Synovial proinflammatory cytokines and their correlation with matrix metalloproteinase-3 expression in Behçet's disease. Does interleukin-1beta play a major role in Behçet's synovitis? Rheumatol Int 2006; 26:608.
  167. Todaro M, Zerilli M, Triolo G, et al. NF-kappaB protects Behçet's disease T cells against CD95-induced apoptosis up-regulating antiapoptotic proteins. Arthritis Rheum 2005; 52:2179.
  168. Fujimori K, Oh-i K, Takeuchi M, et al. Circulating neutrophils in Behçet disease is resistant for apoptotic cell death in the remission phase of uveitis. Graefes Arch Clin Exp Ophthalmol 2008; 246:285.
  169. Ozkan Y, Yardim-Akaydin S, Sepici A, et al. Assessment of homocysteine, neopterin and nitric oxide levels in Behçet's disease. Clin Chem Lab Med 2007; 45:73.
  170. Erturan I, Basak PY, Ozturk O, et al. Is there any relationship between serum and urine neopterin and serum interferon-gamma levels in the activity of Behcet's disease? J Eur Acad Dermatol Venereol 2009; 23:1414.
  171. Tulunay A, Dozmorov MG, Ture-Ozdemir F, et al. Activation of the JAK/STAT pathway in Behcet's disease. Genes Immun 2015; 16:170.
  172. Suh CH, Park YB, Song J, et al. Oligoclonal B lymphocyte expansion in the synovium of a patient with Behçet's disease. Arthritis Rheum 2001; 44:1707.
  173. Ekşioglu-Demiralp E, Kibaroglu A, Direskeneli H, et al. Phenotypic characteristics of B cells in Behçet's disease: increased activity in B cell subsets. J Rheumatol 1999; 26:826.
  174. Aydìntug AO, Tokgöz G, D'Cruz DP, et al. Antibodies to endothelial cells in patients with Behçet's disease. Clin Immunol Immunopathol 1993; 67:157.
  175. Direskeneli H, Keser G, D'Cruz D, et al. Anti-endothelial cell antibodies, endothelial proliferation and von Willebrand factor antigen in Behçet's disease. Clin Rheumatol 1995; 14:55.
  176. Matsui T, Kurokawa M, Kobata T, et al. Autoantibodies to T cell costimulatory molecules in systemic autoimmune diseases. J Immunol 1999; 162:4328.
  177. Matsui T, Otsuka M, Maenaka K, et al. Detection of autoantibodies to killer immunoglobulin-like receptors using recombinant fusion proteins for two killer immunoglobulin-like receptors in patients with systemic autoimmune diseases. Arthritis Rheum 2001; 44:384.
  178. Orem A, Cimşit G, Değer O, et al. Autoantibodies against oxidatively modified low-density lipoprotein in patients with Behçet's disease. Dermatology 1999; 198:243.
  179. Feng XG, Ye S, Lu Y, et al. Antikinectin autoantibody in Behçet's disease and several other autoimmune connective tissue diseases. Clin Exp Rheumatol 2007; 25:S80.
  180. Choi CH, Kim TI, Kim BC, et al. Anti-Saccharomyces cerevisiae antibody in intestinal Behçet's disease patients: relation to clinical course. Dis Colon Rectum 2006; 49:1849.
  181. Cheng L, Li L, Liu C, et al. Meta-analysis of anti-Saccharomyces cerevisiae antibodies as diagnostic markers of Behçet's disease with gastrointestinal involvement. BMJ Open 2020; 10:e033880.
  182. Kurhan-Yavuz S, Direskeneli H, Bozkurt N, et al. Anti-MHC autoimmunity in Behçet's disease: T cell responses to an HLA-B-derived peptide cross-reactive with retinal-S antigen in patients with uveitis. Clin Exp Immunol 2000; 120:162.
  183. Yamamoto JH, Minami M, Inaba G, et al. Cellular autoimmunity to retinal specific antigens in patients with Behçet's disease. Br J Ophthalmol 1993; 77:584.
  184. de Smet MD, Dayan M. Prospective determination of T-cell responses to S-antigen in Behçet's disease patients and controls. Invest Ophthalmol Vis Sci 2000; 41:3480.
  185. Zhao C, Yang P, He H, et al. S-antigen specific T helper type 1 response is present in Behcet's disease. Mol Vis 2008; 14:1456.
  186. Mahesh SP, Li Z, Buggage R, et al. Alpha tropomyosin as a self-antigen in patients with Behçet's disease. Clin Exp Immunol 2005; 140:368.
  187. Okunuki Y, Usui Y, Takeuchi M, et al. Proteomic surveillance of autoimmunity in Behcet's disease with uveitis: selenium binding protein is a novel autoantigen in Behcet's disease. Exp Eye Res 2007; 84:823.
  188. Takeuchi M, Usui Y, Okunuki Y, et al. Immune responses to interphotoreceptor retinoid-binding protein and S-antigen in Behcet's patients with uveitis. Invest Ophthalmol Vis Sci 2010; 51:3067.
  189. Mor F, Weinberger A, Cohen IR. Identification of alpha-tropomyosin as a target self-antigen in Behçet's syndrome. Eur J Immunol 2002; 32:356.
  190. Lu Y, Ye P, Chen SL, et al. Identification of kinectin as a novel Behçet's disease autoantigen. Arthritis Res Ther 2005; 7:R1133.
  191. Kayikçioğlu M, Aksu K, Hasdemir C, et al. Endothelial functions in Behçet's disease. Rheumatol Int 2006; 26:304.
  192. Chambers JC, Haskard DO, Kooner JS. Vascular endothelial function and oxidative stress mechanisms in patients with Behçet's syndrome. J Am Coll Cardiol 2001; 37:517.
  193. Oflaz H, Mercanoglu F, Karaman O, et al. Impaired endothelium-dependent flow-mediated dilation in Behçet's disease: more prominent endothelial dysfunction in patients with vascular involvement. Int J Clin Pract 2005; 59:777.
  194. Triolo G, Accardo-Palumbo A, Triolo G, et al. Enhancement of endothelial cell E-selectin expression by sera from patients with active Behçet's disease: moderate correlation with anti-endothelial cell antibodies and serum myeloperoxidase levels. Clin Immunol 1999; 91:330.
  195. Kansu E, Sahin G, Sahin F, et al. Impaired prostacyclin synthesis by vessel walls in Behçet's disease. Lancet 1986; 2:1154.
  196. Evereklioglu C, Turkoz Y, Er H, et al. Increased nitric oxide production in patients with Behçet's disease: is it a new activity marker? J Am Acad Dermatol 2002; 46:50.
  197. Evereklioglu C, Cekmen M, Ozkiriş A, et al. The pathophysiological significance of red blood cell nitric oxide concentrations in inflammatory Behçet's disease. Mediators Inflamm 2003; 12:255.
  198. Yilmaz G, Sizmaz S, Yilmaz ED, et al. Aqueous humor nitric oxide levels in patients with Behçet disease. Retina 2002; 22:330.
  199. Buldanlioglu S, Turkmen S, Ayabakan HB, et al. Nitric oxide, lipid peroxidation and antioxidant defence system in patients with active or inactive Behçet's disease. Br J Dermatol 2005; 153:526.
  200. Duygulu F, Evereklioglu C, Calis M, et al. Synovial nitric oxide concentrations are increased and correlated with serum levels in patients with active Behçet's disease: a pilot study. Clin Rheumatol 2005; 24:324.
  201. Sahin M, Arslan C, Naziroglu M, et al. Asymmetric dimethylarginine and nitric oxide levels as signs of endothelial dysfunction in Behcet's disease. Ann Clin Lab Sci 2006; 36:449.
  202. Harzallah O, Kerkeni A, Baati T, Mahjoub S. Oxidative stress: correlation with Behçet's disease duration, activity and severity. Eur J Intern Med 2008; 19:541.
  203. Ozdemir R, Barutcu I, Sezgin AT, et al. Vascular endothelial function and plasma homocysteine levels in Behcet's disease. Am J Cardiol 2004; 94:522.
  204. Er H, Evereklioglu C, Cumurcu T, et al. Serum homocysteine level is increased and correlated with endothelin-1 and nitric oxide in Behçet's disease. Br J Ophthalmol 2002; 86:653.
  205. Ateş A, Aydintuğ O, Olmez U, et al. Serum homocysteine level is higher in Behçet's disease with vascular involvement. Rheumatol Int 2005; 25:42.
  206. Sarican T, Ayabakan H, Turkmen S, et al. Homocysteine: an activity marker in Behçet's disease? J Dermatol Sci 2007; 45:121.
  207. La Regina M, Orlandini F, Prisco D, Dentali F. Homocysteine in vascular Behcet disease: a meta-analysis. Arterioscler Thromb Vasc Biol 2010; 30:2067.
  208. Kuo YS, Chang JY, Wang YP, et al. Significantly higher frequencies of hemoglobin, iron, vitamin B12, and folic acid deficiencies and of hyperhomocysteinemia in patients with Behcet's disease. J Formos Med Assoc 2018; 117:932.
  209. Cekmen M, Evereklioglu C, Er H, et al. Vascular endothelial growth factor levels are increased and associated with disease activity in patients with Behçet's syndrome. Int J Dermatol 2003; 42:870.
  210. Bozoglu E, Dinc A, Erdem H, et al. Vascular endothelial growth factor and monocyte chemoattractant protein-1 in Behçet's patients with venous thrombosis. Clin Exp Rheumatol 2005; 23:S42.
  211. Yalçin B, Arda N, Tezel GG, et al. Expressions of vascular endothelial growth factor and CD34 in oral aphthous lesions of Behçet's disease. Anal Quant Cytol Histol 2006; 28:303.
  212. Hamzaoui K, Ayed K, Hamza M, Hamzaoui A. VEGF and mRNA VEGF expression in CSF from Behçet's disease with neurological involvement. J Neuroimmunol 2009; 213:148.
  213. Nam EJ, Han SW, Kim SU, et al. Association of vascular endothelial growth factor gene polymorphisms with behcet disease in a Korean population. Hum Immunol 2005; 66:1068.
  214. Lee KH, Chung HS, Kim HS, et al. Human alpha-enolase from endothelial cells as a target antigen of anti-endothelial cell antibody in Behçet's disease. Arthritis Rheum 2003; 48:2025.
  215. Lee JH, Cho SB, Bang D, et al. Human anti-alpha-enolase antibody in sera from patients with Behçet's disease and rheumatologic disorders. Clin Exp Rheumatol 2009; 27:S63.
  216. Evereklioglu C, Inalöz HS, Kirtak N, et al. Serum leptin concentration is increased in patients with Behçet's syndrome and is correlated with disease activity. Br J Dermatol 2002; 147:331.
  217. Probst K, Fijnheer R, Rothova A. Endothelial cell activation and hypercoagulability in ocular Behçet's disease. Am J Ophthalmol 2004; 137:850.
  218. Espinosa G, Font J, Tàssies D, et al. Vascular involvement in Behçet's disease: relation with thrombophilic factors, coagulation activation, and thrombomodulin. Am J Med 2002; 112:37.
  219. Haznedaroğlu IC, Ozcebe O, Celik I, et al. Haemostatic markers of procoagulant imbalance in Behçet's disease. Eur J Haematol 1996; 57:107.
  220. Navarro S, Ricart JM, Medina P, et al. Activated protein C levels in Behçet's disease and risk of venous thrombosis. Br J Haematol 2004; 126:550.
  221. Akar S, Ozcan MA, Ateş H, et al. Circulated activated platelets and increased platelet reactivity in patients with Behçet's disease. Clin Appl Thromb Hemost 2006; 12:451.
  222. Usküdar O, Erdem A, Demiroğlu H, Dikmenoğlu N. Decreased erythrocyte deformability in Behçet's disease. Clin Hemorheol Microcirc 2005; 33:89.
  223. Tatlican S, Duran FS, Eren C, et al. Reduced erythrocyte deformability in active and untreated Behçet's disease patients. Int J Dermatol 2010; 49:167.
  224. Yurdakul S, Hekim N, Soysal T, et al. Fibrinolytic activity and d-dimer levels in Behçet's syndrome. Clin Exp Rheumatol 2005; 23:S53.
  225. Becatti M, Emmi G, Silvestri E, et al. Neutrophil Activation Promotes Fibrinogen Oxidation and Thrombus Formation in Behçet Disease. Circulation 2016; 133:302.
  226. Leiba M, Seligsohn U, Sidi Y, et al. Thrombophilic factors are not the leading cause of thrombosis in Behçet's disease. Ann Rheum Dis 2004; 63:1445.
  227. Caramaschi P, Poli G, Bonora A, et al. A study on thrombophilic factors in Italian Behcet's patients. Joint Bone Spine 2010; 77:330.
  228. Ricart JM, Ramón LA, Vayá A, et al. Fibrinolytic inhibitor levels and polymorphisms in Behçet disease and their association with thrombosis. Br J Haematol 2008; 141:716.
  229. Espinosa G, Font J, Tàssies D, et al. Vascular involvement in Behçet's disease: relation with thrombophilic factors, coagulation activation, and thrombomodulin. Am J Med 2002; 112:37.
  230. Leiba M, Seligsohn U, Sidi Y, et al. Thrombophilic factors are not the leading cause of thrombosis in Behçet's disease. Ann Rheum Dis 2004; 63:1445.
  231. Chambers JC, Haskard DO, Kooner JS. Vascular endothelial function and oxidative stress mechanisms in patients with Behçet's syndrome. J Am Coll Cardiol 2001; 37:517.
  232. Toledo-Samaniego N, Oblitas CM, Peñaloza-Martínez E, et al. Arterial and venous involvement in Behçet's syndrome: a narrative review. J Thromb Thrombolysis 2022; 54:162.
  233. Alan S, Ulgen MS, Akdeniz S, et al. Intima-media thickness and arterial distensibility in Behçet's disease. Angiology 2004; 55:413.
  234. Itoh R, Takenaka T, Okitsu-Negishi S, et al. Interleukin 8 in Behçet's disease. J Dermatol 1994; 21:397.
  235. al-Dalaan A, al-Sedairy S, al-Balaa S, et al. Enhanced interleukin 8 secretion in circulation of patients with Behçet's disease. J Rheumatol 1995; 22:904.
  236. Ureten K, Ertenli I, Oztürk MA, et al. Neutrophil CD64 expression in Behçet's disease. J Rheumatol 2005; 32:849.
  237. Sahin S, Akoğlu T, Direskeneli H, et al. Neutrophil adhesion to endothelial cells and factors affecting adhesion in patients with Behçet's disease. Ann Rheum Dis 1996; 55:128.
  238. Saglam K, Yilmaz MI, Saglam A, et al. Levels of circulating intercellular adhesion molecule-1 in patients with Behçet's disease. Rheumatol Int 2002; 21:146.
  239. Ateş A, Tiryaki OA, Olmez U, Tutkak H. Serum-soluble selectin levels in patients with Behçet's disease. Clin Rheumatol 2007; 26:411.
  240. Turkoz Y, Evereklioglu C, Ozkiriş A, et al. Serum levels of soluble P-selectin are increased and associated with disease activity in patients with Behçet's syndrome. Mediators Inflamm 2005; 2005:237.
  241. Lee MT, Hooper LC, Kump L, et al. Interferon-beta and adhesion molecules (E-selectin and s-intracellular adhesion molecule-1) are detected in sera from patients with retinal vasculitis and are induced in retinal vascular endothelial cells by Toll-like receptor 3 signalling. Clin Exp Immunol 2007; 147:71.
  242. Yamashita S, Suzuki A, Kamada M, et al. Possible physiological roles of proteolytic products of actin in neutrophils of patients with Behçet's disease. Biol Pharm Bull 2001; 24:733.
  243. Yamashita S, Suzuki A, Yanagita T, et al. Characterization of a protease responsible for truncated actin increase in neutrophils of patients with Behçet's disease. Biol Pharm Bull 2001; 24:119.
  244. Orem A, Efe H, Değer O, et al. Relationship between lipid peroxidation and disease activity in patients with Behçet's disease. J Dermatol Sci 1997; 16:11.
  245. Yoshida T, Tanaka M, Sotomatsu A, et al. Serum of Behçet's disease enhances superoxide production of normal neutrophils. Free Radic Res 1998; 28:39.
  246. Kawakami T, Ohashi S, Kawa Y, et al. Elevated serum granulocyte colony-stimulating factor levels in patients with active phase of sweet syndrome and patients with active behcet disease: implication in neutrophil apoptosis dysfunction. Arch Dermatol 2004; 140:570.
  247. Değer O, Orem A, Akyol N, et al. Polymorphonuclear leukocyte elastase levels in patients with Behçet's disease. Clin Chim Acta 1995; 236:129.
  248. Yazici C, Köse K, Caliş M, et al. Increased advanced oxidation protein products in Behçet's disease: a new activity marker? Br J Dermatol 2004; 151:105.
  249. Safi R, Kallas R, Bardawil T, et al. Neutrophils contribute to vasculitis by increased release of neutrophil extracellular traps in Behçet's disease. J Dermatol Sci 2018; 92:143.
  250. Li L, Yu X, Liu J, et al. Neutrophil Extracellular Traps Promote Aberrant Macrophages Activation in Behçet's Disease. Front Immunol 2020; 11:590622.
  251. Hamzaoui K, Maître B, Hamzaoui A. Elevated levels of MMP-9 and TIMP-1 in the cerebrospinal fluid of neuro-Behçet's disease. Clin Exp Rheumatol 2009; 27:S52.
  252. Cañete JD, Celis R, Noordenbos T, et al. Distinct synovial immunopathology in Behçet disease and psoriatic arthritis. Arthritis Res Ther 2009; 11:R17.
  253. Sahin S, Lawrence R, Direskeneli H, et al. Monocyte activity in Behçet's disease. Br J Rheumatol 1996; 35:424.
  254. Neves FS, Carrasco S, Goldenstein-Schainberg C, et al. Neutrophil hyperchemotaxis in Behçet's disease: a possible role for monocytes orchestrating bacterial-induced innate immune responses. Clin Rheumatol 2009; 28:1403.
  255. Alipour S, Nouri M, Sakhinia E, et al. Epigenetic alterations in chronic disease focusing on Behçet's disease: Review. Biomed Pharmacother 2017; 91:526.
  256. Hughes T, Ture-Ozdemir F, Alibaz-Oner F, et al. Epigenome-wide scan identifies a treatment-responsive pattern of altered DNA methylation among cytoskeletal remodeling genes in monocytes and CD4+ T cells from patients with Behçet's disease. Arthritis Rheumatol 2014; 66:1648.
  257. Zhu Y, Qiu Y, Yu H, et al. Aberrant DNA methylation of GATA binding protein 3 (GATA3), interleukin-4 (IL-4), and transforming growth factor-β (TGF-β) promoters in Behcet's disease. Oncotarget 2017; 8:64263.
  258. Ehrlich GE. Vasculitis in Behçet's disease. Int Rev Immunol 1997; 14:81.
  259. Onder M, Gürer MA. Behçet's disease: an enigmatic vasculitis. Clin Dermatol 1999; 17:571.
  260. Kose AA. Direct immunofluorescence in Behçet's disease: a controlled study with 108 cases. Yonsei Med J 2009; 50:505.
  261. Inaloz HS, Evereklioglu C, Unal B, et al. The significance of immunohistochemistry in the skin pathergy reaction of patients with Behçet's syndrome. J Eur Acad Dermatol Venereol 2004; 18:56.
  262. Ozluk E, Balta I, Akoguz O, et al. Histopathologic Study of Pathergy Test in Behçet's Disease. Indian J Dermatol 2014; 59:630.
  263. Alpsoy E, Uzun S, Akman A, et al. Histological and immunofluorescence findings of non-follicular papulopustular lesions in patients with Behçet's disease. J Eur Acad Dermatol Venereol 2003; 17:521.
  264. Ilknur T, Pabuççuoglu U, Akin C, et al. Histopathologic and direct immunofluorescence findings of the papulopustular lesions in Behçet's disease. Eur J Dermatol 2006; 16:146.
  265. Hatemi G, Bahar H, Uysal S, et al. The pustular skin lesions in Behcet's syndrome are not sterile. Ann Rheum Dis 2004; 63:1450.
  266. Hirohata S. Histopathology of central nervous system lesions in Behçet's disease. J Neurol Sci 2008; 267:41.
  267. Ardalan MR, Sadreddini S, Noshad H, et al. Renal involvement in Behcet's disease. Saudi J Kidney Dis Transpl 2009; 20:618.
Topic 8233 Version 25.0

References

1 : Behçet's disease: infectious aetiology, new autoantigens, and HLA-B51.

2 : Is Smoking a Risk Factor in Ocular Behçet Disease?

3 : Cigarette smoking and risk of Behcet's disease: a propensity score matching analysis.

4 : Association between smoking and Behçet's disease: a nationwide population-based study in Korea.

5 : Secukinumab induced Behçet's syndrome: a report of two cases.

6 : Report of two cases of Behçet's disease developed during treatment with secukinumab.

7 : Behçet's-like disease during secukinumab treatment: new paradoxical reaction?

8 : A case report of recalcitrant aphthous ulcers in two patients treated with interleukin-17 inhibitors.

9 : Proteomics Landscape Mapping of Organ-Resolved Behçet's Disease Using In-Depth Plasma Proteomics for Identifying Hyaluronic Binding Protein 2 Expression Associated With Vascular Involvement.

10 : Identification of the immune-related biomarkers in Behcet's disease by plasma proteomic analysis.

11 : The association of Behçet's syndrome with HLA-B51 as understood in 2021.

12 : HLA-B51/B5 and the risk of Behçet's disease: a systematic review and meta-analysis of case-control genetic association studies.

13 : Behçet's disease.

14 : Close association of HLA-B51 and B52 in Israeli patients with Behçet's syndrome.

15 : Association of MICA alleles and HLA-B51 in Italian patients with Behçet's disease.

16 : Comparative analysis of the association of HLA-B*51 suballeles with Behçet's disease in patients of German and Turkish origin.

17 : Mapping the HLA association in Behçet's disease: a role for tumor necrosis factor polymorphisms?

18 : Detection of parvovirus B19 DNA in the lesional skin of patients with Behçet's disease.

19 : Association of Major Histocompatibility Complex Class I Chain-Related Gene A and HLA-B Alleles with Behçet's Disease in Turkey.

20 : Current concepts in the etiology and treatment of Behçet disease.

21 : [HLA polymorphism and Behçet's disease in Moroccan population].

22 : [Four-digit allele genotyping of HLA-A and HLA-B genes in Japanese patients with Behçet's disease (BD) by a PCR-SSOP-luminex method and stratification analysis according to each major symptom of BD].

23 : Genetics of Behçet disease inside and outside the MHC.

24 : The immunogenetics of Behçet's disease: A comprehensive review.

25 : Evidence for linkage of the HLA-B locus in Behçet's disease, obtained using the transmission disequilibrium test.

26 : Novel approaches to Behçet's disease.

27 : Frequency of HLA in patients with Behçet's disease and association with occlusive retinal vasculitis.

28 : HLA-B phenotype modifies the course of Behçet's disease in Moroccan patients.

29 : Lack of association of HLA-B*51 with a severe disease course in Behçet's disease.

30 : HLA-B51 Impact on Clinical Symptoms in Behcet's Disease.

31 : Pathogenic gene responsible for the predisposition of Behçet's disease.

32 : Sampling of major histocompatibility complex class I-associated peptidome suggests relatively looser global association of HLA-B*5101 with peptides.

33 : Cross-reactivity between an HLA-B27-derived peptide and a retinal autoantigen peptide: a clue to major histocompatibility complex association with autoimmune disease.

34 : The critical region for Behçet disease in the human major histocompatibility complex is reduced to a 46-kb segment centromeric of HLA-B, by association analysis using refined microsatellite mapping.

35 : Allelic diversity and affinity variants of MICA are imbalanced in Spanish patients with Behçet's disease.

36 : Associations of major histocompatibility complex class I chain-related molecule polymorphisms with Behcet's disease in Caucasian patients.

37 : Linkage mapping of a novel susceptibility locus for Behçet's disease to chromosome 6p22-23.

38 : Identification of multiple independent susceptibility loci in the HLA region in Behçet's disease.

39 : Genome-wide association analysis identifies new susceptibility loci for Behçet's disease and epistasis between HLA-B*51 and ERAP1.

40 : A meta-analysis of the association between Behçet's disease and MICA-A6.

41 : Association between Functional MICA-TM and Behcet's Disease: A Systematic Review and Meta-analysis.

42 : Associations between major histocompatibility complex class I chain-related gene A polymorphisms and susceptibility to Behcet's disease. A meta-analysis.

43 : The Behçet's disease-associated variant of the aminopeptidase ERAP1 shapes a low-affinity HLA-B*51 peptidome by differential subpeptidome processing.

44 : The Peptidome of Behçet's Disease-Associated HLA-B*51:01 Includes Two Subpeptidomes Differentially Shaped by Endoplasmic Reticulum Aminopeptidase 1.

45 : Behçet's disease risk-variant HLA-B51/ERAP1-Hap10 alters human CD8 T cell immunity.

46 : Redundancy and Complementarity between ERAP1 and ERAP2 Revealed by their Effects on the Behcet's Disease-associated HLA-B*51 Peptidome.

47 : From structure to function for the characterization of ERAP1 active site in Behçet syndrome. A novel polymorphism associated with known gene variations.

48 : ERAP1 polymorphisms interactions and their association with Behçet's disease susceptibly: Application of Model-Based Multifactor Dimension Reduction Algorithm (MB-MDR).

49 : A comprehensive overview on the genetics of Behçet's disease.

50 : Familial Behçet's disease.

51 : Familial aggregation in Behçet's disease: high frequency in siblings and parents of pediatric probands.

52 : Familial risk of Behçet's disease among first-degree relatives: a population-based aggregation study in Korea.

53 : Genetic anticipation in Behçet's syndrome.

54 : Triplet repeat polymorphism in the transmembrane region of the MICA gene: a strong association of six GCT repetitions with Behçet disease.

55 : Whole-genome screening for susceptibility genes in multicase families with Behçet's disease.

56 : Endothelial nitric oxide synthase gene polymorphisms in Behçet's disease.

57 : Analysis of CD28 and CTLA-4 gene polymorphisms in Turkish patients with Behcet's disease.

58 : Polymorphisms in the endothelial nitric oxide synthase gene are associated with Behçet's disease.

59 : Vascular endothelial growth factor gene polymorphisms in Behçet's disease.

60 : Endothelial nitric oxide synthase gene polymorphisms in Behçet's disease and rheumatic diseases with vasculitis.

61 : HLA and tumour necrosis factor (TNF) polymorphisms in ocular Behçet's disease.

62 : TNF and TNF receptor polymorphisms in Korean Behcet's disease patients.

63 : Tumor necrosis factor gene polymorphisms in Tunisian patients with Behcet's disease.

64 : Nitric oxide synthase and superoxide dismutase gene polymorphisms in Behçet disease.

65 : Cytochrome P450 polymorphisms in patients with Behcet's disease.

66 : T helper 1 type cytokines polymorphisms: association with susceptibility to Behçet's disease.

67 : Interleukin-18 promoter polymorphisms in patients with Behçet's disease.

68 : TNF-alpha gene 1031 T/C polymorphism in Turkish patients with Behçet's disease.

69 : The ICAM-1 469 T/C gene polymorphism but not 241 G/A is associated with Behçets disease in the Lebanese population.

70 : Identification of novel genetic susceptibility loci for Behçet's disease using a genome-wide association study.

71 : TNF polymorphisms in patients with Behçet disease: a meta-analysis.

72 : Cytokine gene polymorphisms in Behçet's disease and their association with clinical and laboratory findings.

73 : Vascular endothelial growth factor gene polymorphisms and serum levels in Behçet's disease.

74 : CTLA4 gene polymorphisms and soluble CTLA4 protein in Behcet's disease.

75 : Association of TLR4 polymorphisms with Behcet's disease in a Korean population.

76 : Brief report: association of CCR1, KLRC4, IL12A-AS1, STAT4, and ERAP1 With Behçet's disease in Iranians.

77 : Pathogenesis of Behçet's disease: autoinflammatory features and beyond.

78 : Interleukin-10 gene polymorphisms are associated with Behcet's disease but not with Vogt-Koyanagi-Harada syndrome in the Chinese Han population.

79 : Endoplasmic reticulum-associated amino-peptidase 1 and rheumatic disease: genetics.

80 : Association of interleukin-23 receptor gene polymorphism with Behçet disease.

81 : Genetic Association of a Gain-of-Function IFNGR1 Polymorphism and the Intergenic Region LNCAROD/DKK1 With Behçet's Disease.

82 : Identification of Novel Risk Loci for Behçet's Disease-Related Uveitis in a Chinese Population in a Genome-Wide Association Study.

83 : Association of miRNA-146a Gene Polymorphism Rs2910164 with Behcet's Disease: A Meta-analysis.

84 : A single mutated MEFV allele in Israeli patients suffering from familial Mediterranean fever and Behçet's disease (FMF-BD).

85 : Common MEFV mutations among Jewish ethnic groups in Israel: high frequency of carrier and phenotype III states and absence of a perceptible biological advantage for the carrier state.

86 : Common FMF alleles may predispose to development of Behcet's disease with increased risk for venous thrombosis.

87 : Genetic analysis of MEFV gene pyrin domain in patients with Behçet's disease.

88 : Recognition of B-cell epitopes of the 65 kDa HSP in Behçet's disease.

89 : Circulating antibodies to inducible heat shock protein 70 in patients with uveitis.

90 : Increased peripheral blood gamma delta+ T cells and natural killer cells in Behçet's disease.

91 : Skin hypersensitivity to streptococcal antigens and the induction of systemic symptoms by the antigens in Behçet's disease--a multicenter study. The Behcet's Disease Research Committee of Japan.

92 : Association of salivary S. mutans colonisation and mannose-binding lectin deficiency with gender in Behçet's disease.

93 : The oral mucosal and salivary microbial community of Behçet's syndrome and recurrent aphthous stomatitis.

94 : Antibody response to oral streptococci in Behçet's disease.

95 : Chemiluminescence of neutrophils from patients with Behçet's disease and its correlation with an increased proportion of uncommon serotypes of Streptococcus sanguis in the oral flora.

96 : Effect of prophylactic benzathine penicillin on mucocutaneous symptoms of Behçet's disease.

97 : Streptococcal-related antigens stimulate production of IL6 and interferon-gamma by T cells from patients with Behcet's disease.

98 : Fine antigen specificity of human gamma delta T cell lines (V gamma 9+) established by repetitive stimulation with a serotype (KTH-1) of a gram-positive bacterium, Streptococcus sanguis.

99 : Serum levels of TNF-alpha, sIL-2R, IL-6, and IL-8 are increased and associated with elevated lipid peroxidation in patients with Behçet's disease.

100 : The effect of prophylactic penicillin treatment on the course of arthritis episodes in patients with Behçet's disease. A randomized clinical trial.

101 : Behçet's syndrome patients exhibit specific microbiome signature.

102 : A metagenomic study of the gut microbiome in Behcet's disease.

103 : Behçet's Disease Under Microbiotic Surveillance? A Combined Analysis of Two Cohorts of Behçet's Disease Patients.

104 : Intestinal microbiota composition of patients with Behçet's disease: differences between eye, mucocutaneous and vascular involvement. The Rheuma-BIOTA study.

105 : Microbiome and Behçet's disease: a systematic review.

106 : Increased seropositivity of Helicobacter pylori cytotoxin-associated gene-A in Behçet's disease.

107 : Is Helicobacter pylori associated with Behçet's syndrome? A meta-analysis.

108 : Serum mannose-binding lectin levels are decreased in behcet's disease and associated with disease severity.

109 : Differential expression of toll-like receptor 6 on granulocytes and monocytes implicates the role of microorganisms in Behcet's disease etiopathogenesis.

110 : The role of TLR2 and 4 in Behçet's disease pathogenesis.

111 : Higher expression of Toll-like receptors 2, 3, 4, and 8 in ocular Behcet's disease.

112 : Effects of vitamin D on expression of Toll-like receptors of monocytes from patients with Behcet's disease.

113 : IL-1βtriggered by peptidoglycan and lipopolysaccharide through TLR2/4 and ROS-NLRP3 inflammasome-dependent pathways is involved in ocular Behçet's disease.

114 : Involvement of innate immunity in the pathogenesis of intestinal Behçet's disease.

115 : Evaluation of DNA methylation status of toll-like receptors 2 and 4 promoters in Behcet's disease.

116 : Remission induction in Behçet's disease following lymphocyte depletion by the anti-CD52 antibody CAMPATH 1-H.

117 : Adenosine deaminase enzyme activity is increased and negatively correlates with catalase, superoxide dismutase and glutathione peroxidase in patients with Behçet's disease: original contributions/clinical and laboratory investigations.

118 : Adenosine deaminase enzyme levels, their relation with disease activity, and the effect of colchicine on adenosine deaminase levels in patients with Behçet's disease.

119 : Serum and erythrocyte adenosine deaminase activities in patients with Behçet's disease.

120 : Cytokine profile in Behçet's disease patients. Relationship with disease activity.

121 : Divergent cytokine production profile in Behçet's disease. Altered Th1/Th2 cell cytokine pattern.

122 : Expression of cytokines, chemokines, and chemokine receptors in oral ulcers of patients with Behcet's disease (BD) and recurrent aphthous stomatitis is Th1-associated, although Th2-association is also observed in patients with BD.

123 : Pathological implications of Th1/Th2 cytokine genetic variants in Behçet's disease: Data from a pilot study in a Sicilian population.

124 : Increased frequencies of interleukin-2- and interferon-gamma-producing T cells in patients with active Behçet's disease.

125 : Th1 polarization of the immune response in Behçet's disease: a putative pathogenetic role of interleukin-12.

126 : Intercellular adhesion molecule-1 gene polymorphisms in Behçet's Disease.

127 : Involvement of chemokines and Th1 cytokines in the pathogenesis of mucocutaneous lesions of Behçet's disease.

128 : The demonstration of serum interleukin 6-8, tumor necrosis factor-alpha, complement, and immunoglobulin levels in Behçet's disease with ocular involvement.

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

130 : Involvement of Th1 cells and heat shock protein 60 in the pathogenesis of intestinal Behcet's disease.

131 : Systemic levels of the T cell regulatory cytokines IL-10 and IL-12 in Bechçet's disease; soluble TNFR-75 as a biological marker of disease activity.

132 : Adamantiades-Behçet's disease: serum IL-8 is a more reliable marker for disease activity than C-reactive protein and erythrocyte sedimentation rate.

133 : Serum interleukin-18 levels in patients with Behçet's disease. Is its expression associated with disease activity or clinical presentations?

134 : Soluble tumour necrosis factor receptors sTNFR1 and sTNFR2 are produced at sites of inflammation and are markers of arthritis activity in Behçet's disease.

135 : Significance of serum interleukin-8 levels in patients with Behcet's disease: high levels may indicate vascular involvement.

136 : Overproduction of monocyte derived tumor necrosis factor alpha, interleukin (IL) 6, IL-8 and increased neutrophil superoxide generation in Behçet's disease. A comparative study with familial Mediterranean fever and healthy subjects.

137 : Inflammatory mediators and posterior segment involvement in ocular Behcet disease.

138 : Interleukin-6 in neuro-Behçet's disease: association with disease subsets and long-term outcome.

139 : Increased expression of interleukin-23 p19 mRNA in erythema nodosum-like lesions of Behçet's disease.

140 : Dendritic cell subsets and type I interferon system in Behçet's disease: does functional abnormality in plasmacytoid dendritic cells contribute to Th1 polarization?

141 : Serum levels of Th2 cytokines IL-4 and IL-10 in Behçet's disease.

142 : Inhibition of Th17 differentiation by anti-TNF-alpha therapy in uveitis patients with Behçet's disease.

143 : Excessive CD4+ T cells co-expressing interleukin-17 and interferon-γin patients with Behçet's disease.

144 : Th17 cells in Behçet's disease: a new immunoregulatory axis.

145 : Critical role of IL-21 in modulating TH17 and regulatory T cells in Behçet disease.

146 : [The changes of Th lymphocyte subsets in patients with Behcet disease].

147 : Genome-wide association study identifies GIMAP as a novel susceptibility locus for Behcet's disease.

148 : The Role of Th17 Cells in the Pathogenesis of Behcet's Disease.

149 : Th17-Inducing Conditions Lead to in vitro Activation of Both Th17 and Th1 Responses in Behcet's Disease.

150 : Interleukin-26 is overexpressed in Behçet's disease and enhances Th17 related -cytokines.

151 : Gammadelta T cells in Behçet's disease (BD) and recurrent aphthous stomatitis (RAS).

152 : CD56+ T cells in the peripheral blood of uveitis patients.

153 : Increased CD4+CD16+ and CD4+CD56+ T cell subsets in Behçet's disease.

154 : Chemokine expression of intraocular lymphocytes in patients with Behçet uveitis.

155 : Expansion of gammadelta T-cells in Behçet's disease: role of disease activity and microbial flora in oral ulcers.

156 : Phenotype markers and cytokine intracellular production by CD8+ gammadelta T lymphocytes do not support a regulatory T profile in Behçet's disease patients and healthy controls.

157 : Diversity of gammadelta T cells in patients with Behcet's disease is indicative of polyclonal activation.

158 : CTLA-4 +49A/G polymorphism is associated with Behçet's disease in a Tunisian population.

159 : Autoreactive CD8+ cytotoxic T lymphocytes to major histocompatibility complex class I chain-related gene A in patients with Behçet's disease.

160 : The number of CD8+ T cells and NKT cells increases in the aqueous humor of patients with Behçet's uveitis.

161 : Clonally accumulating T cells in the anterior chamber of Behçet disease.

162 : Capacity of ocular infiltrating T helper type 1 cells of patients with non-infectious uveitis to produce chemokines.

163 : CD8brightCD56+ T cells are cytotoxic effectors in patients with active Behcet's uveitis.

164 : Intraocular cytokine environment in active Behçet uveitis.

165 : [Production of Th1/Th2 cytokines and nitric oxide in Behçet's uveitis and idiopathic uveitis].

166 : Synovial proinflammatory cytokines and their correlation with matrix metalloproteinase-3 expression in Behçet's disease. Does interleukin-1beta play a major role in Behçet's synovitis?

167 : NF-kappaB protects Behçet's disease T cells against CD95-induced apoptosis up-regulating antiapoptotic proteins.

168 : Circulating neutrophils in Behçet disease is resistant for apoptotic cell death in the remission phase of uveitis.

169 : Assessment of homocysteine, neopterin and nitric oxide levels in Behçet's disease.

170 : Is there any relationship between serum and urine neopterin and serum interferon-gamma levels in the activity of Behcet's disease?

171 : Activation of the JAK/STAT pathway in Behcet's disease.

172 : Oligoclonal B lymphocyte expansion in the synovium of a patient with Behçet's disease.

173 : Phenotypic characteristics of B cells in Behçet's disease: increased activity in B cell subsets.

174 : Antibodies to endothelial cells in patients with Behçet's disease.

175 : Anti-endothelial cell antibodies, endothelial proliferation and von Willebrand factor antigen in Behçet's disease.

176 : Autoantibodies to T cell costimulatory molecules in systemic autoimmune diseases.

177 : Detection of autoantibodies to killer immunoglobulin-like receptors using recombinant fusion proteins for two killer immunoglobulin-like receptors in patients with systemic autoimmune diseases.

178 : Autoantibodies against oxidatively modified low-density lipoprotein in patients with Behçet's disease.

179 : Antikinectin autoantibody in Behçet's disease and several other autoimmune connective tissue diseases.

180 : Anti-Saccharomyces cerevisiae antibody in intestinal Behçet's disease patients: relation to clinical course.

181 : Meta-analysis of anti-Saccharomyces cerevisiae antibodies as diagnostic markers of Behçet's disease with gastrointestinal involvement.

182 : Anti-MHC autoimmunity in Behçet's disease: T cell responses to an HLA-B-derived peptide cross-reactive with retinal-S antigen in patients with uveitis.

183 : Cellular autoimmunity to retinal specific antigens in patients with Behçet's disease.

184 : Prospective determination of T-cell responses to S-antigen in Behçet's disease patients and controls.

185 : S-antigen specific T helper type 1 response is present in Behcet's disease.

186 : Alpha tropomyosin as a self-antigen in patients with Behçet's disease.

187 : Proteomic surveillance of autoimmunity in Behcet's disease with uveitis: selenium binding protein is a novel autoantigen in Behcet's disease.

188 : Immune responses to interphotoreceptor retinoid-binding protein and S-antigen in Behcet's patients with uveitis.

189 : Identification of alpha-tropomyosin as a target self-antigen in Behçet's syndrome.

190 : Identification of kinectin as a novel Behçet's disease autoantigen.

191 : Endothelial functions in Behçet's disease.

192 : Vascular endothelial function and oxidative stress mechanisms in patients with Behçet's syndrome.

193 : Impaired endothelium-dependent flow-mediated dilation in Behçet's disease: more prominent endothelial dysfunction in patients with vascular involvement.

194 : Enhancement of endothelial cell E-selectin expression by sera from patients with active Behçet's disease: moderate correlation with anti-endothelial cell antibodies and serum myeloperoxidase levels.

195 : Impaired prostacyclin synthesis by vessel walls in Behçet's disease.

196 : Increased nitric oxide production in patients with Behçet's disease: is it a new activity marker?

197 : The pathophysiological significance of red blood cell nitric oxide concentrations in inflammatory Behçet's disease.

198 : Aqueous humor nitric oxide levels in patients with Behçet disease.

199 : Nitric oxide, lipid peroxidation and antioxidant defence system in patients with active or inactive Behçet's disease.

200 : Synovial nitric oxide concentrations are increased and correlated with serum levels in patients with active Behçet's disease: a pilot study.

201 : Asymmetric dimethylarginine and nitric oxide levels as signs of endothelial dysfunction in Behcet's disease.

202 : Oxidative stress: correlation with Behçet's disease duration, activity and severity.

203 : Vascular endothelial function and plasma homocysteine levels in Behcet's disease.

204 : Serum homocysteine level is increased and correlated with endothelin-1 and nitric oxide in Behçet's disease.

205 : Serum homocysteine level is higher in Behçet's disease with vascular involvement.

206 : Homocysteine: an activity marker in Behçet's disease?

207 : Homocysteine in vascular Behcet disease: a meta-analysis.

208 : Significantly higher frequencies of hemoglobin, iron, vitamin B12, and folic acid deficiencies and of hyperhomocysteinemia in patients with Behcet's disease.

209 : Vascular endothelial growth factor levels are increased and associated with disease activity in patients with Behçet's syndrome.

210 : Vascular endothelial growth factor and monocyte chemoattractant protein-1 in Behçet's patients with venous thrombosis.

211 : Expressions of vascular endothelial growth factor and CD34 in oral aphthous lesions of Behçet's disease.

212 : VEGF and mRNA VEGF expression in CSF from Behçet's disease with neurological involvement.

213 : Association of vascular endothelial growth factor gene polymorphisms with behcet disease in a Korean population.

214 : Human alpha-enolase from endothelial cells as a target antigen of anti-endothelial cell antibody in Behçet's disease.

215 : Human anti-alpha-enolase antibody in sera from patients with Behçet's disease and rheumatologic disorders.

216 : Serum leptin concentration is increased in patients with Behçet's syndrome and is correlated with disease activity.

217 : Endothelial cell activation and hypercoagulability in ocular Behçet's disease.

218 : Vascular involvement in Behçet's disease: relation with thrombophilic factors, coagulation activation, and thrombomodulin.

219 : Haemostatic markers of procoagulant imbalance in Behçet's disease.

220 : Activated protein C levels in Behçet's disease and risk of venous thrombosis.

221 : Circulated activated platelets and increased platelet reactivity in patients with Behçet's disease.

222 : Decreased erythrocyte deformability in Behçet's disease.

223 : Reduced erythrocyte deformability in active and untreated Behçet's disease patients.

224 : Fibrinolytic activity and d-dimer levels in Behçet's syndrome.

225 : Neutrophil Activation Promotes Fibrinogen Oxidation and Thrombus Formation in Behçet Disease.

226 : Thrombophilic factors are not the leading cause of thrombosis in Behçet's disease.

227 : A study on thrombophilic factors in Italian Behcet's patients.

228 : Fibrinolytic inhibitor levels and polymorphisms in Behçet disease and their association with thrombosis.

229 : Vascular involvement in Behçet's disease: relation with thrombophilic factors, coagulation activation, and thrombomodulin.

230 : Thrombophilic factors are not the leading cause of thrombosis in Behçet's disease.

231 : Vascular endothelial function and oxidative stress mechanisms in patients with Behçet's syndrome.

232 : Arterial and venous involvement in Behçet's syndrome: a narrative review.

233 : Intima-media thickness and arterial distensibility in Behçet's disease.

234 : Interleukin 8 in Behçet's disease.

235 : Enhanced interleukin 8 secretion in circulation of patients with Behçet's disease.

236 : Neutrophil CD64 expression in Behçet's disease.

237 : Neutrophil adhesion to endothelial cells and factors affecting adhesion in patients with Behçet's disease.

238 : Levels of circulating intercellular adhesion molecule-1 in patients with Behçet's disease.

239 : Serum-soluble selectin levels in patients with Behçet's disease.

240 : Serum levels of soluble P-selectin are increased and associated with disease activity in patients with Behçet's syndrome.

241 : Interferon-beta and adhesion molecules (E-selectin and s-intracellular adhesion molecule-1) are detected in sera from patients with retinal vasculitis and are induced in retinal vascular endothelial cells by Toll-like receptor 3 signalling.

242 : Possible physiological roles of proteolytic products of actin in neutrophils of patients with Behçet's disease.

243 : Characterization of a protease responsible for truncated actin increase in neutrophils of patients with Behçet's disease.

244 : Relationship between lipid peroxidation and disease activity in patients with Behçet's disease.

245 : Serum of Behçet's disease enhances superoxide production of normal neutrophils.

246 : Elevated serum granulocyte colony-stimulating factor levels in patients with active phase of sweet syndrome and patients with active behcet disease: implication in neutrophil apoptosis dysfunction.

247 : Polymorphonuclear leukocyte elastase levels in patients with Behçet's disease.

248 : Increased advanced oxidation protein products in Behçet's disease: a new activity marker?

249 : Neutrophils contribute to vasculitis by increased release of neutrophil extracellular traps in Behçet's disease.

250 : Neutrophil Extracellular Traps Promote Aberrant Macrophages Activation in Behçet's Disease.

251 : Elevated levels of MMP-9 and TIMP-1 in the cerebrospinal fluid of neuro-Behçet's disease.

252 : Distinct synovial immunopathology in Behçet disease and psoriatic arthritis.

253 : Monocyte activity in Behçet's disease.

254 : Neutrophil hyperchemotaxis in Behçet's disease: a possible role for monocytes orchestrating bacterial-induced innate immune responses.

255 : Epigenetic alterations in chronic disease focusing on Behçet's disease: Review.

256 : Epigenome-wide scan identifies a treatment-responsive pattern of altered DNA methylation among cytoskeletal remodeling genes in monocytes and CD4+ T cells from patients with Behçet's disease.

257 : Aberrant DNA methylation of GATA binding protein 3 (GATA3), interleukin-4 (IL-4), and transforming growth factor-β(TGF-β) promoters in Behcet's disease.

258 : Vasculitis in Behçet's disease.

259 : Behçet's disease: an enigmatic vasculitis.

260 : Direct immunofluorescence in Behçet's disease: a controlled study with 108 cases.

261 : The significance of immunohistochemistry in the skin pathergy reaction of patients with Behçet's syndrome.

262 : Histopathologic Study of Pathergy Test in Behçet's Disease.

263 : Histological and immunofluorescence findings of non-follicular papulopustular lesions in patients with Behçet's disease.

264 : Histopathologic and direct immunofluorescence findings of the papulopustular lesions in Behçet's disease.

265 : The pustular skin lesions in Behcet's syndrome are not sterile.

266 : Histopathology of central nervous system lesions in Behçet's disease.

267 : Renal involvement in Behcet's disease.

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟