HLA-B5 prevalence in patients with spondyloarthritis and impact on disease phenotype: a multicentric case-control study.

OBJECTIVE: The study aimed to estimate the prevalence of HLA-B51 and HLA-B52 in Lebanese patients with spondyloarthritis (SpA) compared to healthy controls (HC). We further aimed to evaluate the impact of HLA-B51 on phenotype and identify the distribution of the alleles in the HLA-B locus. METHODS: A case-control study enrolled consecutive SpA patients from three rheumatology clinics in Lebanon, including axial (axSpA), peripheral SpA (pSpA), and psoriatic arthritis (PsA) and HC from blood donors. Demographic and disease data were collected through interviews and file reviews, with testing of the entire HLA-B locus using molecular techniques. The prevalence of HLA-B51 and B52 was estimated in SpA patients versus controls. Prevalence comparisons were made, and logistic regression identified factors associated with HLA-B51 in patients. RESULTS: Data from 120 HC and 86 SpA patients (65 axSpA, 15 pSpA, 6 PsA), mean age 25.6 and 46.4 years, respectively, showed a higher HLA-B51 prevalence in SpA (25.6%), especially axSpA (29.2%) versus HC (12.5%), p = 0.016, and a numerically higher HLA-B52 prevalence (8.1% versus 4.2%, p = 0.230). HLA-B51 correlated with recurrent oral ulcerations (OR 7.99(95%CI 2.14-29.84) and radiographic juxta-articular erosions (OR 7.65(95%CI 1.14-38.03)). HLA-B35 was the most dominant allele in both groups (18.7%), followed by HLA-B27 (15.7%) and HLA-B51 (13.4%) in SpA. CONCLUSION: HLA-B51 was identified more frequently in patients with SpA compared to HC and was associated with recurrent oral ulcerations and juxta-articular radiographic erosions. Longitudinal studies are needed to determine whether this association indicates a disease overlap or might correlate with a specific SpA phenotype.

Significant association of HLA-A26 with uveitis and gastrointestinal involvement in patients with Behçet's disease in a multicenter study.

OBJECTIVES: Specific HLA haplotypes are associated with Behçet's disease (BD). Because the effects of HLA-A26 and its combination with HLA-B51 on organ involvement in BD have not been well demonstrated, we aimed to examine them. METHODS: This multicenter, cross-sectional, observational study enrolled patients with BD who visited Kyoto University Hospital between 2018 and 2021 or Kurashiki Central Hospital between 2006 and 2016 (n = 200). Disease severity was evaluated using the Krause score. RESULTS: Uveitis and gastrointestinal involvement were observed in 95/196 and 57/167 patients, respectively. The HLA alleles identified were HLA-B51 (n = 52/106), HLA-A26 (n = 25/88), and HLA-B51 and HLA-A26 (n = 6/88). In patients harboring HLA-B51, the presence of HLA-A26 was associated with higher frequencies of uveitis (p = 0.03) and coexistence of uveitis and gastrointestinal involvement (p = 0.002), and higher Krause scores (p = 0.02). Furthermore, the presence of HLA-A26 was associated with a higher frequency of uveitis in patients with gastrointestinal involvement (p = 0.001) and gastrointestinal involvement in patients with uveitis (p = 0.001). CONCLUSIONS: Since specific HLA haplotypes and their combinations are associated with organ involvement, both HLA-A and HLA-B haplotypes should be confirmed when screening for affected organs.

Immunopathogenesis of Behçet's disease.

Behçet's disease (BD) is a multi-system inflammatory disorder with vasculitic features. It does not suit any of the current pathogenesis-driven disease classifications well, a unifying concept of its pathogenesis is not unanimously conceivable at present, and its etiology is obscure. Still, evidence from immunogenetic and other studies supports the notion of a complex-polygenic disease with robust innate effector responses, reconstitution of regulatory T cells upon successful treatment, and first clues to the role of an, as of yet, underexplored adaptive immune system and its antigen recognition receptors. Without an attempt to be comprehensive, this review aims to collect and organize impactful parts of this evidence in a way that allows the reader to appreciate the work done and define the efforts needed now. The focus is on literature and notions that drove the field into new directions, whether recent or more remote.

When it looks like Behçet's syndrome but is something else: differential diagnosis of Behçet's syndrome: a two-centre retrospective analysis.

OBJECTIVE: To investigate the differential diagnostic spectrum in patients with suspected Behçet's syndrome (BS) in low prevalence regions. In addition, the number of patients fulfilling the ICBD criteria despite not having BS was evaluated. METHODS: This retrospective analysis was performed in two referral centres for BS. Patients with confirmed BS (clinical diagnosis with fulfilment of ISG criteria or a score of ≥5 points in the ICBD criteria) were excluded. The remaining patients were divided into 11 differential diagnosis categories. If no definitive alternative diagnosis could be established, patients were termed 'probable BS' in case of (i) relapsing orogenital aphthosis in the absence of other causes and either HLA-B51 positivity, or origin from an endemic area or presence of an additional typical BS symptom that is not part of the classification criteria, or (ii) with 3-4 points scored in the ICBD criteria. RESULTS: In total 202 patients were included and categorized as follows: 58 patients (28.7%) as 'probable BS', 57 (28.2%) skin disease, 26 (12.9%) chronic pain syndrome, 14 (6.9%) eye disease, 11 (5.4%) spondyloarthropathy, 9 (4.5%) gastrointestinal disease, 7 (3.5%) neurological disease, 4 (2%) arthritis, 3 (1.5%) auto-inflammation, 3 (1.5%) connective tissue disease and 10 (5.0%) miscellaneous disease. HLA-B51 was positive in 55/132 (41.7%); 75/202 (37.1%) of the patients fulfilled the ICBD criteria. CONCLUSION: In a low disease prevalence setting, the straightforward application of the ICBD criteria may lead to overdiagnosis of BS. The differential diagnosis of BS is enormously broad. Clinicians should be aware that HLA-B51 positivity is still not considered as a diagnostic feature in BS.

Behçet's Disease: A Comprehensive Review on the Role of HLA-B*51, Antigen Presentation, and Inflammatory Cascade.

Behçet's disease (BD) is a complex, recurring inflammatory disorder with autoinflammatory and autoimmune components. This comprehensive review aims to explore BD's pathogenesis, focusing on established genetic factors. Studies reveal that HLA-B*51 is the primary genetic risk factor, but non-HLA genes (ERAP1, IL-10, IL23R/IL-12RB2), as well as innate immunity genes (FUT2, MICA, TLRs), also contribute. Genome-wide studies emphasize the significance of ERAP1 and HLA-I epistasis. These variants influence antigen presentation, enzymatic activity, and HLA-I peptidomes, potentially leading to distinct autoimmune responses. We conducted a systematic review of the literature to identify studies exploring the association between HLA-B*51 and BD and further highlighted the roles of innate and adaptive immunity in BD. Dysregulations in Th1/Th2 and Th17/Th1 ratios, heightened clonal cytotoxic (CD8+) T cells, and reduced T regulatory cells characterize BD's complex immune responses. Various immune cell types (neutrophils, γδ T cells, natural killer cells) further contribute by releasing cytokines (IL-17, IL-8, GM-CSF) that enhance neutrophil activation and mediate interactions between innate and adaptive immunity. In summary, this review advances our understanding of BD pathogenesis while acknowledging the research limitations. Further exploration of genetic interactions, immune dysregulation, and immune cell roles is crucial. Future studies may unveil novel diagnostic and therapeutic strategies, offering improved management for this complex disease.

Rheumatologist's Perspective on Non-Infectious Uveitis: Patterns from Tertiary Referral Rheumatologic Clinics in Italy.

Non-infectious uveitis (NIU) can be an early or even the first extra-articular manifestation of systemic rheumatic diseases, or the first one; thus, rheumatologists are often involved in the diagnostic and therapeutic assessment of NIU. We evaluated 130 patients with a diagnosis of NIU who were admitted to two Italian rheumatologic clinics (Tor Vergata University Hospital in Rome, and Federico II University in Naples) from January 2018 to December 2021. Anterior uveitis (AU) occurred in 75.4% of patients, followed by posterior uveitis (PU, 21.5%); acute (54.6%) and recurrent (35.4%) NIU were more documented than chronic NIU (10%), and a bilateral involvement was observed in 38.7% of cases. Half of NIU cases were associated with spondyloarthritis (SpA); the remaining were affected by Behçet disease (BD)-related uveitis (13.9%) and idiopathic NIU (9.2%). HLA-B27+ patients (34.8%) had a higher prevalence of anterior and unilateral NIU (p = 0.005) with acute course (p = 0.04) than HLA-B27- patients. On the contrary, HLA-B51+ patients (19.6%) had mostly PU and bilateral NIU (p < 0.0001) and recurrent course (p = 0.04) than HLA-B51- patients. At the first rheumatologic referral, 117 patients (90%) received systemic treatments. Findings from this study demonstrate that rheumatologic referral has a pivotal role in the diagnostic work-up of NIU and may dramatically influence NIU-treatment strategies.

Neuro-Behçet's Disease Onset in the Context of Tuberculous Meningoencephalitis: A Case Report.

Behçet's disease (BD) is a systemic vasculitis that frequently presents with a relapsing-remitting pattern. CNS involvement (Neuro-Behçet) is rare, affecting approximately 10% of patients. Its etiological mechanisms are not yet fully understood. The most commonly accepted hypothesis is that of a systemic inflammatory reaction triggered by an infectious agent or by an autoantigen, such as heat shock protein, in genetically predisposed individuals. Mycobacterium tuberculosis is known to be closely interconnected with BD, both affecting cell-mediated immunity to a certain extent and probably sharing a common genetic background. We present the case of a 34-year-old Caucasian woman who had been diagnosed with tuberculous meningitis 15 months prior, with significant neurological deficits and lesional burden on MRI with repeated relapses whenever treatment withdrawal was attempted. These relapses were initially considered as reactivation of tuberculous meningoencephalitis, and symptoms improved after a combination of antituberculous treatment and corticosteroid therapy. After the second relapse, the diagnosis was reconsidered, as new information emerged about oral and genital aphthous lesions, making us suspect a BD diagnosis. HLA B51 testing was positive, antituberculous treatment was stopped, and the patient was started on high doses of oral Cortisone and Azathioprine. Consequently, the evolution was favorable, with no further relapses and slow improvements in neurological deficits. To our knowledge, this is the first report of Neuro-Behçet's disease onset precipitated by tuberculous meningitis. We include a review of the available literature on this subject. Our case reinforces the fact that Mycobacterium tuberculosis infection can precipitate BD in genetically predisposed patients, and we recommend HLA B51 screening in patients with prolonged or relapsing meningoencephalitis, even if an infectious agent is apparently involved.

Identification of an Unconventional Subpeptidome Bound to the Behçet's Disease-associated HLA-B*51:01 that is Regulated by Endoplasmic Reticulum Aminopeptidase 1 (ERAP1).

Human leukocyte antigen (HLA) B*51:01 and endoplasmic reticulum aminopeptidase 1 (ERAP1) are strongly genetically associated with Behçet's disease (BD). Previous studies have defined two subgroups of HLA-B*51 peptidome containing proline (Pro) or alanine (Ala) at position 2 (P2). Little is known about the unconventional non-Pro/Ala2 HLA-B*51-bound peptides. We aimed to study the features of this novel subpeptidome, and investigate its regulation by ERAP1. CRISPR-Cas9 was used to generate an HLA-ABC-triple knockout HeLa cell line (HeLa.ABC-KO), which was subsequently transduced to express HLA-B*51:01 (HeLa.ABC-KO.B51). ERAP1 was silenced using lentiviral shRNA. Peptides bound to HLA-B*51:01 were eluted and analyzed by mass spectrometry. The characteristics of non-Pro/Ala2, Pro2, and Ala2 peptides and their alteration by ERAP1 silencing were investigated. Effects of ERAP1 silencing on cell surface expression of HLA-B*51:01 were studied using flow cytometry. More than 20% of peptides eluted from HLA-B*51:01 lacked Pro or Ala at P2. This unconventional group of HLA-B*51:01-bound peptides was relatively enriched for 8-mers (with relatively fewer 9-mers) compared with the Pro2 and Ala2 subpeptidomes and had similar N-terminal and C-terminal residue usages to Ala2 peptides (with the exception of the less abundant leucine at position Ω). Knockdown of ERAP1 increased the percentage of non-Pro/Ala2 from 20% to ∼40%, increased the percentage of longer (10-mer and 11-mer) peptides eluted from HLA-B*51:01 complexes, and abrogated the predominance of leucine at P1. Interestingly knockdown of ERAP1 altered the length and N-terminal residue usage of non-Ala2&Pro2 and Ala2 but not the Pro2 peptides. Finally, ERAP1 silencing regulated the expression levels of cell surface HLA-B*51 in a cell-type-dependent manner. In conclusion, we have used a novel methodology to identify an unconventional but surprisingly abundant non-Pro/Ala2 HLA-B*51:01 subpeptidome. It is increased by knockdown of ERAP1, a gene affecting the risk of developing BD. This has implications for theories of disease pathogenesis.

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

The endoplasmic reticulum aminopeptidases ERAP1 and ERAP2 trim peptides to be loaded onto HLA molecules, including the main risk factor for Behçet's disease HLA-B*51. ERAP1 is also a risk factor among HLA-B*51-positive individuals, whereas no association is known with ERAP2. This study addressed the mutual relationships between both enzymes in the processing of an HLA-bound peptidome, interrogating their differential association with Behçet's disease. CRISPR/Cas9 was used to generate knock outs of ERAP1, ERAP2 or both from transfectant 721.221-HLA-B*51:01 cells. The surface expression of HLA-B*51 was reduced in all cases. The effects of depleting each or both enzymes on the B*51:01 peptidome were analyzed by quantitative label-free mass spectrometry. Substantial quantitative alterations of peptide length, subpeptidome balance, N-terminal residue usage, affinity and presentation of noncanonical ligands were observed. These effects were often different in the presence or absence of the other enzyme, revealing their mutual dependence. In the absence of ERAP1, ERAP2 showed similar and significant processing of B*51:01 ligands, indicating functional redundancy. The high overlap between the peptidomes of wildtype and double KO cells indicates that a large majority of B*51:01 ligands are present in the ER even in the absence of ERAP1/ERAP2. These results indicate that both enzymes have distinct, but complementary and partially redundant effects on the B*51:01 peptidome, leading to its optimization and maximal surface expression. The distinct effects of both enzymes on the HLA-B*51 peptidome provide a basis for their differential association with Behçet's disease and suggest a pathogenetic role of the B*51:01 peptidome.

Vascular involvement in Behçet's disease: the immunopathological process.

Behçet's disease is a rare form of systemic vasculitis that affects small to large vessels. It is characterized by mucocutaneous, pulmonary, cardiovascular, gastrointestinal, and neurological manifestations. Its clinical presentation is quite wide, ranging from milder cases to severe cases, with multisystemic involvement, characteristically with exacerbations and remissions. Its etiopathogenesis is still unclear, although there is evidence of genetic, environmental, and immunological factors, such as the association with the HLA-B51 allele. In conjunction, all of these point to an abnormal immunopathological process, with activation of cells of innate and adaptive immunity, such as NK cells, neutrophils, and T cells, which generate specific response patterns and cytokines capable of generating mediators that can damage and inflame blood vessels, resulting in venous and arterial occlusions and/or aneurysm formation.

Behçet disease (BD) and BD-like clinical phenotypes: NF-κB pathway in mucosal ulcerating diseases.

Behçet's disease (BD) is a heterogeneous multi-organ disorder in search of a unified pathophysiological theory and classification. The disease frequently has overlapping features resembling other disease clusters, such as vasculitides, spondyloarthritides and thrombophilias with similar genetic risk variants, namely HLA-B*51, ERAP1, IL-10, IL-23R. Many of the BD manifestations, such as unprovoked recurrent episodes of inflammation and increased expression of IL-1, IL-6 and TNFα, overlap with those of the hereditary monogenic autoinflammatory syndromes, positioning BD at the crossroads between autoimmune and autoinflammatory syndromes. BD-like disease associates with various inborn errors of immunity, including familial Mediterranean fever, conditions related to dysregulated NF-κB activation (eg TNFAIP3, NFKB1, OTULIN, RELA, IKBKG) and either constitutional trisomy 8 or acquired trisomy 8 in myelodysplastic syndromes. We review here the recent advances in the immunopathology of BD, BD-like diseases and the NF-κB pathway suggesting new elements in the elusive BD etiopathogenesis.

Frequency of HLA-B5, HLA-B51 and HLA-B27 in patients with idiopathic uveitis and Behçet's disease: a case-control study.

OBJECTIVES: Idiopathic uveitis is the most common form of uveitis in most countries. Uveitis affects about 40-80% of patients with Behçet's disease (BD). Class I, HLA-B5, and its subclass B51 allele have the strongest association with BD, but its role in idiopathic uveitis is unclear. The aim of this study was to determine the frequency of HLA-B5, HLA-B51 and HLA-B27 in patients with idiopathic uveitis, BD and the control group. MATERIAL AND METHODS: Forty-eight patients with idiopathic uveitis, 62 patients with BD, and 49 control subjects were compared. The presence of HLA-B5, HLA-B51 and HLA-B27 was checked by reviewing the charts of patients with idiopathic uveitis and Behçet's disease referred to the rheumatologic center of Shiraz University of Medical Sciences. The control group consisted of a sex-matched normal control population, among which HLA typing was done. RESULTS: HLA-B5 was significantly higher in patients with idiopathic uveitis and BD compared to the control group (p = 0.029 and 0.0001). It was significantly higher in patients with BD compared to those with idiopathic uveitis (p = 0.001). The difference of HLA-B51 between the groups was not statistically significant although it was higher in the BD group than the controls. The presence of HLA-B51 was significantly associated with ocular involvement in the BD group (p = 0.013). HLA-B27 was the least common type of HLA in all groups. CONCLUSIONS: HLA-B5 was the most common, compared to HLA-B51 and HLA-27, in patients with idiopathic uveitis and BD. There was an association between HLA-B51 positivity and ocular involvement in patients with BD. It seems that the pattern of HLA in our patients with idiopathic uveitis was different from that observed in some other studies.

A novel case of renal pathergy reaction in a Behçet's disease patient complicated by IgA vasculitis.

BACKGROUND: A pathergy reaction is defined as a hyperreactivity of the skin in response to minimal trauma, which is important in the diagnosis of Behçet's disease (BD). However, a pathergy reaction may not be restricted to the skin, and little is known about whether an invasive medical procedure can induce the reaction. Here we present a pathergy reaction induced by renal biopsy, an invasive procedure. CASE PRESENTATION: A 46-year-old man who was diagnosed with IgA vasculitis (IgAV) at the age of 38 was treated with prednisolone and mizoribine. However, complications such as common carotid arteritis or recurrent oral ulcer suggested the possibility of another pathophysiology. Later, increasing urine protein developed, suggesting disease aggravation. However, renal biopsy showed arteriosclerotic changes caused mainly by hypertension, negating exacerbation. After renal biopsy, his renal dysfunction and body temperature fluctuated, and detailed examinations revealed recurrent oral and genital ulcers and a folliculitis-like rash on his scrotum. Later, he complained of myodesopsia caused by hemorrhage in the ocular fundus due to occlusive vasculitis. Complete BD was diagnosed after development of the symptoms, and he was treated with prednisolone and colchicine. CONCLUSION: Co-occurrence of BD with IgAV is very rare and may be associated with immune disorders. Interestingly, a renal biopsy revealed BD, which was masked by the presence of IgAV, and elucidated the etiology of the unexplainable symptoms. To the best of our knowledge, this is the first report of renal pathergy. This case enlightens clinicians to the fact that not only a needle stimulation but also an invasive procedure can cause a pathergy reaction.

Characteristics of patients with intestinal Behçet's disease requiring treatment with immunosuppressants or anti-TNFα antibody.

OBJECTIVES: To identify the specific characteristics of patients with refractory intestinal Behçet's disease (BD) who required more than glucocorticoid (GC) and/or 5-aminosalicylic acid (5-ASA) treatment. METHODS: A retrospective review of the patient records in a university hospital identified 34 patients with intestinal BD. The patients treated only with glucocorticoid and/or 5-ASA (n = 8) were compared with refractory cases which required additional immunosuppressants, anti-TNFα antibodies, or surgery (n = 12). RESULTS: In the refractory group, ulcers were found outside the ileocecal region more often, and more active intestinal bleeding or melena was observed, than in the GC/5ASA-controlled group (75% vs 0%, p = 0.001), (58% vs 0%, p = 0.015). The refractory group also showed higher positivity for HLA-B51 (45% vs 0%, p = 0.044), higher blood C-reactive protein (CRP) levels (14.7 ± 8.74 vs 3.93 ± 6.33 mg/dL, p = 0.046), and a higher white blood cell or WBC count (14750 ± 6760 vs 7210 ± 1830/µl, p = 0.025) at onset. The existence of either HLA-B51, melena, or elevated CRP of more than 4 mg/dL predicted the refractory form of BD with 100% sensitivity and 85.7% specificity. CONCLUSIONS: Refractory intestinal BD was distinguished from the non-refractory form by distinct clinical and laboratory findings. These findings will be useful in identifying patients who require intensive therapy (e.g., anti-TNFα antibodies) in addition to GC/5ASA.

Rapid detection of HLA-B*51 by real-time polymerase chain reaction and high-resolution melting analysis.

HLA-B*51, a class I human leukocyte antigen (HLA) molecule, is the strongest known genetic risk factor for Behçet disease. However, there are only few articles reporting methods to determine the presence or absence of HLA-B51. For this reason, we designed and developed an easy, fast, and inexpensive real-time high-resolution melting (HRM) assay to detect HLA-B*51. We genotyped 61 samples by our HRM assay and by conventional polymerase chain reaction, and no discrepancies were found between results. Besides, a subgroup of 25 samples was also genotyped in a different laboratory, and another subgroup of 16 samples was obtained from the International Histocompatibility Working Group DNA Bank, and a full concordance of results was observed with those obtained by HRM. Regarding the identifying system evaluated, we obtained 100% of specificity, sensibility, and repeatability, and 0% of false positive and false negative rates. Therefore, this HRM analysis is easily applicable to the rapid detection of HLA-B*51, exhibits a high speed, and requires a very low budget.

Two novel alleles, HLA-B*46:01:11 and HLA-B*51:01:39 were identified in Chinese bone marrow donors.

HLA-B*46:01:11 has 219 G>A compared with HLA-B*46:01:01, and HLA-B*51:01:39 shows 561 G>A with HLA-B*51:01:01.

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

Behçet's disease is a chronic multisystem inflammatory disorder characterized mainly by recurrent oral ulcers, ocular involvement, genital ulcers, and skin lesions, presenting with remissions and exacerbations. It is thought that both environmental and genetic factors contribute to its onset and development. Although the etiology of Behçet's disease remains unclear, recent immunogenetic findings are providing clues to its pathogenesis. In addition to the positive association of HLA-B*51, which was identified more than four decades ago, and which has since been confirmed in multiple populations, recent studies report additional independent associations in the major histocompatibility complex class I region. HLA-B*15, -B*27, -B*57, and -A*26 are independent risk factors for Behçet's disease, while HLA-B*49 and -A*03 are independent class I alleles that are protective for Behçet's disease. Genome-wide association studies have identified associations with genome-wide significance (P < 5 × 10(-8)) in the IL23R-IL12RB2, IL10, STAT4, CCR1-CCR3, KLRC4, ERAP1, TNFAIP3, and FUT2 loci. In addition, targeted next-generation sequencing has revealed the involvement of rare nonsynonymous variants of IL23R, TLR4, NOD2, and MEFV in Behçet's disease pathogenesis. Significant differences in gene function or mRNA expression associated with the risk alleles of the disease susceptibility loci suggest which genes in a disease-associated locus influence disease pathogenesis. These genes encompass both innate and adaptive immunity and confirm the importance of the predominant polarization towards helper T cell (Th) 1 versus Th2 cells, and the involvement of Th17 cells. In addition, epistasis observed between HLA-B*51 and the risk coding haplotype of the endoplasmic reticulum-associated protease, ERAP1, provides a clue that an HLA class I-peptide presentation-based mechanism contributes to this complex disease.

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

OBJECTIVE: The purpose of this work was to investigate whether major histocompatibility complex class I chain-related gene A (MICA) polymorphisms are associated with susceptibility to Behcet's disease (BD). METHODS: A meta-analysis was conducted on the associations between the MICA-transmembrane (TM) A6 allele and the 009 allele of MICA exon 2-4 (MICA*009) and BD with or without HLA-B51 overall and in each ethnic group. RESULTS: Fifteen comparison studies were included in this meta-analysis. The meta-analysis revealed a significant association between the MICA-TM A6 allele and BD in European, Asian, and Arab populations [odds ratio (OR) 1.436, 95 % confidence interval (CI) 1.111-1.857, p = 0.006; OR 1.999, 95 % CI 1.551-2.575, p = 8.0 × 10(-8); OR 1.333, 95 % CI 1.058-2.300, p = 0.025, respectively,]). Stratification by HLA-B51 showed an association between the MICA-TM A6 allele and BD with HLA-B51 in the overall group and in the European population. Meta-analysis showed a significant association between the MICA*009 allele and BD in the overall group (OR 3.948, 95 % CI 2.680-5.815, p < 1.0 × 10(-8)) and in the European population (OR 3.392, 95 % CI 2.118-5.433, p = 5.6 × 10(-6)). A significant association was found between the MICA*009 allele and B51-positive BD. CONCLUSION: This meta-analysis shows that the MICA-TM A6 allele and the MICA*009 allele are associated with BD susceptibility in various ethnic populations, and that MICA alleles are in strong linkage disequilibrium with HLA-B51 in BD.

Identification of a novel HLA-B*51 allele, HLA-B*51:144, in a Chinese individual.

The novel HLA-B*51:144 allele shows one nucleotide difference from B*51:02:02 in exon 3.

Description and molecular modeling of four novel HLA-B alleles identified in Brazilian individuals.

Four novel HLA-B alleles, B*42:20, B*51:151, B*57:64 and B*58:42 were identified in Brazilian individuals.