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Objective: To investigate the association of HLA-B51-positivity to clinical manifestations of Behçet's disease (BD)., Study Design: Descriptive study., Place and Duration of Study: Clinic of Rheumatology, Dıskapi Education and Research Hospital, Health Sciences University, Turkey, from December 2018 to December 2020., Methodology: Patients who had HLA-B5 genetic results and fulfilled the international criteria for BD were included in the study. HLA-B51 status was determined and compared with the symptomatology., Results: Mean age of 204 cases was 39.9±11.4 years. There were 52.5% female and 47.5% male patients. One hundred (61.7%) patients were HLA-B51-positive. The frequency of papulopustular lesions (PPL), ocular involvement, neurologic involvement, and vascular involvement was significantly higher in HLA-B51-positive patients compared to HLA-B51 negative patients (p=0.044, 0.012, 0.039, and 0.022 respectively). HLA-B51-positivity was found to be a significant risk factor for PPL (OR and 95% CI:1.946 and 1.044-3.629), ocular involvement (OR and 95% CI:2.399 and 1.165-4.938), and neurological involvement (OR and 95% CI:5.404 and 1.119-26.093). Significant risk factors for vascular involvement were male gender (OR and 95% CI:2.810 and 1.403-5.627) and low age of disease onset (OR and 95% CI:0.935 and 0.894-0.979)., Conclusion: Ocular, vascular, and neurological involvements are more common in patients with BD with HLA-B51-positive. HLA-B51 was found to be an independent risk factor for papulopustular lesion, ocular and neurological involvement, while the male gender was found to be an independent risk factor for vascular involvement., Key Words: Behcet syndrome / genetics, HLA-B51, Neurologic involvement, Ocular involvement, Vascular involvement, Vasculitis* / diagnosis.

The novel SARS-CoV-2 coronavirus infection has become a global health concern, causing the COVID-19 pandemic. The disease symptoms and outcomes depend on the host immunity, in which the human leukocyte antigen (HLA) molecules play a distinct role. The HLA alleles have an inter-population variability, and understanding their link to the COVID-19 in an ethnically distinct population may contribute to personalized medicine. The present study aimed at detecting associations between common HLA alleles and COVID-19 susceptibility and severity in Armenians. In 299 COVID-19 patients (75 asymptomatic, 102 mild/moderate, 122 severe), the association between disease severity and classic HLA-I and II loci was examined. We found that the advanced age, male sex of patients, and sex and age interaction significantly contributed to the severity of the disease. We observed that an age-dependent effect of HLA-B*51:01 carriage [odds ratio (OR)=0.48 (0.28-0.80), P bonf <0.036] is protective against severe COVID-19. Contrary, the HLA-C*04:01 allele, in a dose-dependent manner, was associated with a significant increase in the disease severity [OR (95% CI) =1.73 (1.20-2.49), P bonf <0.021] and an advancing age (P<0.013). The link between HLA-C*04:01 and age was secondary to a stronger association between HLA-C*04:01 and disease severity. However, HLA-C*04:01 exerted a sex-dependent differential distribution between clinical subgroups [females: P<0.0012; males: P=0.48]. The comparison of HLA-C*04:01 frequency between subgroups and 2,781 Armenian controls revealed a significant incidence of HLA-C*04:01 deficiency in asymptomatic COVID-19. HLA-C*04:01 homozygous genotype in patients blueprinted a decrease in heterozygosity of HLA-B and HLA class-I loci. In HLA-C*04:01 carriers, these changes translated to the SARS-CoV-2 peptide presentation predicted inefficacy by HLA-C and HLA class-I molecules, simultaneously enhancing the appropriate HLA-B potency. In patients with clinical manifestation, due to the high prevalence of HLA-C*04:01, these effects provided a decrease of the HLA class-I heterozygosity and an ability to recognize SARS-CoV-2 peptides. Based on our observations, we developed a prediction model involving demographic variables and HLA-C*04:01 allele for the identification of potential cases with the risk of hospitalization (the area under the curve (AUC) = 86.2%) or severe COVID-19 (AUC =71%)., Competing Interests: RA and ZM declare that they work at the ClinSoft Armenia, Yerevan, Armenia, and ClinStat Group, Lexington, MA. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hovhannisyan, Madelian, Avagyan, Nazaretyan, Hyussyan, Sirunyan, Arakelyan, Manukyan, Yepiskoposyan, Mayilyan and Jordan.)

Behçet's disease is a rare disease characterised by recurrent oral ulcers, with systemic manifestations including genital ulcers, ocular disease, skin lesions, gastrointestinal disease, neurologic disease, vascular disease and arthritis. Most clinical manifestations of Behçet's disease are believed to be due to vasculitis. The heterogeneous clinical spectrum is influenced by sex, ethnicity and country of residence. Vascular manifestation in the form of isolated large brachial artery aneurysm is rare in children. Treatment involves aneurysmorrhaphy to avoid rupture or ischaemic sequelae in addition to lifelong medical management to control vasculitis.

Aims: To investigate susceptible human leukocyte antigen (HLA) alleles and their associations with clinical features in Thai patients with Behçet's disease (BD)., Method: Eighteen HLA-A and 36 HLA-B alleles were determined in 42 Thai BD patients and 99 healthy controls (HCs) by reverse line blot assay, and reconfirmed by MICRO SSP assay., Results: The BD patients had significantly higher allele frequency (AF) of HLA-B*51 than the HCs (13.10% vs 5.05%, P = .025). The AF of HLA-A*26, -A*26:01 and -B*51:01 also was higher and almost reached statistical significance (5.59% vs 1.52%, P = .054, 5.95% vs 1.52%, P = .054 and 10.71% vs 4.04%, P = .051, respectively). However, the BD patients had significantly higher AF of either HLA-A*26:01 or -B*51:01 (16.67% vs 5.56%, P = .005), or -A*26:01 or -B*51X (19.05% vs 6.56%, P = .003). The AF of HLA-B*51:01 and -B*51X increased significantly in -A*26:01 non-carrier BD patients (12.16% vs 4.17%, P = .024 and 14.86% vs 5.21%, P = .019, respectively); and that of HLA-A*26:01 was significantly higher in -B*51X non-carrier BD patients (7.58% vs 1.67%, P = .034). HLA-B*51:01 associated significantly with the presence of posterior uveitis and visual impairment (18.18% vs 2.50%, P = .031 for both conditions). HLA-B*51:01 was not observed in BD patients with gastrointestinal involvement or arthritis. Furthermore, the AF of HLA-B*51:01 was significantly higher in HLA-A*26:01 non-carrier BD patients without arthritis (17.30% vs 0%, P = .050)., Conclusion: HLA-B*51:01 was a susceptible allele for Thai BD patients, and associated with posterior uveitis and visual impairment. HLA-A*26:01 was another susceptible allele in HLA-B*51X non-carrier patients. The protective effect of HLA-B*51:01 on arthritis needs further investigation., (© 2020 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Behçet's disease (BD) is presumably an autoinflammatory disease of unknown etiology for which several animal models have been described over the years. Agents and methods used for the development of these models have ranged from the herpes simplex type one virus (hsv-1) pathogen to the use of transgenic mice. Other models have also been used to investigate a possible autoimmune component. Each model possesses its own unique set of benefits and shortcomings, with no one model fully being able to recapitulate the disease phenotype. Here, we review the proposed models and provide commentary on their effectiveness and usefulness in studying the disease., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Immune thrombocytopenic purpura (ITP) is a bleeding disorder characterized by low platelet counts in peripheral blood, impairment of thrombopoiesis in bone marrow, and risk of mild to severe bleedings. ITP can be seen among both sexes in different ages. Although definitive pathogenesis of this disorder is still ambiguous, some of risk factors for ITP are recognized, including human leukocyte antigens (HLAs)., Objective: Our goal was to evaluate the possible association between HLA-B5, 7, 8, 27, and 51 antigens with ITP for the first time. We were hoping to achieve new hypothetical diagnostic/prognostic biomarkers to introduce a new subject for further studies on HLA class I antigens as possible risk factors for ITP., Materials and Methods: A total of 37 patients with ITP were included in this study. After confirmation of ITP diagnosis, peripheral blood samples were collected from them. The expression of each of HLA antigens was evaluated by standard lymphocytotoxicity technique., Results: Compared with other studied antigens, the expression of HLA-B5 and HLA-B51 was more prevalent among our patients. According to the results, 22% of patients were positive for HLA-B5 and HLA-B51. Furthermore, no significant association was found between HLAs expressions with complete blood count parameters., Conclusions: We conclude that there is an association between HLA-B5 and HLA-B51 with ITP and that they are not likely to be used as diagnostic or prognostic biomarkers. We suggest studying the association between HLA-B antigens and ITP in large-scale studies to determine whether or not there is a significant association.

Behçet's disease (BD) is a chronic and rare multisystemic disorder defined by autoimmunity and inflammatory characteristics, manifested by ocular lesions, recurrent genital and oral ulcers, skin symptoms and arthritis as well as neurological, intestinal, and vascular involvement. Despite the unknown cause of BD, there is some strong documentation for immunological, genetic, environmental, and infectious factors playing a role in the pathogenesis of BD. While the nature of the genetic variants remains unidentified, many genetic risk factors are considered to contribute to BD susceptibility. Along with human leukocyte antigen gene encoding B*51 (HLA-B*51) and areas including the major histocompatibility complex class I, genome-wide association studies have recognized numerous other BD susceptibility genes including those encoding interleukin (IL)-10, IL-12 receptor β 2 (IL-12RB2), IL-23 receptor (IL-23R), C-C chemokine receptor 1 gene, signal transducer and activator of transcription 4 (STAT4), endoplasmic reticulum aminopeptidase (ERAP1), and genes encoding killer cell lectin-like receptor family members (KLRC4-KLRK1). It is believed that BD could be considered as a disorder lying in between autoimmune and autoinflammatory syndromes. The positive responses to classical immunosuppressive agents like azathioprine and cyclosporine and involvement of autoantigens in the initiation of the disorder are the main BD features that reflect the autoimmune nature of the disorder. In this review, we address recent findings on the role of common cytokines, antibodies and immunogenetic factors in BD., (© 2018 Wiley Periodicals, Inc.)

Objectives: The epidemiology of Behçet's disease (BD) remains poorly understood with limited international data on disease burden, progression and treatment outcomes. The aims of this study were to determine the natural history of BD in the Midwest region of Ireland and compare our findings with those from other European and Mediterranean studies., Methods: We established a cohort of patients with BD in the Midwest Region of Ireland based on ISGBD and/or ICBD criteria. Longitudinal data were captured on demographic and clinical characteristics, disease activity and clinical outcomes., Results: The cohort included 24 Caucasian patients (16 women, 8 men) and one male patient with Middle Eastern ancestry, who satisfied the diagnostic criteria for BD. Based on the ISGBD criteria, the point prevalence of BD was 6.2 per 100,000 population. The most common clinical manifestation was oral aphthosis (100%) followed by genital aphthosis (92%) and skin lesions (92%), arthralgia/arthritis (40%), ocular involvement (32%), vascular thrombosis (12%) and pathergy phenomenon (8%). Only 1 patient was HLA-B*51 positive. A long-term multidisciplinary approach that included physician specialists, nurse specialists, and general practitioners was adopted for ongoing patient care., Conclusions: The prevalence of BD in Ireland is higher than previously reported with a significant proportion experiencing laryngeal destruction. There are many similarities as well as several differences in the epidemiology of BD by country and indeed within countries. We fully advocate the need for national and international collaborative efforts in order to further understand the complex aetiology and immunopathology of BD in order to improve the clinical, physical, psychological wellbeing of patients.

Behçet's disease (BD) is a chronic inflammatory disease characterized by recurrent mucocutaneous, ocular, and skin lesions. Immunosenescence is associated with increased susceptibility to infection and chronic low grade inflammation. This study aimed to investigate the differences in the frequencies of immunosenescent cells in the peripheral blood mononuclear cells (PBMCs) of patients with BD. PBMCs were isolated from age-matched patients with active BD (n = 19), inactive BD (n = 20), disease controls (DCs, n = 15) and healthy controls (HCs, n = 15). The frequencies of senescent CD4+ T cells (CD3+ CD4+ CD27- CD28- cells), CD8+ T cells (CD3+ CD8+ CD27- CD28- cells) and B cells (CD19+ CD27- IgD- cells) were analyzed using flow cytometry. Senescence-associated β galactosidase activity was also measured in CD8+ T cells using flow cytometry with 5-dodecanoylaminofluorescein di-β-D-galactopyranoside. Frequencies of senescent CD4+ and CD19+ cells were not significantly different between the groups. The frequency of senescent CD8+ T cells was significantly higher in active BD than in DCs and HCs. C-reactive protein and erythrocyte sedimentation rate levels, which indicate disease activity, did not correlate with increased frequencies of immunosenescent cells. Steroid treatment, specific organ involvement, and HLA-B51 status did not have a significant influence on the frequencies of immunosenescent cells. Frequencies of senescence-associated β galactosidase+ CD8+ T cells were significantly higher in active BD and inactive BD compared to DCs and HCs. There was an increased frequency of senescent CD8+ T cells in the PBMCs of patients with BD.

The association between carriage of the human leucocyte antigen (HLA)-B*51 allele and development of Behçet's disease (BD) has been known since the early 1970s, but the exact mechanisms responsible for its role in pathogenesis remain much-debated. In an effort to explain the disease process, it has been suggested that BD constitutes one of a newly termed group of diseases, the 'MHC-I-opathies'. Other MHC-I-opathies include ankylosing spondylitis and HLA-B*27-associated spondyloarthropathies and HLA-C*0602-associated skin psoriasis. Recent work analysing the peptidome of HLA-B*51 suggests that altered peptide presentation by HLA-B*51 is vital to the disease process. In this review, we argue that immune receptor interactions with HLA-B*51 or the HLA-B*51-peptide complex could lead to development of inflammation in BD. The evidence for CD8 + T cell involvement is weak, and based on emerging studies it seems more likely that natural killer (NK) or other cell interactions, perhaps mediated by leucocyte immunoglobulin-like receptor (LILR) or killer immunoglobulin-like receptor (KIR) receptors, are culpable in pathogenesis. HLA misfolding leading directly to inflammation is another hypothesis for BD pathogenesis that deserves greater investigation. Ultimately, greater understanding of HLA-B*51's unique role in BD will probably lead to improved development of therapeutic strategies., (© 2017 British Society for Immunology.)

HLA-B*51:226 was initially identified in a Chinese-related donor for stem cell transplantation., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

A low-activity variant of endoplasmic reticulum aminopeptidase 1 (ERAP1), Hap10, is associated with the autoinflammatory disorder Behçet's disease (BD) in epistasis with HLA-B*51, which is the main risk factor for this disorder. The role of Hap10 in BD pathogenesis is unknown. We sought to define the effects of Hap10 on the HLA-B*51 peptidome and to distinguish these effects from those due to HLA-B*51 polymorphisms unrelated to disease. The peptidome of the BD-associated HLA-B*51:08 subtype expressed in a Hap10-positive cell line was isolated, characterized by mass spectrometry, and compared with the HLA-B*51:01 peptidome from cells expressing more active ERAP1 allotypes. We additionally performed synthetic peptide digestions with recombinant ERAP1 variants and estimated peptide-binding affinity with standard algorithms. In the BD-associated ERAP1 context of B*51:08, longer peptides were generated; of the two major HLA-B*51 subpeptidomes with Pro-2 and Ala-2, the former one was significantly reduced, and the latter was increased and showed more ERAP1-susceptible N-terminal residues. These effects were readily explained by the low activity of Hap10 and the differential susceptibility of X -Pro and X -Ala bonds to ERAP1 trimming and together resulted in a significantly altered peptidome with lower affinity. The differences due to ERAP1 were clearly distinguished from those due to HLA-B*51 subtype polymorphism, which affected residue frequencies at internal positions of the peptide ligands. The alterations in the nature and affinity of HLA-B*51·peptide complexes probably affect T-cell and natural killer cell recognition, providing a sound basis for the joint association of ERAP1 and HLA-B*51 with BD., (© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)

Behcet's disease (BD) is an immuno-mediated vasculitis in which knowledge of its etiology and genetic basis is limited. To improve the current knowledge, a genetic analysis performed with the Immunochip platform was carried out in a population from Spain. A discovery cohort comprising 278 BD cases and 1,517 unaffected controls were genotyped using the Immunochip platform. The validation step was performed on an independent replication cohort composed of 130 BD cases and 600 additional controls. The strongest association signals were observed in the HLA class I region, being HLA-B*51 the highest peak (overall P = 6.82E-32, OR = 3.82). A step-wise conditional logistic regression with classical alleles identified HLA-B*57 and HLA-A*03 as additional independent markers. The amino acid model that best explained the association, includes the position 97 of the HLA-B molecule and the position 66 of the HLA-A. Among the non-HLA loci, the most significant in the discovery analysis were: IL23R (rs10889664: P = 3.81E-12, OR = 2.00), the JRKL/CNTN5 region (rs2848479: P = 5.00E-08, OR = 1.68) and IL12A (rs1874886: P = 6.67E-08, OR = 1.72), which were confirmed in the validation phase (JRKL/CNTN5 rs2848479: P = 3.29E-10, OR = 1.66; IL12A rs1874886: P = 1.62E-08, OR = 1.61). Our results confirm HLA-B*51 as a primary-association marker in predisposition to BD and suggest additional independent signals within the class I region, specifically in the genes HLA-A and HLA-B. Regarding the non-HLA genes, in addition to IL-23R, previously reported in our population; IL12A, described in other populations, was found to be a BD susceptibility factor also in Spaniards; finally, a new associated locus was found in the JRKL/CNTN5 region., Competing Interests: The authors have declared that no competing interests exist.

Cytotoxic T lymphocyte (CTL) responses play pivotal roles in controlling the replication of human immunodeficiency virus type 1 (HIV-1), but the correlation between CTL responses and the progression of HIV-1 infection are controversial on account of HIV immune escape mutations driven by CTL pressure were reported.The acute HIV-1-infected patients from Beijing were incorporated into our study to investigate the effects of CTL response on the progression of HIV-1 infection.A longitudinal study was performed on acute HIV-1-infected patients to clarify the kinetic of T-cell responses, the dynamic of escape mutations, as well as the correlation between effective T-cell response and the progression of HIV infection.Seven human leukocyte antigen-B51+ (HLA-B51+) individuals were screened from 105 acute HIV-1 infectors. The detailed kinetic of HLA-B51-restricted CTL responses was described through blood sampling time points including seroconversion, 3 and 6 months after HIV-1 infection in the 7 HLA-B51+ individuals, by using 16 known HLA-B51 restricted epitopes. Pol743-751 (LPPVVAKEI, LI9), Pol283-289 (TAFTIPSI, TI8), and Gag327-3459 (NANPDCKTI, NI9) were identified as 3 dominant epitopes, and ranked as starting with LI9, followed by TI8 and NI9 in the ability to induce T-cell responses. The dynamics of escape mutations in the 3 epitopes were also found with the same order as T-cell response, by using sequencing for viral clones on blood sampling at seroconversion, 3 and 6 months after HIV-1 infection.We use solid evidence to demonstrate the correlation between T-cell response and HIV-1 mutation, and postulate that multiple T-cell responses might benefit the control of HIV-1 infection, especially in acute infection phase., Competing Interests: The authors have no conflicts of interest to disclose.

A 34-year-old man who had been referred to our hospital was diagnosed with acute promyelocytic leukemia (APL). All-trans retinoic acid (ATRA), oral administration, was initiated. On day 25, he developed fever and respiratory distress with bilateral pulmonary infiltrates, suggesting differentiation syndrome (DS) caused by ATRA. These symptoms showed amelioration after discontinuing ATRA and initiating methylprednisolone. ATRA was re-started on day 29 at half the original dose because of residual APL blasts. The patient subsequently developed fever, severe stomatitis, and oropharyngeal ulcers, which persisted even after discontinuing ATRA. On day 48, he suddenly developed severe abdominal pain with free air, observable on an abdominal X-ray, and underwent emergency ileocecal resection. Pathological examination of the resected ileocecal intestines revealed multiple ulcers and perforations. No leukemic cell infiltration was observed. In this case, only ATRA was administered for APL treatment. These findings suggest that ileocecal ulcerations and perforations, as well as oropharyngeal ulcers, might have been caused by DS or ATRA. Furthermore, DNA typing of the HLA-B locus revealed that the patient had HLA-B51 associated with Behçet's disease. Therefore, hypercytokinemia with DS might have induced Behçet's disease-like symptoms, including stomatitis and ileocecal perforation, complications that are particularly observed in patients with HLA-B51.

Human leucocyte antigen (HLA) alleles influence the rate of CD4 decline among HIV-infected individuals. We investigated the association between HLA B35 and HLA B51 and the rate of CD4 decline and/or opportunistic infections, among 294 HIV-positive individuals from Manitoba, Canada. All individuals presenting with a CD4 count >200 cells μL(-1) , who had at least two CD4 counts, and no evidence of co-infection were included. Individuals bearing HLA B35 or HLA B51 were compared to controls. A multivariate model demonstrated that HLA B35 allele was associated with a hazard ratio of 2.05 (95% CI 1.31-3.18) for reaching AIDS and HLA B51 allele with HR of 2.03 (95% CI 1.18-3.49) for reaching the same end-point. High prevalence of HLA B35 was seen in the patient population receiving care in Manitoba. Our observations confirm the association of HLA B35 with rapid disease progression. We report, for the first time, faster CD4 decline among individuals with HLA B51 allele., (© 2015 John Wiley & Sons Ltd.)

Behçet's disease (BD), a multi-organ inflammatory disorder, is associated with the presence of the human leukocyte antigen (HLA) HLA-B*51 allele in many ethnic groups. The possible antigen involvement of the major histocompatibility complex class I chain related gene A transmembrane (MICA-TM) nonapeptide (AAAAAIFVI) has been reported in BD symptomatic patients. This peptide has also been detected in HLA-A*26:01 positive patients. To investigate the link of BD with these two specific HLA alleles, molecular dynamics (MD) simulations were applied on the MICA-TM nonapeptide binding to the two BD-associated HLA alleles in comparison with the two non-BD-associated HLA alleles (B*35:01 and A*11:01). The MD simulations were applied on the four HLA/MICA-TM peptide complexes in aqueous solution. As a result, stabilization for the incoming MICA-TM was found to be predominantly contributed from van der Waals interactions. The P2/P3 residue close to the N-terminal and the P9 residue at the C-terminal of the MICA-TM nonapeptide served as the anchor for the peptide accommodated at the binding groove of the BD associated HLAs. The MM/PBSA free energy calculation predicted a stronger binding of the HLA/peptide complexes for the BD-associated HLA alleles than for the non-BD-associated ones, with a ranked binding strength of B*51:01 > B*35:01 and A*26:01 > A*11:01. Thus, the HLAs associated with BD pathogenesis expose the binding efficiency with the MICA-TM nonapeptide tighter than the non-associated HLA alleles. In addition, the residues 70, 73, 99, 146, 147 and 159 of the two BD-associated HLAs provided the conserved interaction for the MICA-TM peptide binding.

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., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Behçet's disease (BD) is an inflammatory disorder of unknown aetiology characterised by recurrent attacks affecting the mucocutaneous tissues, eyes, joints, blood vessels, brain and gastrointestinal tract. It is a multifactorial disease classified as a variable vessel vasculitis, and several environmental triggers may induce inflammatory episodes in genetically susceptible individuals. BD has several autoinflammatory features including recurrent self-limited clinical manifestations overlapping with monogenic autoinflammatory disorders, significant host predisposition and abnormally increased inflammatory response, with a robust innate component. Human leukocyte antigen (HLA)-B*51 is the strongest susceptibility factor described so far affecting the disease risk and typical phenotype. Non-HLA genetic associations such as endoplasmic reticulum aminopeptidase 1 (ERAP1), interleukin 23 receptor (IL23R) and IL10 variations suggest that BD shares susceptibility genes and inflammatory pathways with spondyloarthritis. Although genomewide association studies revealed an increased risk associated with recessively inherited ERAP1 variations in HLA-B*51 positive patients, it is not clear yet whether certain peptide-HLA allele combinations result in an adaptive response by a self-antigen-directed cytotoxic response or an innate response by modulating an NK cell activity or causing an unfolded protein response. Understanding of major histocompatibility complex (MHC) Class I-driven inflammatory response is expected to provide insights for the development of better treatment and remission-induction options in BD as well as in ankylosing spondylitis (AS) and psoriasis.

Behçet's disease (BD) is a multisystemic inflammatory disease believed to be triggered by microbial or environmental factors on a genetic platform. Clinically, it may have an impact on many body systems, including the mucocutaneous, ocular, articular, vascular, and neurological systems. In this study, we aimed to determine the HLA-B51 subtypes and their correlations with the clinical findings of BD. Fifty-one patients with BD and 44 gender- and age-matched healthy subjects were included in this study. The HLA-B51 subtypes of all participants were determined, and the correlations of the clinical manifestations of the disease with the HLA-B51 subtypes were analyzed. HLA-B51 positivity was found to be significantly higher in the patient group (P < 0.001, RR = 15.20), which had significantly more frequent HLA-B5101, HLA-B5102(01), HLA-B5109, and HLA-B5122 subtypes than the healthy subjects (all P < 0.05). Furthermore, considering the correlation between the genetic makeup and clinical findings, the HLA-B5109 subtype was found to be less frequent in patients with papulopustular skin lesions (P = 0.042). The frequency of HLA-B5103 was significantly higher in patients with central nervous system involvement (P = 0.015). There may be a relationship between HLA-B5102(01), HLA-B5109, and HLA-B5122 in addition to HLA-B51 and HLA-B5101(01) in Turkish patients with BD. The HLA-B5109 subtype can be protective against papulopustular lesion development; however, the HLA-B5103 subtype may pose a risk for neuro-Behçet development in BD.

Uveitis is the most common ophthalmological finding in the practice of rheumatology and clinical immunology. The condition is frequently idiopathic and defined by the inflammatory status of the uvea, the part of the middle eye that includes the iris, ciliary body and choroid. Anterior uveitis involves the iris and ciliary body, while the posterior form is limited to the retina and choroid. Both forms represent indications for an urgent evaluation by an ophthalmologist as untreated cases may cause blindness. Anterior uveitis is associated with the HLA-B27 allele and is a classification criterion for seronegative arthritis forms such as ankylosing spondylitis, psoriatic arthropathy, arthritis associated with Crohn's disease and ulcerative colitis, and reactive arthritis. Posterior uveitis is associated with Behcet's disease and HLA-B51. The clinical suspicion is raised by self-reported symptoms in the case of anterior involvement and floaters for posterior uveitis while the diagnosis, in the absence of established criteria, is made by an experienced ophthalmologist., (Copyright © 2014 Elsevier B.V. All rights reserved.)

CD8(+) CTL responses directed toward the HLA-B*51:01-restricted HIV-RT128-135 epitope TAFTIPSI (TI8) are associated with long-term nonprogression to AIDS. Clonotypic analysis of responses to B51-TI8 revealed a public clonotype using TRAV17/TRBV7-3 TCR genes in six out of seven HLA-B*51:01(+) patients. Structural analysis of a TRAV17/TRBV7-3 TCR in complex with HLA-B51-TI8, to our knowledge the first human TCR complexed with an 8-mer peptide, explained this bias, as the unique combination of residues encoded by these genes was central to the interaction. The relatively featureless peptide-MHC (pMHC) was mainly recognized by the TCR CDR1 and CDR2 loops in an MHC-centric manner. A highly conserved residue Arg(97) in the CDR3α loop played a major role in recognition of peptide and MHC to form a stabilizing ball-and-socket interaction with the MHC and peptide, contributing to the selection of the public TCR clonotype. Surface plasmon resonance equilibrium binding analysis showed the low affinity of this public TCR is in accordance with the only other 8-mer interaction studied to date (murine 2C TCR-H-2K(b)-dEV8). Like pMHC class II complexes, 8-mer peptides do not protrude out the MHC class I binding groove like those of longer peptides. The accumulated evidence suggests that weak affinity might be a common characteristic of TCR binding to featureless pMHC landscapes.

The aim of this study was to investigate the subclasses and the immunophenotypic profile of peripheral mononuclear cells in patients with Behçet's disease (BD) and to assess associations between the expression of HLA-B51 antigen and that of other cell markers. Thirty healthy volunteer blood donors and forty patients with BD were enrolled into this study. Phenotyping was performed using two color flow cytometry. HLA-B51 typing was performed using the complement dependent microlymphocytotoxicity assay. Unlike controls, patients with BD presented a modified immunophenotypic profile of lymphocytes. Compared to those in the remission phase, patients with active BD showed an increased mean of MFI ratio of CD56 on CD16+CD56+ cells (32.47 ± 14.26 versus 23.87 ± 10.3; p = 0.032), increased absolute numbers of CD4(-)CD8(bright) and CD4(+)CD8(+) cells (657.1 ± 463.6 cells/µL versus 319.24 ± 116.4 cells/µL; p = 0.017 and 40.77 ± 36.41 cells/µL versus 10.77 ± 9.78 cells/µL; p < 0.0001, respectively) and an elevated mean of MFI ratio of CD19 on B cells (252.3 ± 56.7 versus 205.67 ± 32.3; p = 0.021). However, expression of HLA-B51 was not associated with any specific immunophenotypic profile. In conclusion, abnormal immunophenotypic profile of peripheral lymphocytes was found in patients with BD, especially in active phase, reflecting an immune dysregulation. Moreover, HLA-B51 expression was not found to be related to the expression of other cell markers.

The Hodgkin's lymphoma disease (HD) is a common malignant neoplasm with germinal centre B-cell origin. It has been suggested that the HLA class I and class II regions have susceptibility effects on HD. In different ethnic groups, different HLA class I and class II alleles affect HD. As a result, there is no consensus which of the different HLA alleles confers susceptibility to HD. In this study, we aimed to ascertain the role of HLA class I and class II alleles in association with Hodgkin's lymphoma in Iranian patients. We performed a case-control genotyping study in 85 Iranian HD patients which were selected from the Bone Marrow Transplantation Department of Taleghani Hospital and 150 controls using the SSP-PCR. Our results demonstrated that the HLA-A*68, HLA-B*51, and HLA-DRB1*15 alleles were significantly more frequent in HD patients in comparison to controls (P = 0.026; OR = 6.188, P = 0.00008; OR = 2.86, P = 0.00006; OR = 5.315, resp.) and they have significant susceptibility effects on HD in Iranian population. There are reports of other populations with regard to consistency and inconsistency to our results. Further studies with large sample size or the meta-analysis are needed to explain the exact associations of HLA gene with HD.

Pol283-8-specific, HLA-B*51:01-restricted, cytotoxic T cells (CTLs) play a critical role in the long-term control of HIV-1 infection. However, these CTLs select for the reverse transcriptase (RT) I135X escape mutation, which may be accumulating in circulating HIV-1 sequences. We investigated the selection of the I135X mutation by CTLs specific for the same epitope but restricted by HLA-B*52:01. We found that Pol283-8-specific, HLA-B*52:01-restricted CTLs were elicited predominantly in chronically HIV-1-infected individuals. These CTLs had a strong ability to suppress the replication of wild-type HIV-1, though this ability was weaker than that of HLA-B*51:01-restricted CTLs. The crystal structure of the HLA-B*52:01-Pol283-8 peptide complex provided clear evidence that HLA-B*52:01 presents the peptide similarly to HLA-B*51:01, ensuring the cross-presentation of this epitope by both alleles. Population level analyses revealed a strong association of HLA-B*51:01 with the I135T mutant and a relatively weaker association of HLA-B*52:01 with several I135X mutants in both Japanese and predominantly Caucasian cohorts. An in vitro viral suppression assay revealed that the HLA-B*52:01-restricted CTLs failed to suppress the replication of the I135X mutant viruses, indicating the selection of these mutants by the CTLs. These results suggest that the different pattern of I135X mutant selection may have resulted from the difference between these two CTLs in the ability to suppress HIV-1 replication.

The human leukocyte antigen (HLA)-B*51 genotype is one of the well-known genetic factors associated with the development of Behcet's disease. We evaluated three sequence-specific priming (SSP) assays and one real-time PCR assay for detecting HLA-B*51 alleles using 93 whole blood samples, which were genotyped by high-resolution sequence-based typing (SBT). All HLA-B*51 alleles determined by SBT were detected by the four evaluated assays, and the results for all HLA-B alleles other than HLA-B*51 were negative on all assays. Thus, all HLA-B51 tests showed 100% sensitivity and 100% specificity for detecting HLA-B*51 alleles. The three SSP assays and the real-time PCR test for HLA-B*51 genotyping are simple, but reliable for detecting HLA-B*51 alleles in clinical laboratories., (© 2012 John Wiley & Sons A/S.)

Background: Many researchers have tried to investigate the association of HLA-B51 with the severity and the clinical features of BD with conflicting results., Methods: We aimed at investigating the association of HLA-B51 with demographical and clinical manifestations as well as the severity of BD, by studying 178 native Tunisian BD patients, fulfilling the International Study group criteria for the BD classification recruited from the Department of Internal Medicine, Rabta Hospital in Tunis and compared with 125 native Tunisian healthy age and sex matching volunteers., Results: According to our findings, the frequency of HLAB 51 was significantly higher in BD patients than in controls (p<0.001). Positive pathergy test (PPT) (p = 0.01) and retinal vasculitis (p = 0.045), were significantly more frequent in HLA B51(+) patients, while the frequency of arterial aneurysms (p = 0.009) and neurological involvement, especially the parenchymal involvement (p<0.001), were significantly and clearly higher in HLA B51(-) patients. The patients without HLA B51 had a significantly less severe disease (p = 0.001). Discussion/conclusion We conclude that HLA B51 is a predisposing marker for BD in our population as in most ethnic groups. It seems to be associated with a subgroup of BD patients characterized by a higher frequency of ocular involvement and PPT, but a lower frequency of arterial aneurysm and neurological involvement, and a less severe disease course., (Copyright © 2011 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Humanized mice are expected to be useful as small animal models for in vivo studies on the pathogenesis of infectious diseases. However, it is well known that human CD8(+) T cells cannot differentiate into effector cells in immunodeficient mice transplanted with only human CD34(+) hematopoietic stem cells (HSCs), because human T cells are not educated by HLA in the mouse thymus. We here established HLA-B*51:01 transgenic humanized mice by transplanting human CD34(+) HSCs into HLA-B*51:01 transgenic NOD/SCID/Jak3(-/-) mice (hNOK/B51Tg mice) and investigated whether human effector CD8(+) T cells would be elicited in the mice or in those infected with HIV-1 NL4-3. There were no differences in the frequency of late effector memory and effector subsets (CD27(low)CD28(-)CD45RA(+/-)CCR7(-) and CD27(-)CD28(-)CD45RA(+/-)CCR7(-), respectively) among human CD8(+) T cells and in that of human CD8(+) T cells expressing CX3CR1 and/or CXCR1 between hNOK/B51Tg and hNOK mice. In contrast, the frequency of late effector memory and effector CD8(+) T cell subsets and of those expressing CX3CR1 and/or CXCR1 was significantly higher in HIV-1-infected hNOK/B51Tg mice than in uninfected ones, whereas there was no difference in that of these subsets between HIV-1-infected and uninfected hNOK mice. These results suggest that hNOK/B51Tg mice had CD8(+) T cells that were capable of differentiating into effector T cells after viral antigen stimulation and had a greater ability to elicit effector CD8(+) T cells than hNOK ones.