Protective Human Leukocyte Antigen Alleles Research Articles

Two Novel Human Leukocyte Antigen Alleles Are Associated with Decreased Risk of Onychomycosis in a Large Cohort of Danish Blood Donors

Introduction: Antigen presentation and antimicrobial immune responses involve the human leukocyte antigen (HLA) system. Onychomycosis is primarily caused by dermatophytes and affects around 5.5% of the population worldwide. Yet, only limited data exist on the associations between the HLA system and onychomycosis. Thus, the objective of the study was to investigate if there is an association between HLA alleles and onychomycosis. Methods: Participants in the Danish Blood Donor Study were defined as cases of onychomycosis and controls based on antifungal prescriptions in the national prescription registry. Associations were investigated using logistic regressions adjusted for confounders and were Bonferroni corrected for multiple tests. Results: A total of 3,665 participants were considered onychomycosis cases, and 24,144 participants were considered controls. We found two protective HLA alleles of onychomycosis: DQB1*06:04, odds ratios (OR) 0.80 (95% confidence interval (CI) 0.71–0.90), and DRB1*13:02, OR 0.79 (95% CI: 0.71–0.89). Conclusion: The finding of two novel protective alleles of onychomycosis indicates that certain HLA alleles have certain antigen presentation properties affecting the risk of fungal infection. These findings may provide the basis for future research identifying immunologically relevant antigens of fungi causing onychomycosis, which could ultimately lead to targets of new drugs with antifungal effects.

Association between Human Leukocyte Antigen (HLA) DQB1*06 and HLA DQB1*03 and adverse outcomes in a group of critically ill patients with COVID-19 in Tunisia: a cross-sectional study.

Human Leukocyte Antigen (HLA) system is a highly polymorphic genetic system associated with the prognosis of several infectious diseases. The aim of this study is to investigate the association of HLA polymorphism with the outcome of coronavirus disease 2019 (COVID-19) in Tunisian critically ill patients. this retrospective cross-sectional study included 42 consecutive patients hospitalized in intensive care unit (ICU) for COVID-19 in March 2021. Genotyping of HLA loci was performed by LABType™ sequence-specific oligonucleotide (SSO) typing kits (One lambda Inc, USA). Statistical analyses were performed using Statistical Package for Social Sciences (SPSS®) version 23.0. A p-value <0.05 was considered significant. Multivariable regression analysis was performed for the association between HLA polymorphism with adverse outcomes with adjustment for potential confounders such as age, sex, co-morbidities and blood type. patients included in our study had a mean age of 64.5 ± 11.5 (34-83) years and were mainly men (64.3%; (n=27)). The most common cardiovascular risk factors were obesity (61.9%; (n=26)) and hypertension (26.2%; (n=11)). Thirty-two patients died (76.2%). Eleven patients (26.2%) required intubation during hospitalization. We found that HLA DQB1*06 allele was significantly associated with protection against mortality aOR: 0.066, 95% CI 0.005-0.821; p = 0.035. HLA DQB1*03 allele was significantly associated with protection against intubation aOR: 0.151, 95% CI 0.023-0.976; p = 0.047. it was found that there are 2 protective HLA alleles against COVID-19 severity and mortality in critically ill patients. This could allow focusing on people genetically predisposed to develop severe forms of COVID-19.

Susceptibility and Severity of COVID-19 Are Both Associated With Lower Overall Viral-Peptide Binding Repertoire of HLA Class I Molecules, Especially in Younger People.

An important number of studies have been conducted on the potential association between human leukocyte antigen (HLA) genes and COVID-19 susceptibility and severity since the beginning of the pandemic. However, case–control and peptide-binding prediction methods tended to provide inconsistent conclusions on risk and protective HLA alleles, whereas some researchers suggested the importance of considering the overall capacity of an individual’s HLA Class I molecules to present SARS-CoV-2-derived peptides. To close the gap between these approaches, we explored the distributions of HLA-A, -B, -C, and -DRB1 1st-field alleles in 142 Iranian patients with COVID-19 and 143 ethnically matched healthy controls, and applied in silico predictions of bound viral peptides for each individual’s HLA molecules. Frequency comparison revealed the possible predisposing roles of HLA-A*03, B*35, and DRB1*16 alleles and the protective effect of HLA-A*32, B*58, B*55, and DRB1*14 alleles in the viral infection. None of these results remained significant after multiple testing corrections, except HLA-A*03, and no allele was associated with severity, either. Compared to peptide repertoires of individual HLA molecules that are more likely population-specific, the overall coverage of virus-derived peptides by one’s HLA Class I molecules seemed to be a more prominent factor associated with both COVID-19 susceptibility and severity, which was independent of affinity index and threshold chosen, especially for people under 60 years old. Our results highlight the effect of the binding capacity of different HLA Class I molecules as a whole, and the more essential role of HLA-A compared to HLA-B and -C genes in immune responses against SARS-CoV-2 infection.

Impact of Micropolymorphism Outside the Peptide Binding Groove in the Clinically Relevant Allele HLA-C*14 on T Cell Responses in HIV-1 Infection.

ABSTRACTThere is increasing evidence for the importance of human leukocyte antigen C (HLA-C)-restricted CD8+ T cells in HIV-1 control, but these responses are relatively poorly investigated. The number of HLA-C-restricted HIV-1 epitopes identified is much smaller than those of HLA-A-restricted or HLA-B-restricted ones. Here, we utilized a mass spectrometry-based approach to identify HIV-1 peptides presented by HLA-C*14:03 protective and HLA-C*14:02 nonprotective alleles. We identified 25 8- to 11-mer HLA-I-bound HIV-1 peptides from HIV-1-infected HLA-C*14:02+/14:03+ cells. Analysis of T cell responses to these peptides identified novel 6 T cell epitopes targeted in HIV-1-infected HLA-C*14:02+/14:03+ subjects. Analyses using HLA stabilization assays demonstrated that all 6 epitope peptides exhibited higher binding to and greater cell surface stabilization of HLA-C*14:02 than HLA-C*14:03. T cell response magnitudes were typically higher in HLA-C*14:02+ than HLA-C*14:03+ individuals, with responses to the Pol KM9 and Nef epitopes being significantly higher. The results show that HLA-C*14:02 can elicit stronger T cell responses to HIV-1 than HLA-C*14:03 and suggest that the single amino acid difference between these HLA-C14 subtypes at position 21, outside the peptide-binding groove, indirectly influences the stability of peptide-HLA-C*14 complexes and induction/expansion of HIV-specific T cells. Taken together with a previous finding that KIR2DL2+ NK cells recognized HLA-C*14:03+ HIV-1-infected cells more than HLA-C*14:02+ ones, the present study indicates that these HLA-C*14 subtypes differentially impact HIV-1 control by T cells and NK cells.IMPORTANCE Some human leukocyte antigen (HLA) class I alleles are associated with good clinical outcomes in HIV-1 infection and are called protective HLA alleles. Identification of T cell epitopes restricted by protective HLA alleles can give important insight into virus-immune system interactions and inform design of immune-based prophylactic/therapeutic strategies. Although epitopes restricted by many protective HLA-A/B alleles have been identified, protective HLA-C alleles are relatively understudied. Here, we identified 6 novel T cell epitopes presented by both HLA-C*14:02 (no association with protection) and HLA-C*14:03 (protective) using a mass spectrometry-based immunopeptidome profiling approach. We found that these peptides bound to and stabilized HLA-C*14:02 better than HLA-C*14:03 and observed differences in induction/expansion of epitope-specific T cell responses in HIV-infected HLA-C*14:02+ versus HLA-C*14:03+ individuals. These results enhance understanding of how the microstructural difference at position 21 between these HLA-C*14 subtypes may influence cellular immune responses involved in viral control in HIV-1 infection.

HLA Expression in Relation to HLA Type in Classic Hodgkin Lymphoma Patients.

Simple SummaryClassic Hodgkin lymphoma (cHL) is a B-cell malignancy with involvement of Epstein–Barr virus (EBV) in about 30% of the European population. The risk to develop cHL is strongly linked to genetic variants in the human leukocyte antigen (HLA) genomic region and to certain HLA alleles. This may be caused by the function of HLA alleles, or by genetic linkage to non-HLA genes. HLA can present EBV-derived and tumour-cell specific antigens and this may lead to anti-tumour immune responses. However, the tumour cells downregulate HLA expression in a proportion of the cases, which may result in immune escape. In this study, we tested whether the loss of HLA expression is related to the presence of certain protective HLA alleles. We found that loss and retention of HLA expression is indeed associated with presence of known susceptibility HLA alleles. These findings suggest that HLA itself is involved in development of cHL.Several human leukocyte antigen (HLA) alleles are strongly associated with susceptibility to classic Hodgkin lymphoma (cHL), also in subgroups stratified for presence of the Epstein–Barr virus (EBV). We tested the hypothesis that the pressure on cHL tumour cells to lose HLA expression is associated with HLA susceptibility alleles. A meta-analysis was carried out to identify consistent protective and risk HLA alleles in a combined cohort of 839 cHL patients from the Netherlands and the United Kingdom. Tumour cell HLA expression was studied in 338 cHL cases from these two cohorts and correlated to the presence of specific susceptibility HLA alleles. Carriers of the HLA-DRB1*07 protective allele frequently lost HLA class II expression in cHL overall. Patients carrying the HLA-DRB1*15/16 (DR2) risk allele retained HLA class II expression in EBV− cHL and patients with the HLA-B*37 risk allele retained HLA class I expression more frequently than non-carriers in EBV+ cHL. The other susceptibility alleles showed no significant differences in expression. Thus, HLA expression by tumour cells is associated with a subset of the protective and risk alleles. This strongly suggests that HLA associations in cHL are related to peptide binding capacities of specific HLA alleles.

Association of HLA genotypes, AB0 blood type and chemokine receptor 5 mutant CD195 with the clinical course of COVID-19

BackgroundCOVID-19, the pandemic disease caused by infection with SARS-CoV-2, may take highly variable clinical courses, ranging from symptom-free and pauci-symptomatic to fatal disease. The goal of the current study was to assess the association of COVID-19 clinical courses controlled by patients’ adaptive immune responses without progression to severe disease with patients’ Human Leukocyte Antigen (HLA) genetics, AB0 blood group antigens, and the presence or absence of near-loss-of-function delta 32 deletion mutant of the C–C chemokine receptor type 5 (CCR5).Patient and methodsAn exploratory observational study including 157 adult COVID-19 convalescent patients was performed with a median follow-up of 250 days. The impact of different HLA genotypes, AB0 blood group antigens, and the CCR5 mutant CD195 were investigated for their role in the clinical course of COVID-19. In addition, this study addressed levels of severity and morbidity of COVID-19. The association of the immunogenetic background parameters were further related to patients’ humoral antiviral immune response patterns by longitudinal observation.ResultsUnivariate HLA analyses identified putatively protective HLA alleles (HLA class II DRB1*01:01 and HLA class I B*35:01, with a trend for DRB1*03:01). They were associated with reduced durations of disease instead decreased (rather than increased) total anti-S IgG levels. They had a higher virus neutralizing capacity compared to non-carriers. Conversely, analyses also identified HLA alleles (HLA class II DQB1*03:02 und HLA class I B*15:01) not associated with such benefit in the patient cohort of this study. Hierarchical testing by Cox regression analyses confirmed the significance of the protective effect of the HLA alleles identified (when assessed in composite) in terms of disease duration, whereas AB0 blood group antigen heterozygosity was found to be significantly associated with disease severity (rather than duration) in our cohort. A suggestive association of a heterozygous CCR5 delta 32 mutation status with prolonged disease duration was implied by univariate analyses but could not be confirmed by hierarchical multivariate testing.ConclusionThe current study shows that the presence of HLA class II DRB1*01:01 and HLA class I B*35:01 is of even stronger association with reduced disease duration in mild and moderate COVID-19 than age or any other potential risk factor assessed. Prospective studies in larger patient populations also including novel SARS-CoV-2 variants will be required to assess the impact of HLA genetics on the capacity of mounting protective vaccination responses in the future.

A review of HLA and COVID-19 association studies

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is reported to vary across different populations in the prevalence of infection, in the death rate of patients, in the severity of symptoms and in the drug response of patients. Among host genetic factors that can influence all these attributes human leukocyte antigen (HLA) genetic system stands out as one of the leading candidates. Case-control studies, large-scale population-based studies, as well as experimental bioinformatics studies are of utmost importance to confirm HLA susceptibility spectrum of COVID-19. This review presents the results of the first case-control and epidemiological studies performed in several populations, early after the pandemic breakout. The results are pointing to several susceptible and protective HLA alleles and haplotypes associations with COVID-19, some of which might be of interest for the future studies in Croatia, due to its common presence in the population. However, further multiple investigations from around the world, as numerous as possible, are needed to confirm or deteriorate these preliminary results.

CD32+CD4+ memory T cells are enriched for total HIV-1 DNA in tissues from humanized mice

SummaryCD32 has raised conflicting results as a putative marker of the HIV-1 reservoir. We measured CD32 expression in tissues from viremic and virally suppressed humanized mice treated relatively early or late after HIV-1 infection with combined antiretroviral therapy. CD32 was expressed in a small fraction of the memory CD4+ T-cell subsets from different tissues in viremic and aviremic mice, regardless of treatment initiation time. CD32+ memory CD4+ T cells were enriched in cell-associated (CA) HIV-1 DNA but not in CA HIV-1 RNA as compared to the CD32−CD4+ fraction. Using multidimensional reduction analysis, several memory CD4+CD32+ T-cell clusters were identified expressing HLA-DR, TIGIT, or PD-1. Importantly, although tissue-resident CD32+CD4+ memory cells were enriched with translation-competent reservoirs, most of it was detected in memory CD32-CD4+ T cells. Our findings support that CD32 labels highly activated/exhausted memory CD4+ T-cell subsets that contain only a small proportion of the translation-competent reservoir.

Enterovirus Neutralizing Antibodies, Monocyte Toll Like Receptors Expression and Interleukin Profiles Are Similar Between Non-affected and Affected Siblings From Long-Term Discordant Type 1 Diabetes Multiplex-Sib Families: The Importance of HLA Background

Enteroviruses are main candidates among environmental agents in the development of type 1 diabetes (T1D). However, the relationship between virus and the immune system response during T1D pathogenesis is heterogeneous. This is an interesting paradigm and the search for answers would help to highlight the role of viral infection in the etiology of T1D. The current data is a cross-sectional study of affected and non-affected siblings from T1D multiplex-sib families to analyze associations among T1D, genetic, islet autoantibodies and markers of innate immunity. We evaluated the prevalence of anti-virus antibodies (Coxsackie B and Echo) and its relationships with human leukocyte antigen (HLA) class II alleles, TLR expression (monocytes), serum cytokine profile and islet β cell autoantibodies in 51 individuals (40 T1D and 11 non-affected siblings) from 20 T1D multiplex-sib families and 54 healthy control subjects. The viral antibody profiles were similar among all groups, except for antibodies against CVB2, which were more prevalent in the non-affected siblings. TLR4 expression was higher in the T1D multiplex-sib family's members than in the control subjects. TLR4 expression showed a positive correlation with CBV2 antibody prevalence (rS: 0.45; P = 0.03), CXCL8 (rS: 0.65, P = 0.002) and TNF-α (rS: 0.5, P = 0.01) serum levels in both groups of T1D multiplex-sib family. Furthermore, within these families, there was a positive correlation between HLA class II alleles associated with high risk for T1D and insulinoma-associated protein 2 autoantibody (IA-2A) positivity (odds ratio: 38.8; P = 0.021). However, the HLA protective haplotypes against T1D prevalence was higher in the non-affected than the affected siblings. This study shows that although the prevalence of viral infection is similar among healthy individuals and members from the T1D multiplex-sib families, the innate immune response is higher in the affected and in the non-affected siblings from these families than in the healthy controls. However, autoimmunity against β-islet cells and an absence of protective HLA alleles were only observed in the T1D multiplex-sib members with clinical disease, supporting the importance of the genetic background in the development of T1D and heterogeneity of the interaction between environmental factors and disease pathogenesis despite the high genetic diversity of the Brazilian population.

In silico assessment of binding affinities of three dementia-protective Human Leukocyte Antigen (HLA) alleles to nine human herpes virus antigens

BackgroundHuman herpes viruses (HHV) have been implicated in dementia. Class II Human Leukocyte Antigens (HLA) play a critical role in host protection from foreign antigens including herpes viruses through stimulating antibody production against them. In the present study we investigated the in silico binding affinity of 9 H HV to three Class II HLA alleles that have been found to protect against dementia: DRB1*01:01, DRB1*13:02, and DRB1*15:01. MethodsA sliding window approach was used to partition the amino acid sequences of surface glycoproteins from HHV 1–8 into subsequences. The binding affinity of the HHV subsequences to Class II HLA surface receptor proteins was predicted using the Sturniolo method in the Immune Epitope Database and reported as a percentile rank. The binding affinity of HHV subsequences to protective alleles was compared to that of three dementia-neutral Class II HLA alleles: DRB1*03:01, DRB1*07:01, and DRB1*08:01. FindingsBinding affinity varied widely for each HLA allele, HHV type, and HHV subsequence. The protective alleles had significantly higher binding affinity that than the neutral alleles. The largest differences in binding affinity between the protective and neutral alleles was shown for HHV-6A and HHV-6B, which had the best overall binding affinity with the protective alleles. InterpretationThe dementia protection conferred by the three protective HLA alleles investigated here is related to their superior ability to bind and successfully eliminate HHV epitopes – in particular, HHV6 - that could otherwise cause dementia if they persisted.

HLA Heterozygote Advantage against HIV-1 Is Driven by Quantitative and Qualitative Differences in HLA Allele-Specific Peptide Presentation.

Pathogen-mediated balancing selection is regarded as a key driver of host immunogenetic diversity. A hallmark for balancing selection in humans is the heterozygote advantage at genes of the human leukocyte antigen (HLA), resulting in improved HIV-1 control. However, the actual mechanism of the observed heterozygote advantage is still elusive. HLA heterozygotes may present a broader array of antigenic viral peptides to immune cells, possibly resulting in a more efficient cytotoxic T-cell response. Alternatively, heterozygosity may simply increase the chance to carry the most protective HLA alleles, as individual HLA alleles are known to differ substantially in their association with HIV-1 control. Here, we used data from 6,311 HIV-1-infected individuals to explore the relative contribution of quantitative and qualitative aspects of peptide presentation in HLA heterozygote advantage against HIV. Screening the entire HIV-1 proteome, we observed that heterozygous individuals exhibited a broader array of HIV-1 peptides presented by their HLA class I alleles. In addition, viral load was negatively correlated with the breadth of the HIV-1 peptide repertoire bound by an individual’s HLA variants, particularly at HLA-B. This suggests that heterozygote advantage at HLA-B is at least in part mediated by quantitative peptide presentation. We also observed higher HIV-1 sequence diversity among HLA-B heterozygous individuals, suggesting stronger evolutionary pressure from HLA heterozygosity. However, HLA heterozygotes were also more likely to carry certain HLA alleles, including the highly protective HLA-B*57:01 variant, indicating that HLA heterozygote advantage ultimately results from a combination of quantitative and qualitative effects in antigen presentation.

HIV Transmission Chains Exhibit Greater HLA-B Homogeneity Than Randomly Expected.

HIV's capacity to escape immune recognition by human leukocyte antigen (HLA) is a core component of HIV pathogenesis. A better understanding of the distribution of HLA class I in HIV-infected patients would improve our knowledge of pathogenesis in relation to the host HLA type and could better improve therapeutic strategies against HIV. Three hundred one to 325 transmission pairs and 469-496 clusters were identified for analysis among Swiss HIV Cohort Study (SHCS) participants using HIV pol sequences from the drug resistance database. HLA class I data were compiled at 3 specificity levels: 4-digit, 2-digit alleles, and HLA-B supertype. The analysis tabulated HLA-I homogeneity as 2 measures: the proportion of transmission pairs, which are HLA concordant, and the average percentage of allele matches within all clusters. These measures were compared with the mean value across randomizations with randomly assorted individuals. We repeated the analysis for different HLA classification levels and separately for HLA-A, -B, and -C. Subanalyses by the risk group were performed for HLA-B. HLA-B showed significantly greater homogeneity in the transmission chains (2-digit clusters: 0.291 vs. 0.251, P value = 0.009; supertype clusters: 0.659 vs. 0.611, P value = 0.002; supertype pairs: 0.655 vs. 0.608, P value = 0.014). Risk group restriction caused the effect to disappear for men-who-have-sex-with-men but not for other risk groups. We also examined if protective HLA alleles B27 and B57 were under- or overrepresented in the transmission chains, although this yielded no significant pattern. The HLA-B alleles of patients within HIV-1 transmission chains segregate in homogenous clusters/pairs, potentially indicating preferential transmission among HLA-B concordant individuals.

Immune Control of HIV

The human immunodeficiency virus (HIV) infection of the immune cells expressing the cluster of differentiation 4 cell surface glycoprotein (CD4+ cells) causes progressive decline of the immune system and leads to the acquired immunodeficiency syndrome (AIDS). The ongoing global HIV/AIDS pandemic has already claimed over 35 million lives. Even after 37 years into the epidemic, neither a cure is available for the 37 million people living with HIV (PLHIV) nor is a vaccine discovered to avert the millions of new HIV infections that continue to occur each year. If left untreated, HIV infection typically progresses to AIDS and, ultimately, causes death in a majority of PLHIV. The recommended combination antiretroviral therapy (cART) suppresses virus replication and viremia, prevents or delays progression to AIDS, reduces transmission rates, and lowers HIV-associated mortality and morbidity. However, because cART does not eliminate HIV, and an enduring pool of infected resting memory CD4+ T cells (latent HIV reservoir) is established early on, any interruption to cART leads to a relapse of viremia and disease progression. Hence, strict adherence to a life-long cART regimen is mandatory for managing HIV infection in PLHIV. The HIV-1-specific cytotoxic T cells expressing the CD8 glycoprotein (CD8+ CTL) limit the virus replication in vivo by recognizing the viral antigens presented by human leukocyte antigen (HLA) class I molecules on the infected cell surface and killing those cells. Nevertheless, CTLs fail to durably control HIV-1 replication and disease progression in the absence of cART. Intriguingly, <1% of cART-naive HIV-infected individuals called elite controllers/HIV controllers (HCs) exhibit the core features that define a HIV-1 "functional cure" outcome in the absence of cART: durable viral suppression to below the limit of detection, long-term non-progression to AIDS, and absence of viral transmission. Robust HIV-1-specific CTL responses and prevalence of protective HLA alleles associated with enduring HIV-1 control have been linked to the HC phenotype. An understanding of the molecular mechanisms underlying the CTL-mediated suppression of HIV-1 replication and disease progression in HCs carrying specific protective HLA alleles may yield promising insights towards advancing the research on HIV cure and prophylactic HIV vaccine.

A Subset of Extreme Human Immunodeficiency Virus (HIV) Controllers Is Characterized by a Small HIV Blood Reservoir and a Weak T-Cell Activation Level.

BackgroundHuman immunodeficiency virus controllers (HICs) form a heterogeneous group of patients with regard to formal definitions, immunologic characteristics, and changes over time in viral load.Patients and MethodsThe HICs with undetectable viral load ([uHICs] ie, for whom a viral load had never been detected with routine assays; n = 52) were compared with 178 HICs with blips during the follow up (bHICs). Clinical characteristics, ultrasensitive HIV-ribonucleic acid (RNA) and HIV-deoxyribonucleic acid (DNA) loads, HIV1-Western blot profiles, and immune parameters were analyzed.ResultsRelative to bHICs, uHICs had significantly lower ultrasensitive plasma HIV-RNA loads (P < .0001) and HIV-DNA levels in peripheral blood mononuclear cells (P = .0004), higher CD4+ T-cell count (P = .04) at enrollment, and lower T-cell activation levels. Between diagnosis and inclusion in the cohort, the CD4+ T-cell count had not changed in uHICs but had significantly decreased in bHICs. Twenty-one percent of the uHICs lacked specific anti-HIV immunoglobulin G antibodies, and these individuals also had very low levels of HIV-DNA. Half of the uHICs had a protective human leukocyte antigen (HLA) allele (-B57/58/B27), a weak CD8+ T-cell response, and very small HIV-DNA reservoir.ConclusionsWe suggest that an interesting HIC phenotype combines protective HLA alleles, low level of HIV blood reservoirs, and reduced immune activation. Prospective studies aimed at evaluating the benefit of combined antiretroviral therapy in HICs might take into account the identification of uHICs and bHICs.

Actinic Prurigo in Singaporean Chinese: A Positive Association with HLA-DRB1*03:01.

Studies have reported the association of human leukocyte antigen (HLA) genes with susceptibility to develop actinic prurigo (AP) in Caucasians, but there were no studies in Asian populations, including the Chinese. Our study was performed to determine if AP is associated with susceptibility or protective HLA alleles or haplotypes in Singaporean Chinese. All Chinese patients diagnosed with AP at National Skin Center, Singapore, from January 2002 to April 2015 were invited to participate in the study. Clinical data and phototesting results were collated, and HLA typing was performed. Among 14 patients included, 11 were male and the mean age was 49.6 (37.9-61.3) years. All patients did not have a family history of AP and none had mucosal involvement, as such these clinical features differed from Caucasian AP patients. The frequency of DRB1*03:01 in AP patients was significantly higher compared to healthy controls (43% vs 16%, P = 0.022, odds ratio (OR) 3.89). Concurrently, the frequency of HLA-B*58:01-DRB1*03:01 haplotype was also significantly increased (25% vs 7%, P = 0.004, OR 4.23). In conclusion, HLA-DRB1*03:01 was associated with AP in Singaporean Chinese patients. This novel allelic association may possibly be utilized as a biological marker to aid in the diagnosis of AP in Chinese patients.

The polymorphisms of human leukocyte antigen loci may contribute to the susceptibility and severity of severe aplastic anemia in Chinese patients

The human leukocyte antigen (HLA) system has been reported to be involved in the development of aplastic anemia (AA). We compared and analyzed HLA-A, B, C, DRB1 and DQB1 alleles in 96 Chinese severe AA (SAA) patients to those in 600 healthy people chosen randomly from the China Marrow Donor Program to investigate the association of HLA class I and II allele polymorphisms with disposition of SAA and its severity degree in Chinese population. The DNA of patients was extracted and HLA high-resolution genotyping was conducted using polymerase chain reaction-sequence based typing technique. The gene frequencies of A∗02:01, A∗02:06, B∗13:01, DRB1∗07:01, DRB1∗09:01, DRB1∗15:01 and DQB1∗06:02 in SAA patients were significantly higher than in controls (all P<0.05), while the allelic frequencies of A∗02:07, A∗11:01 and B∗40:01 were notably lower in SAA patients than those in the controls (P=0.001, 0.002, 0.005, respectively). Comparison among different severity of SAA groups exhibited significant increases of DRB1∗15:01 (P=0.027) and DQB1∗06:02 (P=0.013), but obviously lower frequencies of B∗46:01 (P=0.023) and DRB1∗09:01 (P=0.020) in non-VSAA patients than in VSAA patients. Thus, our results identified several risk and protective HLA alleles for Chinese SAA patients. Moreover, DRB1∗15:01, DQB1∗06:02, B∗46:01 and DRB1∗09:01 may be associated with severity of SAA.

Immune Responses Driven by Protective Human Leukocyte Antigen Alleles From Long-term Nonprogressors Are Associated With Low HIV Reservoir in Central Memory CD4 T Cells

The stable immune control of human immunodeficiency virus (HIV) in long-term nonprogressors (LTNPs) with protective human leukocyte antigen (HLA) alleles raises the question of whether and how these alleles influence the immune distribution of the HIV reservoirs. Cell-associated HIV-DNA levels were quantified in blood sorted resting CD4 T-cell subsets from 8 LTNPs with and 10 without HLA-B*27 or HLA-B*57 alleles (HLA-B27/B57). A remarkably lower infection level of central memory CD4 T cells (T(CM)) was an exclusive feature that distinguished the HLA-B27/B57 HIV reservoirs from the other ones. In LTNPs, T(CM) protection was correlated with preservation of T(CM) counts, which correlated positively with the magnitude of HIV Gag-specific CD8 T cells. In HLA-B27/B57 LTNPs, a lower activation level of their memory CD4 T cells was associated with lower amounts of cell HIV-DNA in each resting memory CD4 subset and were also associated with higher ratios of HIV Gag-specific CD8 T cells per infected resting CD4 T cell (effector/target [E/T]). As a result, HLA-B27/B57 E/T ratios were negatively correlated with the contribution of memory CD4 T-cell subsets to the total HIV reservoirs. The potent antiviral immunity governed by the protective HLA-B27/B57 alleles, by limiting T(CM) infection and pool exhaustion, are associated with a reduced T(CM) contribution to the HIV reservoir.

HLA-DR, HLA-DQB1 and PTPN22 gene polymorphism: association with age at onset for autoimmune diabetes

IntroductionAutoimmune diabetes has different clinical manifestations related to the age at onset. It is divided into several subtypes, including “classical” type 1 diabetes (T1D) and latent autoimmune diabetes in adults (LADA). The LADA is considered a slowly progressing subtype of autoimmune diabetes, although the clinical picture is more similar to type 2 diabetes.Material and methodsThe aim of this study is to investigate whether genetic predisposition influences age at onset in autoimmune diabetes. We studied rs2476601 PTPN22 gene polymorphism and HLA DR, HLA-DQB1 in 175 patients with classical type 1 diabetes, 80 LADA, and 151 control subjects from north-east Poland.ResultsThe frequencies of the PTPN22 TT genotype were higher in the group of patients with classical type 1 diabetes (6.3%) and LADA (11.3%) than in control subjects (0.7%) (p = 0.02 and p = 0007, respectively). In patients with classical type 1 diabetes we observed an increasing trend in frequencies of genotype TT dependent on age at onset (3.9% (0-5 year olds), 6.0% (6-15 year-olds), 8.2% (16-25 year olds), p = 0.048). The incidence of predisposing human leukocyte antigen (HLA) genotypes HLA DR3/DQB1*02 and DR4/DQB1*0302 was found to decrease in the group with type 1 diabetes in relation to age at onset and LADA (HLA DR3/DQB1*02 – 69.2% (0-5 year olds), 57.0% (6-15 year olds), 51.0% (16-25 year olds), 46.3% (LADA), p = 0.032; HLA DR4/DQB1*0302 – 80.8% (0-5 year olds), 63.0% (6-15 year olds), 51.0% (16-25 year olds), 43.8% (LADA), p = 0.0003), and to increase for the protective allele DQB1*0602 (0.0% (0-5 year olds), 1.0% (6-15 year olds), 2.0% (16-25 year olds), 6.3% (LADA), p = 0.029).ConclusionsThus, age at onset for autoimmune diabetes appears to be related to a combination of predisposing and protective HLA alleles. Against a background of HLA genetic predisposition, other non-HLA loci may influence age at onset for late autoimmune diabetes.

Autoimmune polyglandular syndrome type 2 shows the same HLA class II pattern as type 1 diabetes†

Autoimmune polyglandular syndrome (APS) type 2 is defined by the manifestation of at least two autoimmune endocrine diseases. Only few data exist on genetic associations of APS type 2. In this controlled study, 98 patients with APS type 2, 96 patients with type 1 diabetes (T1D), and 92 patients with autoimmune thyroid disease, both as a single autoimmune endocrinopathy, were tested for association with alleles of the human leukocyte antigen (HLA) class II loci DRB1, DQA1, and DQB1. Patients with APS type 2 had significantly more often the alleles DRB1*03 (P(c) < 0.0001), DRB1*04 (P(c) < 0.000005), DQA1*03 (P(c) < 0.0001), and DQB1*02 (P(c) < 0.05), when compared with controls. Less frequent in APS were DRB1*15 (P(c) < 0.05), DQA1*01 (P(c) < 0.0005), and DQB1*05 (P(c) < 0.005). With regard to frequency and linkage of these alleles, the susceptible haplotypes DRB1*0301-DQA1*0501-DQB1*0201 and DRB1*0401/04-DQA1*0301-DQB1*0302 were deduced. Protective haplotypes in this study were DRB1*1501-DQA1*0102-DQB1*0602 and DRB1*0101-DQA1*0101-DQB1*0501. Comparing APS patients with vs without AD, no significant differences regarding HLA class II alleles were noted in our collective. Patients with T1D as a singular disease had the same susceptible and protective HLA alleles and haplotypes. The prevalence of DRB1*03 and DRB1*04 in APS patients was not because of the presence of diabetes, as the APS type 2 patients without diabetes had the same allele distribution. In conclusion, these data suggest a common immunogenetic pathomechanism for T1D and APS type 2, which might be different from the immunogenetic pathomechanism of other autoimmune endocrine disease.

Impact of Select Immunologic and Virologic Biomarkers on CD4 Cell Count Decrease in Patients with Chronic HIV‐1 Subtype C Infection: Results from Sinikithemba Cohort, Durban, South Africa

The extent to which immunologic and clinical biomarkers influence human immunodeficiency virus type 1 (HIV-1) infection outcomes remains incompletely characterized, particularly for non-B subtypes. On the basis of data supporting in vitro HIV-1 protein-specific CD8 T lymphocyte responses as correlates of immune control in cross-sectional studies, we assessed the relationship of these responses, along with established HIV-1 biomarkers, with rates of CD4 cell count decrease in individuals infected with HIV-1 subtype C.Bivariate and multivariate mixed-effects models were used to assess the relationship of baseline CD4 cell count, plasma viral load, human leukocyte antigen (HLA) class I alleles, and HIV-1 protein-specific CD8 T cell responses with the rate of CD4 cell count decrease in a longitudinal population-based cohort of 300 therapy-naive, chronically infected adults with baseline CD4 cell counts >200 cells/mm(3) and plasma viral loads >500 copies/mL over a median of 25 months of follow-up.In bivariate analyses, baseline CD4 cell count, plasma viral load, and possession of a protective HLA allele correlated significantly with the rate of CD4 cell count decrease. No relationship was observed between HIV-1 protein-specific CD8 T cell responses and CD4 cell count decrease. Results from multivariate models incorporating baseline CD4 cell counts (201-350 vs >350 cells/mm(3)), plasma viral load (< or =100,000 vs >100,000 copies/mL), and HLA (protective vs not protective) yielded the ability to discriminate CD4 cell count decreases over a 10-fold range. The fastest decrease was observed among individuals with CD4 cell counts >350 cells/mm(3) and plasma viral loads >100,000 copies/mL with no protective HLA alleles (-59 cells/mm(3) per year), whereas the slowest decrease was observed among individuals with CD4 cell counts 201-350 cells/mm(3), plasma viral loads < or =100,000 copies/mL, and a protective HLA allele (-6 cells/mm(3) per year).The combination of plasma viral load and HLA class I type, but not in vitro HIV-1 protein-specific CD8 T cell responses, differentiates rates of CD4 cell count decrease in patients with chronic subtype-C infection better than either marker alone.