Behçet disease in Latin American countries: A systematic literature review of demographic and clinical features, and HLA-B*51 allele frequency / Enfermedad de Behçet en países de Latinoamérica: Revisión sistemática de la literatura sobre datos demográficos, hallazgos clínicos y frecuencia del alelo HLA-B*51

Objective: To describe the demographic and clinical features, as well as the frequency of the HLA-B*51 allele in Behçet disease (BD) patients in Latin American countries. Methods: A systematic literature review of PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines was conducted without performing a meta-analysis. We included observational studies (cross-sectional or cohort) of BD patients fulfilling the International Study Group for BD classification criteria and reported the demographic, clinical, and laboratory features of the disease in adult patients. Results: Twelve studies were included in the SLR. Information from 532 patients across 5 Latin American countries was included for the analysis. Mean age at disease diagnosis was 33 years, 58.3% were female and 41.7% male; most patients were non-Caucasian. The most common clinical manifestations were recurrent oral ulcers and genital ulcers, followed by skin, eye, joint, neurological, gastrointestinal, vascular, and cardiac involvement. The prevalence of BD was described in 2 studies, 1 conducted in Brazil that reported a prevalence of .3/100,000 inhabitants, and another in Colombia with a prevalence of 1.1/100,000 inhabitants. The frequency of HLA-B*51 allele in BD patients was 38%, 30.1%, and 9% in Argentina, Brazil, and Mexico, respectively. Conclusions: The prevalence of BD in the Latin American countries seems to be low, as well as the frequency of HLA-B*51 allele. However, the strength of association between HLA-B*51 and BD remains high in our population. The key clinical features of BD are like those reported in countries/regions where BD is endemic.(AU)

Objetivo: Describir las características demográficas, clínicas y la frecuencia del alelo HLA-B*51 en pacientes con enfermedad de Behçet (EB) en países de América Latina. Métodos: Se llevó a cabo una revisión sistemática de la literatura (RSL) según la guía PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) sin realizar un metaanálisis final. Se incluyeron estudios observacionales (transversales o de cohortes) de pacientes con EB que cumplieron con los criterios de clasificación del Grupo Internacional de Estudio de la EB e informaron las características demográficas, clínicas y de laboratorio en pacientes adultos con EB. Resultados: Doce estudios fueron incluidos para la RSL. La información de 532 pacientes provenientes de 5 países de América Latina se incluyó para el análisis. La edad media al diagnóstico fue de 33 años, el 58,3% fueron mujeres y el 41,7% hombres; la mayoría de los pacientes fueron no caucásicos. Las manifestaciones clínicas más comunes fueron las úlceras orales y genitales recurrentes, seguidas del compromiso cutáneo, ocular, articular, neurológico, gastrointestinal, vascular y cardíaco. La prevalencia de la EB fue descrita en 2 estudios, uno realizado en Brasil que reportó una prevalencia de 0,3/100.000 habitantes, y otro en Colombia con una prevalencia de 1,1/100.000 habitantes. La frecuencia del HLA-B*51 en pacientes con EB fue del 38%, 30,1% y 9% en Argentina, Brasil y México, respectivamente. Conclusiones: La prevalencia de la EB en los países latinoamericanos parece ser baja, así como la frecuencia del alelo HLA-B*51. Sin embargo, la fuerza de asociación entre el HLA-B*51 y la EB sigue siendo alta en nuestra población. Las características clínicas claves de la EB son similares a las reportadas en países/regiones donde es endémica.(AU)

Characterization of the novel HLA-B*52:01:01:18 allele in a West Indian individual.

The novel HLA-B*52:01:01:18 allele differs from HLA-B*52:01:01:02 by A→C nucleotide change at gDNA -155.

HLA-B52 allele in giant cell arteritis may indicate diffuse large-vessel vasculitis formation: a retrospective study.

BACKGROUND: This study aimed to identify new characteristics of elderly onset large-vessel vasculitis (EOLVV) by focusing on human leucocyte antigen (HLA) genotype, polymyalgia rheumatica (PMR), and affected vascular lesions observed on positron emission tomography/computed tomography (PET/CT) imaging. METHODS: We retrospectively studied 65 consecutive Japanese patients with large-vessel vasculitis (LVV) who had extracranial vasculitis lesions and underwent PET/CT imaging. PET/CT images were assessed using the semi-quantitative PET visual score of each affected vessel, and the PET vascular activity score (PETVAS) and number of affected vessels were calculated. Subjects were subsequently grouped based on age at onset, superficial temporal artery (STA) involvement, and presence of PMR and compared each group according to HLA genotype. Unsupervised hierarchical cluster analysis was used to identify the patients with similar characteristics in terms of affected vascular lesions detected through PET/CT imaging. The clinical characteristics and PET/CT findings of the population newly identified in this study were examined. RESULTS: Twenty-seven patients with EOLVV did not meet the American College of Rheumatology 1990 criteria for giant cell arteritis (GCA) and Takayasu arteritis and were considered as unclassified EOLVV (UEOLVV). The unsupervised hierarchical cluster analysis revealed that UEOLVV with PMR and large-vessel GCA (LV-GCA) formed a cluster of LVV with GCA features (i.e., PMR and/or STA involvement) when restricted to patients who were HLA-B52-positive. Patients who were HLA-B52-positive with LVV and GCA features had similar clinical characteristics and patterns of affected vessels and presented with diffuse LVV lesions. HLA-B52-positive patients who had LVV with GCA features also presented with higher PETVAS, more affected vessels, and lower rates of biologics usage and relapse compared to HLA-B52-positive patients with TAK. CONCLUSIONS: Patients who had UEOLVV with PMR had similar characteristics to patients with LV-GCA. Patients who were HLA-B52-positive and had LVV with GCA features presented with diffuse vascular lesions and may comprise a core population of Japanese patients with EOLVV. The findings of HLA-B52 positivity and diffusely affected vessels in patients with EOLVV can be considered as suspicious findings of LV-GCA.

STING Ligand-Mediated Priming of Functional CD8+ T Cells Specific for HIV-1-Protective Epitopes from Naive T Cells.

Functional HIV-1-specific CD8+ T cells primed from naive T cells are expected to act as effector T cells in a "shock-and-kill" therapeutic strategy for an HIV-1 cure since less functional HIV-1-specific CD8+ T cells are elicited from memory T cells in HIV-1-infected individuals on combined antiretroviral therapy (cART). CD8+ T cells specific for HIV-1 conserved and protective epitopes are candidates for such T cells. We investigated the priming with STING ligand of CD8+ T cells specific for HLA-B*52:01 or HLA-C*12:02-restricted protective epitopes from naive T cells. STING ligand 3'3'-cGAMP effectively primed CD8+ T cells specific for 3 of 4 HLA-B*52:01-restricted epitopes but failed to prime those specific for all 3 HLA-C*12:02-restricted epitopes from the naive T cells of HIV-1-uninfected individuals having an HLA-B*52:01-C*12:02 protective haplotype. These HLA-B*52:01-restricted CD8+ T cells had a strong ability to suppress HIV-1 replication and expressed a high level of cytolytic effector molecules. The viral suppression ability of these T cells was significantly correlated with the expression level of perforin and showed a trend for a positive correlation with the expression level of CD107a. The present study highlighted the priming with STING ligand of functional CD8+ T cells specific for protective epitopes, which T cells would contribute as effector T cells to a shock-and-kill therapy. IMPORTANCE The current "shock-and-kill" therapeutic strategy for HIV cure has been directed toward eliminating latent viral reservoirs by reactivation of latent reservoirs with latency-reversing agents followed by eradication of these cells by immune-mediated responses. Although HIV-1-specific T cells are expected to eradicate viral reservoirs, the function of these T cells is reduced in HIV-1-infected individuals with long-term cART. Therefore, priming of HIV-1-specific T cells with high function from naive T cells is to be expected in these individuals. In this study, we demonstrated the priming with STING ligand 3'3'-cGAMP of CD8+ T cells specific for HIV-1-protective epitopes from naive T cells. cGAMP primed CD8+ T cells specific for 3 HLA-B*52:01-restricted protective epitopes, which cells expressed a high level of cytolytic effector molecules and effectively suppressed HIV-1 replication. The present study suggested that the priming with STING ligand of functional CD8+ T cells specific for protective epitopes would be useful in a therapy for an HIV-1 cure.

HLA-A*11:01:01:01, HLA-C*12:02:02:01-HLA-B*52:01:02:02, Age and Sex Are Associated With Severity of Japanese COVID-19 With Respiratory Failure.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus causing coronavirus disease 2019 (COVID-19) was announced as an outbreak by the World Health Organization (WHO) in January 2020 and as a pandemic in March 2020. The majority of infected individuals have experienced no or only mild symptoms, ranging from fully asymptomatic cases to mild pneumonic disease. However, a minority of infected individuals develop severe respiratory symptoms. The objective of this study was to identify susceptible HLA alleles and clinical markers that can be used in risk prediction model for the early identification of severe COVID-19 among hospitalized COVID-19 patients. A total of 137 patients with mild COVID-19 (mCOVID-19) and 53 patients with severe COVID-19 (sCOVID-19) were recruited from the Center Hospital of the National Center for Global Health and Medicine (NCGM), Tokyo, Japan for the period of February-August 2020. High-resolution sequencing-based typing for eight HLA genes was performed using next-generation sequencing. In the HLA association studies, HLA-A*11:01:01:01 [Pc = 0.013, OR = 2.26 (1.27-3.91)] and HLA-C*12:02:02:01-HLA-B*52:01:01:02 [Pc = 0.020, OR = 2.25 (1.24-3.92)] were found to be significantly associated with the severity of COVID-19. After multivariate analysis controlling for other confounding factors and comorbidities, HLA-A*11:01:01:01 [P = 3.34E-03, OR = 3.41 (1.50-7.73)], age at diagnosis [P = 1.29E-02, OR = 1.04 (1.01-1.07)] and sex at birth [P = 8.88E-03, OR = 2.92 (1.31-6.54)] remained significant. The area under the curve of the risk prediction model utilizing HLA-A*11:01:01:01, age at diagnosis, and sex at birth was 0.772, with sensitivity of 0.715 and specificity of 0.717. To the best of our knowledge, this is the first article that describes associations of HLA alleles with COVID-19 at the 4-field (highest) resolution level. Early identification of potential sCOVID-19 could help clinicians prioritize medical utility and significantly decrease mortality from COVID-19.

Fine Mapping of the Major Histocompatibility Complex Region and Association of the HLA-B*52:01 Allele With Cervical Cancer in Japanese Women.

Importance: Understanding the genetic contribution of the major histocompatibility complex (MHC) region to the risk of cervical cancer (CC) will help understand how immune responses to infection with human papillomaviruses are associated with CC. Objective: To determine whether the HLA-B*52:01 allele is associated with CC in Japanese women. Design, Setting, and Participants: This was a multicenter genetic association study. Genotype and phenotype data were obtained from BioBank Japan Project. Additional patients with CC were enrolled from the Aichi Cancer Center Research Institute. An MHC fine-mapping study was conducted on CC risk in the Japanese population by applying a human leukocyte antigen (HLA) imputation method to the large-scale CC genome-wide association study data of using the Japanese population-specific HLA reference panel. Participants included 540 women in BioBank Japan Project with CC or 39 829 women without gynecologic diseases, malignant neoplasms, and MHC-related diseases as controls. An additional 168 patients with CC were recruited from Aichi Cancer Center Research Institute. Histopathological subtypes and clinical stages were not considered. Participants with low genotype call rate, closely related participants, and outliers in the principal component analysis were excluded. Data analysis was performed from August 2018 to January 2020. Main Outcomes and Measures: Loci within the MHC region associated with CC risk, and the direction and size of association. Results: A total of 704 CC cases and 39 556 controls were analyzed. All participants were Japanese women with a median (range) age of 67 (18 to 100) years. One of the class I HLA alleles of HLA-B*52:01 was significantly associated with CC risk (odds ratio, 1.60; 95% CI, 1.38-1.86; P = 7.4 × 10-10). Allele frequency spectra of HLA-B*52:01 are heterogeneous among worldwide populations with high frequency in Japanese populations (0.109 in controls), suggesting its population-specific risk associated with CC. The conditional analysis suggested that HLA-B*52:01 could explain most of the MHC risk associated with CC because no other HLA alleles remained significant after conditioning on the HLA-B*52:01. The HLA amino acid residue-based analysis suggested that HLA-B p.Tyr171His located in the peptide-binding groove was associated with the most significant CC risk (odds ratio, 1.47; 95% CI, 1.30-1.66; P = 1.2 × 10-9). Conclusions and Relevance: The results of this study contribute to understanding of the genetic background of CC. The results suggest that immune responses mediated by class I HLA molecules are associated with susceptibility to CC.

Molecular dynamics simulations provide molecular insights into the role of HLA-B51 in Behçet's disease pathogenesis.

Behçet's disease is an inflammatory disorder of unknown etiology. Genetic tendency has an important role in its pathogenesis, and HLA-B51, a class I MHC antigen, has been recognized as the strongest susceptibility factor for Behçet's disease. Despite the confirmation of the association of HLA-B51 with Behçet's disease in different populations, its pathogenic mechanisms remain elusive. HLA-B51 differs in only two amino acids from HLA-B52, other split antigen of HLA-B5, which is not associated with Behçet's disease. These two amino acids are located in the B pocket of the antigen-binding groove, which occupies the second amino acids of the bound peptides. To understand the nature of the HLA-peptide interactions, differences in structure and dynamics of two HLA alleles were investigated by molecular dynamics simulations using YAYDGKDYI, LPRSTVINI, and IPYQDLPHL peptides. For HLA-B51, all bound peptides fluctuated to larger extent than HLA-B52. Free energy profiles of unbinding process for YAYDGKDYI by steered molecular dynamics simulations showed that unbinding from HLA-B52 results in greater free energy differences than HLA-B51. These results suggest the possibility of an instability of HLA-B51 associated with the repertoire of peptides, and this finding may provide significant insight to its pathogenic role in Behçet's disease.

Impact of HLA-B*52:01-Driven Escape Mutations on Viral Replicative Capacity.

HLA-B*52:01 is strongly associated with protection against HIV disease progression. However, the mechanisms of HLA-B*52:01-mediated immune control have not been well studied. We here describe a cohort with a majority of HIV C-clade-infected individuals from Delhi, India, where HLA-B*52:01 is highly prevalent (phenotypic frequency, 22.5%). Consistent with studies of other cohorts, expression of HLA-B*52:01 was associated with high absolute CD4 counts and therefore a lack of HIV disease progression. We here examined the impact of HLA-B*52:01-associated viral polymorphisms within the immunodominant C clade Gag epitope RMTSPVSI (here, RI8; Gag residues 275 to 282) on viral replicative capacity (VRC) since HLA-mediated reduction in VRC is a central mechanism implicated in HLA-associated control of HIV. We observed in HLA-B*52:01-positive individuals a higher frequency of V280T, V280S, and V280A variants within RI8 (P = 0.0001). Each of these variants reduced viral replicative capacity in C clade viruses, particularly the V280A variant (P < 0.0001 in both the C clade consensus and in the Indian study cohort consensus p24 Gag backbone), which was also associated with significantly higher absolute CD4 counts in the donors (median, 941.5 cells/mm3; P = 0.004). A second HLA-B*52:01-associated mutation, K286R, flanking HLA-B*52:01-RI8, was also analyzed. Although selected in HLA-B*52:01-positive subjects often in combination with the V280X variants, this mutation did not act as a compensatory mutant but, indeed, further reduced VRC. These data are therefore consistent with previous work showing that HLA-B molecules that are associated with immune control of HIV principally target conserved epitopes within the capsid protein, escape from which results in a significant reduction in VRC.IMPORTANCE Few studies have addressed the mechanisms of immune control in HIV-infected subjects in India, where an estimated 2.7 million people are living with HIV. We focus here on a study cohort in Delhi on one of the most prevalent HLA-B alleles, HLA-B*52:01, present in 22.5% of infected individuals. HLA-B*52:01 has consistently been shown in other cohorts to be associated with protection against HIV disease progression, but studies have been limited by the low prevalence of this allele in North America and Europe. Among the C-clade-infected individuals, we show that HLA-B*52:01 is the most protective of all the HLA-B alleles expressed in the Indian cohort and is associated with the highest absolute CD4 counts. Further, we show that the mechanism by which HLA-B*52:01 mediates immune protection is, at least in part, related to the inability of HIV to evade the HLA-B*52:01-restricted p24 Gag-specific CD8+ T-cell response without incurring a significant loss to viral replicative capacity.

Identification of a novel allele, HLA-B*52:01:24, by sequence-based typing in a Chinese individual.

HLA-B*52:01:24 has one synonymous nucleotide change from HLA-B*52:01:01:01 at nucleotide 384 (codon 104 Glycine).

Takayasu Arteritis: Recent Developments.

PURPOSE OF REVIEW: Takayasu arteritis (TA) is a granulomatous inflammatory disorder that affects large vessels, especially aorta and its proximal branches. Its diagnosis can be extremely challenging due to the non-specificity of the systemic inflammatory manifestations during the early phase of the disease and usually follows an insidious clinical course until the emergence of vascular ischemic complications. RECENT FINDINGS: Its pathogenesis has been better delineated in recent years, especially the role of HLA-B*52 allele in certain ethnic groups, as well as the use of biological therapy, and surgical revascularization. Recent findings are discussed in depth. Clinical and epidemiological aspects of TA, recent developments in pathogenesis, and therapy are presented.

Identification of HLA-A*31:150 by next-generation sequencing in a Chinese Han individual.

HLA-A*31:150 differs from HLA-A*31:01:02:01 in exon 2 by a single nucleotide.

Identification of the novel HLA-B allele, HLA-B*52:56 by sequence-based typing in a Chinese individual.

HLA-B*52:56 differs from HLA-B*52:01:01:01 by one nucleotide exchange at position 107(T > C) with one amino exchange.

Hemoptysis Originating from the Bronchial Artery in Takayasu Arteritis with Ulcerative Colitis.

Takayasu arteritis (TAK) is a large-vessel vasculitis affecting the aorta and its main branches. Hemoptysis can be experienced as the respiratory manifestation, but origination from a bronchial artery is rare. Ulcerative colitis (UC) shares genetic similarities with TAK; HLA-B52*01 is associated with TAK and UC. We herein report a patient who presented with hemoptysis from the right bronchial artery and was diagnosed with TAK during the follow-up of UC. Transcatheter embolization was performed, and prednisolone and tocilizumab induced remission. Complication of TAK should be considered in the clinical course of HLA-B52-positive UC patients, and tocilizumab may be a treatment option.

Genetic determinants and an epistasis of LILRA3 and HLA-B*52 in Takayasu arteritis.

Takayasu arteritis (TAK) is a systemic vasculitis with severe complications that affects the aorta and its large branches. HLA-B*52 is an established susceptibility locus to TAK. To date, there are still only a limited number of reports concerning non-HLA susceptibility loci to TAK. We conducted a genome-wide association study (GWAS) and a follow-up study in a total of 633 TAK cases and 5,928 controls. A total of 510,879 SNPs were genotyped, and 5,875,450 SNPs were imputed together with HLA-B*52. Functional annotation of significant loci, enhancer enrichment, and pathway analyses were conducted. We identified four unreported significant loci, namely rs2322599, rs103294, rs17133698, and rs1713450, in PTK2B, LILRA3/LILRB2, DUSP22, and KLHL33, respectively. Two additional significant loci unreported in non-European GWAS were identified, namely HSPA6/FCGR3A and chr21q.22. We found that a single variant associated with the expression of MICB, a ligand for natural killer (NK) cell receptor, could explain the entire association with the HLA-B region. Rs2322599 is strongly associated with the expression of PTK2B Rs103294 risk allele in LILRA3/LILRB2 is known to be a tagging SNP for the deletion of LILRA3, a soluble receptor of HLA class I molecules. We found a significant epistasis effect between HLA-B*52 and rs103294 (P = 1.2 × 10-3). Enhancer enrichment analysis and pathway analysis suggested the involvement of NK cells (P = 8.8 × 10-5, enhancer enrichment). In conclusion, four unreported TAK susceptibility loci and an epistasis effect between LILRA3 and HLA-B*52 were identified. HLA and non-HLA regions suggested a critical role for NK cells in TAK.

Control of HIV-1 by an HLA-B*52:01-C*12:02 Protective Haplotype.

HLA-B*52:01-C*12:02, which is found in approximately 20% of all Japanese persons, is well known to be associated with ulcerative colitis and Takayasu arteritis. This haplotype is also known to be protective in individuals infected with human immunodeficiency virus (HIV) type 1. Recent studies showed that HLA-B*52:01-restricted HIV-1-specific T cells suppress HIV-1 and that HLA-C*12:02 together with KIR2DL2 play an important role in natural killer cell-mediated control of HIV-1. However, the role of HLA-C*12:02-restricted cytotoxic T lymphocytes (CTLs) in suppressing HIV-1 replication remains unknown. In the present study, we demonstrated that HLA-C*12:02-restricted CTLs specific for 2 immunodominant epitopes, Pol IY11 and Nef MY9, contributed to the suppression of HIV-1 replication in HIV-1-infected individuals. Further analysis demonstrated that these 2 HLA-C*12:02-restricted CTLs together with 4 HLA-B*52:01-restricted ones effectively suppressed HIV-1 in individuals with the HLA-B*52:01-C*12:02 haplotype. Thus, both HLA-C*12:02 and HLA-B*52:01 alleles contribute to HIV-1 suppression via both HIV-1-specific CTLs and natural killer cells in individuals with this haplotype.

Epidemiology of Takayasu arteritis.

Takayasu arteritis (TA), a granulomatous large vessel vasculitis involves mostly the aorta and its proximal branches and occurs most commonly in young females. The data on the epidemiology of TA is limited, probably due to the rarity of the disease. Although the disease has a worldwide distribution, it is generally thought to be much more common among Asian populations. The incidences of TA were estimated to be 1-2 per million in Japan and 2.2 per million in Kuwait. Recent epidemiologic studies suggest that TA is being increasingly recognized in Europe with reported incidence estimates varying from 0.4 to 1.5 per million. The highest ever prevalence of TA at 40 per million was estimated in Japan and the lowest ever one at 0.9 per million in US. The reported prevalences in the European populations vary between the ranges of 4.7 per million and 33 per million. These variations between the studies may be derived from geographical and genetic differences between the populations, but also may be due to the methodological differences.

Full-length sequencing of the HLA region identified a novel allele, HLA-B*52:70.

One nucleotide substitution at position 276 of HLA-B*52:01:01 results in a novel allele, HLA-B*52:70.