A genetic study of Behçet''s disease in Taiwan Chinese

The frequency of HLA-A, B and C antigen in 53 patients and HLA-DR, DQ and Dn antigen in 31 patients of Beh?et's disease was studied. All patients were Chinese, and diagnosis was made according to the Japanese Research Committee on Beh?et's disease. A significantly increased incidence of HLA-B51 (P less than 0.001) and a significantly decreased incidence of HLA-B16 (P less than 0.01) was found. No significant difference was found in HLA-DR, DQ and DN antigens.     

Behçet's disease from the aspect of autoinflammatory disease

Beh?et's disease is a systemic inflammatory disease presented with recurrent oral aphtha, cutaneous manifestations, uveitis, and genital ulcer. The etiology of Beh?et's disease is still unknown, but both genetic background and environmental factors are thought to be important in the pathogenesis of Beh?et's disease. Beh?et's disease has long been regarded as a Th1 type autoimmune disease, because of the association with HLA-B51 and hyperreactivity against streptococcal antigen. However, it was recently found that Beh?et's disease and autoinflammatory diseases share several clinical features. Furthermore, increased activity of neutrophils and elevated levels of interleukin-1β are observed in both Beh?et's disease and autoinflammatory diseases. The relationship between Beh?et's disease and autoinflammatory diseases, especially Familial Mediterranean fever, is speculated, because both diseases are prevalent in the Mediterranean basin and treated with colchicine. Genetic researches on Beh?et's disease and FMF suggest that the MEFV gene mutated in Familial Mediterranean fever is a probable susceptibility gene for Beh?et's disease. Although many observations suggest that Beh?et's disease might be autoinflammatory, there is evidence implying autoimmune pathogenesis of Beh?et's disease. For example, some symptoms of Beh?et's disease is treated with T cell suppressing agents. Recent data suggest that a novel subset of T cells, Th17, plays a crucial role in pathogenesis of Beh?et's disease, and genome-wide association researches verified it. IL-17, which is the secreted from of Th17 activates neutrophils. Hence, IL-17 might cause the symptoms resembling autoinflammatory diseases. Recently, Anti-IL-1 treatment proved to be effective and other susceptibility genes are being investigated. These new findings will shed light on the long-sought pathogenesis of Beh?et's disease.     

Class I and class II MHC polymorphisms in Mexican patients with Behçet's disease

Beh?et's disease is a multi-system inflammatory disorder of unknown etiology. The disease is more prevalent in Eastern Mediterranean countries and Japan where there is a linkage to HLA-B51. Mexican Mestizos are suitable subjects for studying the role of ethnicity in the susceptibility to Beh?et's disease. High-resolution HLA class I and class II typing was performed by polymerase chain reaction sequence-specific oligonucleotide (PCR-SSO) reverse dot blot and PCR-single-strand polymorphism in 32 patients with Beh?et's disease and 99 healthy ethnically-matched controls. A significant increased frequency of HLA-B(*)44 (P = 0.02; OR = 2.78; CI 95% = 1.1-7.7), HLA-B(*)52 (P = 0.02; OR = 5.33; CI 95% = 1.07-29.1), and HLA-B(*)56 (P = 0.003; OR = 4.19; CI 95% = 3.37-5.21) as well as HLA-DRB1(*)01 and HLA-DRB1(*)13 (p = 0.007; OR = 3.36; CI 95% = 1.22-9.27) was found in Mexican patients with Beh?et's disease when compared to controls. The low frequency of native markers in Mexican Mestizo patients with Beh?et's disease suggests that genetic admixture between Eastern Mediterraneans and Orientals with Amerindians is a recent event that increased the risk of developing Beh?et's disease in the Mexican population.     

Significant associations of HLA-B*5101 and B*5108, and lack of association of class II alleles with Behçet's disease in Italian patients

Beh?et's disease has been known to be strongly associated with human leukocyte antigen (HLA) B51, one of the split antigens of HLA-B5. An increased incidence of HLA-B51 in the patient group has also been reported in an Italian population. Since the B51 antigen has been recently identified to comprise nine alleles, B*5101-B*5109, we performed HLA-B51 allele genotyping by the polymerase chain reaction-sequencing based typing (PCR-SBT) method as well as serological HLA-A and -B typing among 21 Italian patients with Beh?et's disease in order to investigate whether there is any correlation of one particular B51-associated allele with Behcet's disease. In addition, HLA class II genotyping was performed by the PCR-restriction fragment length polymorphism (RFLP) method. As a result, only the phenotype frequency of the B51 antigen was found to be significantly increased in the patient group as compared to the ethnically matched control group by the corrected P-value analysis (71.4% in patients vs. 17.9% in controls; chi2 = 14.26, Pc = 0.0042, R.R. = 11.5). In the B51 allele genotyping, 11 out of 15 B51-positive patients were B*5101 and the remaining four were B*5108, whereas all of 5 normal controls were B*5101, showing significant association of each allele with Beh?et's disease. No significant difference was observed between the patient and control groups in the HLA class II allelic distribution. This study revealed a strong association of Beh?et's disease in Italian with B*5108 as well as B*5101, providing important insight into the molecular mechanism underlying an HLA association with Beh?et's disease.     

Neuronal hyaline inclusions observed in an autopsy case of Beh?et's disease.

An autopsy case of Beh?et's disease is reported. The patient, a 59-year-old Japanese woman, died of intestinal bleeding after a 34-year clinical course of Beh?et's disease. She also suffered from recurrent oral aphthous ulcers, erythema nodosum-like cutaneous lesions and genital ulcerated lesions. Autopsy revealed marked atherosclerosis of the aorta and multiple deep ulcerations in the terminal ileum with no significant vascular lesions. Lewy bodies and globular hyaline inclusions in the neurons of the central nervous system were noted, although there were no clinical symptoms of Parkinson's disease throughout the clinical course. These findings appear to suggest that the patient was probably in the preclinical or early stage of Parkinson's disease. However, the presence of Lewy bodies in the 6th decade without any accompanying symptoms is very rare. This case seems to draw attention to the presence of these neuronal inclusions in Beh?et's disease.     

Beh?et's disease sera containing antiendothelial cell antibodies promote adhesion of T lymphocytes to cultured human dermal microvascular endothelial cells.

Antiendothelial cell antibodies (AECA) have been detected in the sera of patients of autoimmune diseases showing vasculitis. Using IgM-ELISA, we found AECA in 42 (56%) of 75 sera samples from patients with Beh?et's disease in a previous study. All of the 15 AECA-positive sera of Beh?et's disease patients had an increased expression of the intercellular cell adhesion molecule-1 (ICAM-1), 93.3% of the sera induced the vascular cell adhesion molecule-1 (VCAM-1), and 100% of the serum induced the E-selectin molecule on human dermal microvascular endothelial cells (HDMEC). After stimulation of HDMEC with AECA-positive sera of Beh?et's disease patients, the expression of ICAM-1 and VCAM-1 on HDMEC increased significantly at 4 hours, reaching a peak at 16 hours. Expression of E-selectin was induced at 1 hour after stimulation with a peak at 4 hours and it decreased thereafter. Adherence of T lymphocytes to HDMEC increased significantly after stimulation with AECA-positive sera from Beh?et's disease patients. Also, the adherence of T lymphocytes to HDMEC increased at 4 hours and returned to its normal level at 48 hours. These results show that AECA-positive sera of Beh?et's disease patients are capable of activating HDMEC to promote the adherence of T lymphocytes to increase the expression of ICAM-1, VCAM-1, and E-selectin on the cell surfaces. The whole process may play an important role in the pathogenesis of vasculitis in Beh?et's disease.     

Serum homocysteine level in Behçet's disease

Recent studies of the prevalence of hyperhomocysteinemia in Beh?et's disease have shown contradicting results. The aim of the present study was to investigate the serum homocysteine level in patients diagnosed as having Beh?et's disease. Venous blood was taken from 27 patients with Beh?et's disease and 21 healthy controls. Serum homocysteine levels were measured using fluorescence polarization immunoassay. In addition, serum vitamin B12 and folic acid levels were measured by chemiluminescent enzyme immunoassay. The mean levels of vitamin B12, folic acid, and homocysteine were not significantly different in patients with Beh?et's disease when compared with the healthy controls (p = 0.17, p = 0.13, and p = 0.05, respectively). The results of this study confirmed that homocysteine levels were not elevated in Beh?et's disease when compared with the control group. Further studies in a subset of Beh?et patients with a history of thrombosis are needed to determine the prevalence of hyperhomocysteinemia in the thrombotic form of the disease.     

The absence of disease-specific polymorphisms within the HLA-B51 gene that is the susceptible locus for Behçet''s disease

Beh?et's disease is known to be associated with HLA-B51 in many different populations. Genetic evidence supports that the susceptible gene for Beh?et's disease is the HLA-B51 allele at the HLA-B locus. This study was aimed to determine the HLA-B51 nucleotide sequence variation in three Beh?et's disease patients and three healthy controls in order to elucidate if any disease specific mutations or polymorphisms may exist in the HLA-B51 gene of patients. Long-range polymerase chain reaction (PCR) was first carried out to give a PCR-amplified product of 9.5 kb which was then used as a template for nested PCR to give a final amplified product of 4.2 kb. This final product containing the 1.3-kb promoter/enhancer region and the entire HLA-B gene except for a 363-bp 3' terminal end segment encoding the 3' untranslated region was subcloned by the BP cloning technique and sequenced. The sequencing results showed that all the patients possessed the HLA-B*51011 allele, and there were no differences in the exonic nucleotide sequences between the three Beh?et's disease patients and the three healthy controls. The HLA-B*51011 intronic and promoter/enhancer nucleotide sequences from the three patients had 22 single nucleotide polymorphisms (SNPs), a single insertion of 6 bp and a single deletion of 2 bp. On the other hand, the three healthy controls had 24 SNPs in their intronic and promoter/enhancer regions. However, none of these polymorphisms in the patients were specific for the disease. Therefore, these results clearly demonstrate that the HLA-B exonic sequence that encodes the HLA-B51 allele is the real pathogenic factor in Beh?et's disease.     

Lymphocyte gamma-glutamyl transferase activity in Beh?et's disease

In this study the activity of a membrane-bound enzyme, gamma-glutamyl transferase GGT (gamma-glutamyl transpeptidase - GGTP), was investigated in the peripheral blood lymphocytes (PBL) from patients with Beh?et's disease. Lymphocyte GGT activity in Beh?et's disease was found to be significantly lower than that of control lymphocytes (p less than 0.01). This altered activity may be due to the abnormality in the membrane of lymphocytes of Beh?et's disease patients.     

Behçet's disease: the first Mongolian case in literature showing HLA B51, MICA gene type *5/*6

Beh?et's disease is a chronic multi-systemic disease of unknown origin that includes mucocutaneous, ocular, cardiac, vascular, renal, gastrointestinal, neurologic and cutaneous involvement. The disease is spread throughout the world, but it is most prevalent in the eastern Mediterranean region-along the Silk Road-, and in Japan, China, and Korea. Recently, we treated a Mongolian patient who had complete-type Beh?et's disease. As far as we know, this case is the first report of a Mongolian with Beh?et's disease in the English literature. HLA typing in this patient revealed A2, A24;B51, B35; Cw4, Cw7; DR9, DR11. Study of the MICA genetype showed *5, *6 positive. Our data provided adequate evidence, from an epidemiological aspect, to support the belief that Beh?et's disease is most prevalent along the old Silk Road.     

HLA antigens in a family with Beh?et's syndrome

A family is described in which 3 of 12 members suffered from Beh?et's syndrome. Four members, including the three patients with Beh?et's syndrome suffered from recurrent aphthous stomatitis. These four family members possessed the HLA-haplotype HLA A2, B15, Cw3, DR4. However, one relative had inherited the same HLA-haplotype without showing any symptoms of the disease. Genetic influence from the actual HLA-haplotype may interact in manifestation of the syndrome.     

Lack of association of MICA transmembrane region polymorphism and Behçet''s disease in Spain

We have analyzed the distribution of the major histocompatibility complex (MHC) class I chain-related gene A (MICA) transmembrane alleles among 58 Spanish patients with Beh?et's disease (BD) and in 194 ethnically matched healthy controls. The study included the characterization of A4, A5, A5.1, A6 "new" and "old" and A9 MICA-TM alleles using polymerase chain reaction. As previously reported, the serological B51 specificity was increased among this BD patient group (36.25% vs. 19.6% in controls; P=0.009; OR=2.33). The MICA-TM alleles A6 ("new" and "old"), in linkage disequilibrium with HLA-B51 and HLA-B14 respectively, were only slightly increased among patients (70.7% vs. 61.3% in controls; P=NS). We conclude that, in contrast to previous finding reporting a strong association of MICA-TM genes and Beh?et disease in Japanese patients, in our population HLA-B51 is more closely associated to Beh?et susceptibility than MICA-TM genes. Finally, our data show that in Spain, as occurs in other populations, some MICA-TM alleles exhibit strong linkage disequilibrium with certain alleles of the HLA-B locus.     

Identification of alpha-tropomyosin as a target self-antigen in Beh?et's syndrome.

Beh?et's syndrome is a multi-system inflammatory disease affecting mainly the oral and urogenital mucosa and the uveal tract. The etiology and pathogenesis of Beh?et's syndrome are unknown, but autoimmune mechanisms are implicated. We initiated this work to identify self-antigens targeted by patients with Beh?et's syndrome. We used patient sera to immuno-blot tissue lysates, and we found that some patients manifest antibodies to a 37-kDa band. The 37-kDa band was detected in extracts of skin, tongue, vagina, muscle and heart but not in brain, kidney, lung, liver, intestine and thymus. In-gel digestion and mass spectrometry revealed the band to be alpha-tropomyosin. Autoimmunity to alpha-tropomyosin can be pathogenic; immunized Lewis rats developed lesions in the uveal tract and skin, with features of Beh?et's disease.     

Crohn's disease in the Japanese is associated with the HLA-DRw53

The association of Crohn's disease (CD) with the HLA system was investigated in Japanese patients by serological and genomic methods. HLA antigens were typed in 30 unrelated Japanese patients with CD and 54 healthy controls. The frequencies of HLA-DR4, DRw53 and DQw3 antigens were increased in CD (76.7, 86.7 and 80.0%) compared with controls [37.0%, p corrected (pc) = 0.007; 52.9%, pc = 0.001; 52.0%, pc = 0.009]. DQw7 and DQw8 antigens, the new split antigens of DQw3 produced by the TA10 antibody and linked to the DR4 and DRw53 antigens, were not significantly different in the DQw3-positive CD and controls. Class I antigens were not significantly different in the CD and controls. HLA-DR-B and DQ-B probes were used to study PstI-generated restriction fragment length polymorphism (RFLP) in CD and controls. The DRw53-specific PstI DR-B 2.6-kb fragment was increased in CD (88.0%) compared with controls (37.5%, pc = 5.6 X 10(-4)). The PstI DR-B 3.2-kb fragment was also increased in CD (80.0%) compared with controls (35.0%, pc = 5.6 X 10(-3)). It is reasonable to infer that the DRw53 is the most important susceptibility antigen in Japanese CD. The subtypes of the DR4 were determined by the hybridization of the DQ-B probe. The DQ-B PstI fragment patterns were not different in CD and controls.     

Ruptured renal artery stump aneurysm in a renal autotransplanted Behçet's disease patient

A recurrent aneurysm at the anastomosis site or the remaining artery frequently occurs after the operative treatment of an aneurysm in Beh?et's disease despite anti-inflammatory medication. Herein, a ruptured left renal artery stump aneurysm in a patient with Beh?et's disease, who received a left nephrectomy, aorto-biiliac bypass and heterotopic autotransplantation of the right kidney for the treatment of an abdominal aortic aneurysm and renal hypertension one year prior to this admission, is reported. An aneurysm and rupture occurred despite the administration of anti-inflammatory medications while monitoring of the clinical findings, such as skin manifestations, erythrocyte segmentation rate (ESR) and C-reactive protein (CRP). Although there is no definite proven treatment modality to prevent recurrent aneurysms at the anastomosis site or a remote artery, close follow-up with anti-inflammatory medications, and surveillance with regular intervals are the only current methods for the prevention and/or to treatment of an arterial complication in patients with Beh?et's disease.     

Case of Beh?et's disease with frequent recurrence of multiple pulmonary abscess-like opacities]

A 39-year-old woman, who had a history of recurrent oral and genital ulcerations and folliculitis and had had a low-grade fever since December 2003, consulted our hospital on February 5, 2004. Chest radiography and computed tomography (CT) showed multiple pulmonary abscess-like opacities. She was admitted to the Department of Respiratory Medicine and Allergology, Kinki University School of Medicine on February 19, 2004. A transbronchial lung biopsy showed nonspecific inflammation with lymphocytic infiltration. The patient was discharged after she showed improvement with antibiotic therapy. She was readmitted to our hospital on October 3, 2006, because of recurrence of pulmonary abscess-like opacities. Bronchoalveolar lavage showed lymphocytosis (53%) but yielded no significant bacteria on culture. Beh?et's disease was diagnosed on the basis of the three major symptoms (recurrent oral and genital ulcerations and folliculitis). The frequent recurrence of pulmonary lesions was suspected to be due to immunological impairment associated with Beh?et's disease, and the pulmonary lesions and inflammatory reaction tests showed improvement after colchicine was administered. The patient was discharged on October 28, 2006. To our knowledge this is the third reported case of frequently recurrent multiple pulmonary abscess-like opacities in Beh?et's disease.     

The F response parameters in Behçet's disease

The F response parameters may provide a sensitive method for detection of mild neuropathy in patients with otherwise normal nerve conduction studies. We investigated conventional nerve conduction studies and F response parameters in patients with Beh?et's disease (BD), but without neurologic involvement. The results indicate that ulnar motor and sensory, tibial motor and sural sensory nerve conduction studies failed to differentiate the patients with BD and controls. In the ulnar nerve, the F response parameters were not significantly different for the populations. In the tibial nerve, the F response latency and chronodispersion were increased while F amplitude, duration, and persistence were all decreased in patients with BD. The results suggests that, (1) peripheral nerve dysfunction occurred especially in lower extremities in patients with Beh?et's disease. (2) The F response parameters were considered the most sensitive method for the detection of neuropathy in Beh?et's disease.     

Beh?et's syndrome. Immunopathologic and histopathologic assessment of pathergy lesions is useful in diagnosis and follow-up

Beh?et's syndrome is a complex multisystem disease that, due to the absence of a pathognomonic laboratory test, must be diagnosed using clinical criteria. Clinical pathergy testing, the induction of a sterile pustule 24 hours after cutaneous trauma, has been proposed as a useful adjunct to diagnosis. We have expanded this concept by showing the usefulness of examining pathergy lesions by routine and immunofluorescence microscopy in the diagnosis of nine patients with Beh?et's syndrome. Furthermore, histopathologic pathergy assessments correlated with clinical disease activity and/or response to experimental oral thalidomide therapy in five of six patients with Beh?et's syndrome who were retested.     

IL-10 genotype analysis in patients with Behçet's disease

Beh?et's disease (BD) is a multisystem inflammatory disease characterized by recurrent orogenital ulceration, ocular inflammation, and skin lesions. The etiology of the disease is currently unknown but evidence suggests that there is a strong genetic component mediating the chronicity of the disorder. We have examined the association between polymorphisms at position -1082, and -819 in the promoter region of the gene encoding IL-10 in patients with Beh?et's disease from two distinct patient populations. The IL-10 -1082AA genotype was weakly associated with BD when all patients were analyzed as a group (pc = 0.04, OR 1.4, 95% CI 1.1-1.9), but not in the UK or Middle Eastern (ME) cohorts of patients alone compared to local controls. An association with IL-10 -819T was evident in all BD patients, (pc = 0.02, OR 1.5, 95% CI 1.1-2.0), and this was because of an association in the UK but not ME patients (pc = 0.0004, OR 2.1, 95% CI 1.4-3.3). The -1082A/-819T haplotype, which is linked to low production of this cytokine, was not significantly associated with Beh?et's disease. This link between BD, a chronic, relapsing, autoinflammatory condition, and a genotype associated with low IL-10 production provides evidence that abnormalities in the genetic control of cytokine levels may be relevant in influencing the immune response in Beh?et's disease in some patient groups.     

Low-dose weekly methotrexate therapy for progressive neuro-Beh?et's disease]

Among a variety of central nervous system (CNS) manifestations of Beh?et's disease, the most serious one is progressive dementia. However, there has been no effective treatment to prevent the progression of dementia. The present studies have examined the efficacy of low-dose weekly methotrexate therapy for the progressive dementia in Beh?et's disease. Six patients with the progressive type of neuro-Beh?et's disease were treated with low-dose weekly methotrexate (7.5-15 mg/week). Neurological findings, psychological findings, brain MRI and IL-6 in cerebrospinal fluid were evaluated at the start and one year after the initiation of the therapy. All the 6 patients were refractory to the conventional therapy for neuro-Beh?et's disease. The progression of neuropsychological abnormalities such as dementia was not recognized after one year from the initiation of methotrexate therapy. Consistently, IL-6 levels in cerebrospinal fluid were significantly decreased after one year from the initiation of therapy. Six months after the discontinuation of low-dose weekly methotrexate, progression of neuropsychological abnormalities such as dementia was recognized, and IL-6 levels in cerebrospinal fluid were significantly increased. These findings may suggest the suppression of the ongoing inflammatory process in the intracranial lesions by methotrexate. These results suggest that low-dose weekly methotrexate therapy may be a new promising method for the treatment of the progressive type of neuro-Beh?et's disease.