Human Leukocyte Antigen Associations Research Articles

Pathology of T-cell-mediated drug hypersensitivity reactions and impact of tolerance mechanisms on patient susceptibility.

T-cell-mediated drug hypersensitivity is responsible for significant morbidity and mortality, and represents a substantial clinical concern. The purpose of this article is to focus on T-cell reactions and discuss recent advances in disease pathogenesis by exploring the impact of tolerance mechanisms in determining susceptibility in genetically predisposed patients. Certain drugs preferentially activate pathogenic T cells that have defined pathways of effector function. Thus, a critical question is what extenuating factors influence the direction of immune activation. A large effort has been given towards identifying phenotypic (e.g., infection) or genotypic (e.g., human leukocyte antigen) associations which predispose individuals to drug hypersensitivity. However, many individuals expressing known risk factors safely tolerate drug administration. Thus, mechanistic insight is needed to determine what confers this tolerance. Herein, we discuss recent clinical/mechanistic findings which indicate that the direction in which the immune system is driven relies upon a complex interplay between co-stimulatory/co-regulatory pathways which themselves depend upon environmental inputs from the innate immune system. It is becoming increasingly apparent that tolerance mechanisms impact on susceptibility to drug hypersensitivity. As the field moves forward it will be interesting to discover whether active tolerance is the primary response to drug exposure, with genetic factors such as HLA acting as a sliding scale, influencing the degree of regulation required to prevent clinical reactions in patients.

Association of Human Leukocyte Antigens (HLA) profile and acute lymphoblastic leukemia in Lebanese pediatric patients: A first report from Lebanon

IntroductionChildhood acute lymphoblastic leukemia is thought to result due to interaction of genetic and environmental factors. The association between it and different alleles of the HLA system has been studied over the past decades in different countries. ObjectiveThe aim of this study is to compare the frequency of HLA alleles in childhood ALL patients to the frequency in Lebanese population. MethodsWe compared the HLA frequency in 92 patients with childhood ALL to frequency in general Lebanese population published in previous studies. ResultsAn increased frequency of HLA A30 (P value = 0.028), HLA B13 (P value = 0.005) and HLA CW17(P value = 0.025) in pediatric ALL patients compared to the general population was noted. No differences in HLA class II alleles were seen. ConclusionThree Class I HLA alleles (HLA A30, HLA B13 and HLA CW 17) might have a predisposing effect on childhood acute lymphoblastic leukemia in Lebanese patients.

Abstract 6344: HLA and non-HLA associations with childhood and adolescent Hodgkin lymphoma risk

Abstract The genetic etiology for Hodgkin lymphoma (HL) has been investigated with findings reported in both human leukocyte antigens (HLA) and non-HLA genomic regions. However, results of genetic association studies that focus on HL developed among children and adolescent individuals are limited. Given the historically high survival rate, it is reasonable to leverage available genetic data for survivors of childhood/adolescent HL for this investigation. Utilizing existing data from the St. Jude Lifetime Cohort, the Childhood Cancer Survivor Study (CCSS) original cohort and CCSS expansion cohort, we performed a fixed-effects meta-analysis of three genome-wide association studies for a total of 1,286 HL cases, 6,824 other childhood cancer cases and 373 non-cancer controls, all of whom are of European ancestry. Three independent SNPs in the HLA locus (rs28383311, Odds Ratio [OR] = 1.80, P = 2.14×10-21; rs3129198, OR = 1.52, P = 2.05×10-14; rs3129890, OR = 1.51, P = 6.21×10-13) were identified using step-wise conditional logistic regression. HLA SNP rs28383311 had a moderate correlation (r2 = 0.46) with rs2858870 reported previously by Cozen et al. (Blood, 2012) in the HLA-DRA gene region in adolescent/young adults onset HL. HLA SNP rs3129198 had a perfect correlation (r2 = 1.0) with rs2281389 (HLA-DPB1) reported previously by Moutsianas et al. (Blood, 2011) in mostly adults-onset HL. In contrast, SNP rs3129890 had a low correlation (r2 = 0.15) with rs2395185 (HLA-DRA) reported previously by Urayama et al. (JNCI, 2012) in HL cases diagnosed across a wide age range between 16 and 80 years old. Our analysis also identified additional SNPs for non-HLA loci at genome-wide significance level including: 1) rs1432297 (OR = 1.30, P = 2.5×10-8), which is in moderate correlation (r2=0.52) with previously reported rs1432295 (REL); 2) rs13279159 (OR = 1.32, P = 1.7×10-8), which is in high correlation (r2=0.75) with previously reported rs2019960 (PVT1); and 3) rs3824662 (OR = 1.52, P = 3.9×10-10), which had a high correlation (r2 = 0.91) with previously reported rs3781093 (GATA3). In addition, a novel uncommon SNP with a large effect size (rs117361561, OR = 1.95, P = 2.50×10-8, minor allele frequency = 0.02) was identified and mapped to PDGFD, a plausible gene for HL susceptibility. Twelve out 18 (67%) previously reported genome-wide significant non-HLA SNPs were replicated with P < 0.05 based on our meta-analysis. By analyzing early onset HL within pediatric and adolescent age range, we further dissected the associations in HLA locus by replicating three independent SNPs. We also found a novel non-HLA locus and replicated the majority of previous findings in the non-HLA region, suggesting mostly overlapping as well as potentially unique genetic etiology for HL risk across different ages of onset. Citation Format: Cheng Chen, Nan Song, Xiaojun Sun, Qian Dong, Zhenghong Li, Hui Wang, Smita Bhatia, Heather Mulder, John Easton, Jinghui Zhang, Yutaka Yasui, Gregory T. Armstrong, Kirsten K. Ness, Melissa M. Hudson, Leslie L. Robison, Zhaoming Wang. HLA and non-HLA associations with childhood and adolescent Hodgkin lymphoma risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6344.

Novel HLA associations with outcomes of Mycobacterium tuberculosis exposure and sarcoidosis in individuals of African ancestry using nearest-neighbor feature selection.

Tuberculosis and sarcoidosis are inflammatory diseases characterized by granulomas that may occur in any organ but are often found in the lung. The panoply of classical human leukocyte antigen (HLA) alleles associated with occurrence and/or severity of both diseases varies considerably across studies. This heterogeneity of results, due to variation in factors like ancestry and disease subphenotype, as well as the use of simple modeling strategies to elucidate likely complex relationships, has made conclusions about underlying commonalities difficult. Here we perform HLA association analyses in individuals of African ancestry, using a greater resolution to include subphenotypes of disease and employing more comprehensive analytical techniques. Using a novel application of nearest-neighbor feature selection to score allelic importance, we investigated HLA allele association with Mycobacterium tuberculosis exposure outcomes in the first analysis of both latent Mycobacterium tuberculosis infection and active disease compared with those who, despite long-term exposure to active index cases, have neither positive diagnostic tests nor display clinical symptoms. We also compared persistent to resolved sarcoidosis. This led to the identification of novel HLA associations and evidence of main effects and interaction effects. We found strikingly similar main effects and interaction effects at HLA-DRB1, -DQB1, and -DPB1 in those resistant to tuberculosis (either latent or active) and persistent sarcoidosis.

Super high-resolution single-molecule sequence-based typing of HLA class I alleles in HIV-1 infected individuals in Ghana.

Polymorphisms in human leukocyte antigen (HLA) class I loci are known to have a great impact on disease progression in HIV-1 infection. Prevailing HIV-1 subtypes and HLA genotype distribution are different all over the world, and the HIV-1 and host HLA interaction could be specific to individual areas. Data on the HIV-1 and HLA interaction have been accumulated in HIV-1 subtype B- and C-predominant populations but not fully obtained in West Africa where HIV-1 subtype CRF02_AG is predominant. In the present study, to obtain accurate HLA typing data for analysis of HLA association with disease progression in HIV-1 infection in West African populations, HLA class I (HLA-A, -B, and -C) four-digit allele typing was performed in treatment-naïve HIV-1 infected individuals in Ghana (n = 324) by a super high-resolution single-molecule sequence-based typing (SS-SBT) using next-generation sequencing. Comparison of the SS-SBT-based data with those obtained by a conventional sequencing-based typing (SBT) revealed incorrect assignment of several alleles by SBT. Indeed, HLA-A*23:17, HLA-B*07:06, HLA-C*07:18, and HLA-C*18:02 whose allele frequencies were 2.5%, 0.9%, 4.3%, and 3.7%, respectively, were not determined by SBT. Several HLA alleles were associated with clinical markers, viral load and CD4+ T-cell count. Of note, the impact of HLA-B*57:03 and HLA-B*58:01, known as protective alleles against HIV-1 subtype B and C infection, on clinical markers was not observed in our cohort. This study for the first time presents SS-SBT-based four-digit typing data on HLA-A, -B, and -C alleles in Ghana, describing impact of HLA on viral load and CD4 count in HIV-1 infection. Accumulation of these data would facilitate high-resolution HLA genotyping, contributing to our understanding of the HIV-1 and host HLA interaction in Ghana, West Africa.

HLA and amyotrophic lateral sclerosis: a systematic review and meta-analysis

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease associated with loss of upper and lower motor neurones. It leads to death by respiratory failure and has a typical prognosis of 2–3 years. The immune system has been shown to play a role in the pathophysiology of ALS. Some of the most important immune genes are within the human leukocyte antigen (HLA) region, and a recent genome-wide association study (GWAS) has identified a risk allele for ALS within the HLA region. Older studies have also suggested an HLA association with ALS, with certain HLA alleles showing differing expression between patients and controls. This systematic review and meta-analysis examines the previous studies performed in this field. Methods: We used established publication search engines. Findings were excluded if they did not meet the selection criteria. We then undertook statistical meta-analysis on the eligible papers, using a fixed effects model. Results: There were eight eligible papers. There were three statistically significant meta-analysis findings, although these would not be significant after correction for multiple comparisons. The frequencies of HLA-A9 and HLA-DR4 genotypes were lower in ALS subjects than controls, and HLA-B35 was higher in ALS subjects. Discussion: This systematic review and meta-analysis do not confirm all the previously reported associations of HLA with ALS, but shows three alleles of interest. However, there are limitations to the studies, which include the use of older serotyping methodology and the small numbers of subjects. Given the recent GWAS association with HLA, further modern HLA studies are warranted.

Diabetic mastopathy: A rare clinicopathologic entity with considerable autoimmune potential.

Introduction and importanceDiabetic mastopathy is a rare entity affecting diabetic patients. It has been previously linked to type 1 diabetes mellitus; however, due to the several accompanying conditions, a theory of autoimmune factors contributing to the origin of this condition has been on the rise. In this paper, we report a case of diabetic mastopathy associated with several autoimmune diseases to highlight the immunological potential of this condition.Case presentationA 25-year-old female, known to have type 1 diabetes mellitus, hypertension, hypothyroidism, adrenal insufficiency, dilated cardiomyopathy and end-stage renal disease, was referred to our clinic for a breast lump. Radiological investigations showed a dense mass with irregular borders in the retroareolar area of the left breast. A core biopsy was obtained which revealed keloid-like fibrosis along with lymphocytes infiltrated, suggestive of lymphocytic mastopathy.Clinical discussionFibrous mastopathy has been merely attributed to a long-standing use of insulin therapy by diabetic patients; recent observations, however, proved the major contribution of immunity to etiopathogenesis. Even though human leukocyte antigen (HLA) association has not been supported in the literature, the histological changes of breast lymphocytic infiltrate are seen in patients who not only have T1DM, but also thyroiditis, systemic lupus erythematosus, Sjogren's syndrome, and Addison's disease. The frequent presence of several possible autoimmune conditions has promoted the theory of an autoimmune process affecting connective tissues, however, these claims are yet to be proven by future studies.ConclusionRecent observations have proved the major contribution of immunity to etiopathogenesis of diabetic mastopathy. We shed light on the role of the immune system in triggering the disease process by reporting a case of diabetic mastopathy with a cluster of autoimmune diseases. Future studies should explore the genetic background of the condition as it would potentially have several clinical implications. The discussed pathophysiologic explanations raise the possibility of autoimmunity as a key driver in pathogenesis and indicate the need to change the nomenclature of this condition.

Human Leukocyte Antigens in Pregnancy and Preeclampsia.

Preeclampsia is a pregnancy-induced hypertensive disorder, the pathophysiology of which includes underlying maternal cardiovascular disease, deficient spiral artery remodeling during placenta development, and inflammatory immune responses at the maternal-fetal interface. Human leukocyte antigens (HLA) are major histocompatibility complex molecules essential for the recognition of foreign antigens that is central to immune defense against pathogens and critical determinants for the immune system discriminating between self and non-self tissues, such as in transplantation. Pregnancy represents a naturally existing “transplantation”, where the maternal immune system must be immunologically tolerant to the developing fetus which is 50% allogeneic. It is then unsurprising that HLA also influence normal pregnancy and pregnancy complications including preeclampsia. Here we review the role of classical and non-classical HLA molecules in influencing normal physiologic function during pregnancy and describe the association of HLA with pathophysiology in preeclampsia.

High resolution HLA-DRB1 analysis and shared molecular amino acid signature of DR\u03b21 molecules in Occult hepatitis B infection

AimTo investigate the association of human leukocyte antigen (HLA)-DRB1 alleles and the variations of polymorphic amino acid changes in DRβ1 chain in Shaanxi Han population with Occult hepatitis B infection (OBI).MethodsHigh-resolution HLA-DRB1 genotyping was performed in 107 OBI carriers and 280 normal controls. Sequence information was used to assign which amino acids were encoded at all polymorphic positions. Three-dimensional modeling was performed to explore the effect of the key residues on the HLA-DRB1 molecule.ResultsStrong susceptible association for allele DRB1*07:01 was observed in OBI carriers. The amino acid variation at HLA-DRβ1 molecule revealed susceptible associations for residues Gln4β, Val57β(P9), Ser60β(P9) and Val78β(P4), the amino acids Arg4β, Asp57β(P9), Tyr60β(P9) and Tyr78β(P4) showed protective associations.ConclusionAlleles DRB1*07:01 showed strong susceptible associations in OBI carriers. The amino acid variations in DRβ molecules revealed significant molecular markers for susceptibility and protection from OBI in Shaanxi Han population.

Differential role of HLA-A and HLA-B, C expression levels as prognostic markers in colon and rectal cancer

PurposeThe association of human leucocyte antigen (HLA) class I expression levels with the clinical course of many malignancies reflects their crucial role in the recognition and elimination of malignant cells...

HLA-disease association and pleiotropy landscape in over 235,000 Finns

The human leukocyte antigen (HLA) system is the single most important genetic susceptibility factor for many autoimmune diseases and immunological traits. For systematic population-level analysis of HLA-phenotype association landscape we imputed the alleles of classical HLA genes in a discovery cohort of 146,630 and replication cohort of 89,340 Finns of whom SNP genotype data and 3,355 disease phenotypes were available as part of the FinnGen project. In total, 3,649 statistically significant single HLA allele associations in 368 phenotypes were found. Known susceptibility associations clearly dominated the landscape but we discovered also a few previously poorly established HLA associations such as DQA1*01:03 and DQB1*06:03 with mental and behavioural disorders due to cannabinoids (p-value = 10-5; beta = 0.6). As certain HLAs were found to be involved in both autoimmune and infectious diseases, we studied further the independence of their associations and statistical pleiotropy. We found that altogether 11 shared HLA alleles were associated independently with both autoimmune and infectious diseases. The most prominent of these were DQA1*03:01 and DQB1*03:02 both of which associated with three infectious and three autoimmune phenotypes. All the shared HLAs showed risk effects in both disease groups, suggesting that infections can increase the risk for autoimmune diseases. The population-level landscape analysis is an excellent resource for estimating the contribution and genetic models of HLA genes in many different phenotypes and for fine-mapping primary associations.

Human leukocyte antigen B polymorphism and association between HLA‐B27 and endoplasmic reticulum aminopeptidase 1 rs30187 SNP in patients with ankylosing spondylitis in Bangladesh

AbstractObjectivesTo determine the association of Human leukocyte antigen B (HLA‑B) alleles with ankylosing spondylitis and the allelic association of HLA‐B27 with endoplasmic reticulum aminopeptidase 1 (ERAP1) single‐nucleotide polymorphism (SNP) rs30187 in patients with ankylosing spondylitis (AS).MethodsWe studied 48 consecutively enrolled well‐defined AS patients and 48 healthy controls recruited from the outpatient clinic of the rheumatology department of Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh. To genotype HLA‐B alleles from peripheral blood DNA, we designed sequence‐specific primers for polymerase chain reaction. Sanger's sequencing method was used to detect the ERAP1 rs30187 SNP. The HLA‐B allele distributions were compared between cases and controls. To infer an allelic association between HLA‐B27 and ERAP1, allele distributions from both loci were compared using cross‐tabulations. Chi‐squared test or Fisher's exact test was used to quantify the association, and their strength of association was tested by odds ratio (OR) with 95% confidence interval (CI).ResultsThe frequency of HLA‐B27 was found to be higher in AS patients (60.4%) than in healthy controls (8.3%). HLA‐B27 allele had an OR of 16.8 (95% CI = 5.2–54.4) for the development of AS. Overall, 4% of AS patients had both HLA‐B27 and HLA‐B40. No significant association was found between ERAP1 rs30187 SNP and HLA‐B27 in patients with AS (OR = 1.7, 95% CI = 0.5–5.6).ConclusionsHLA‐B27 was significantly associated with AS in patients in Bangladesh. However, no association between ERAP1 rs30187 SNP and HLA‐B27 was observed.

HLA-SPREAD: a natural language processing based resource for curating HLA association from PubMed abstracts

Extreme complexity in the Human Leukocyte Antigens (HLA) system and its nomenclature makes it difficult to interpret and integrate relevant information for HLA associations with diseases, Adverse Drug Reactions (ADR) and Transplantation. PubMed search displays ~ 146,000 studies on HLA reported from diverse locations. Currently, IPD-IMGT/HLA (Robinson et al., Nucleic Acids Research 48:D948–D955, 2019) database houses data on 28,320 HLA alleles. We developed an automated pipeline with a unified graphical user interface HLA-SPREAD that provides a structured information on SNPs, Populations, REsources, ADRs and Diseases information. Information on HLA was extracted from ~ 28 million PubMed abstracts extracted using Natural Language Processing (NLP). Python scripts were used to mine and curate information on diseases, filter false positives and categorize to 24 tree hierarchical groups and named Entity Recognition (NER) algorithms followed by semantic analysis to infer HLA association(s). This resource from 109 countries and 40 ethnic groups provides interesting insights on: markers associated with allelic/haplotypic association in autoimmune, cancer, viral and skin diseases, transplantation outcome and ADRs for hypersensitivity. Summary information on clinically relevant biomarkers related to HLA disease associations with mapped susceptible/risk alleles are readily retrievable from HLASPREAD. The resource is available at URL http://hla-spread.igib.res.in/. This resource is first of its kind that can help uncover novel patterns in HLA gene-disease associations.

Association of HLA DRB1 allele profile with paediatric autoimmune liver disease in India

Background and Aim: Association of human leucocyte antigen (HLA) DRB1 alleles with treatment response in pediatric autoimmune liver disease (pAILD) has been observed in previous studies. The aim of this study was whether HLA DRB1 alleles are associated with treatment response in Indian children with AILD.

Association of HLA B1 allele profile with pediatric autoimmune liver disease in India

Background and Aim: Association of human leucocyte antigen (HLA) B1 alleles with treatment response in pediatric autoimmune liver disease (pAILD) has been observed in previous studies. The aim of this study was whether HLA B1 alleles are associated with treatment response in Indian children with pAILD.

Differential HLA Association of GAD65 and IA2 Autoantibodies in North Indian Type 1 Diabetes Patients.

The human leucocyte antigen (HLA) association with type 1 diabetes (T1D) is well known but there are limited studies investigating the association between β-cell autoantibodies and HLA genes. We evaluated the prevalence of GAD65 and IA-2 autoantibodies (GADA and IA2A) in 252 T1D patients from North India and investigated the genetic association of GADA and IA2A with HLA class I and class II genes/haplotypes. GADA and IA2A were detected in 50.79% and 15.87% of T1D patients, respectively, while only 8.73% had both GADA and IA2A. HLA-DRB1∗03 was observed to be significantly higher in GADA+ T1D patients as compared to GADA– (91.41% vs. 66.13%, Bonferroni-corrected P (Pc) = 1.11 × 10−5; OR = 5.45; 95% CI: 2.67-11.08). Similarly, HLA-DQB1∗02 was found to be significantly increased in GADA+ patients (94.53%, Pc = 2.19 × 10−5; OR = 6.27; 95% CI: 2.7-14.49) as compared to GADA– (73.39%). The frequencies of HLA-DRB1∗04 and DQB1∗03 were increased in IA2A+ patients (45.0% and 52.5%, respectively) as compared to that in IA2A– (25.94% and 33.96%, respectively). Further, the frequency of DRB1∗03-DQB1∗02 haplotype was found to be significantly increased in GADA+ T1D patients as compared to GADA- (60.55% vs. 41.94%, P = 3.94 × 10−5; OR = 2.13; 95%CI = 1.49-3.03). Similarly, HLA-DRB1∗04-DQB1∗03 haplotype was found to be significantly increased in IA2A+ T1D patients compared to IA2A– patients (22.5% vs. 12.97%; P = 0.041; OR = 1.95; 95%CI = 1.08-3.52). None of the HLA class I genes (HLA-A, B, and Cw) was found to be associated with GADA or IA2A in people with T1D. Our findings suggest that HLA-DRB1∗03/DQB1∗02 and HLA-DRB1∗04/DQB1∗03 might play an important role in the development of GADA and IA2A, respectively.

Systematic review of associations between HLA and renal function.

IntroductionKidney dysfunction is a highly significant disease, both in the United Kingdom and globally. Many previous studies have reported associations between human leukocyte antigens (HLA) and renal function; this systematic review attempts to identify, summarize and appraise all published studies of these associations.MethodsA literature search was performed using Medline, Embase and Cochrane Central Register of Controlled Trials to identify papers whose keywords included each of the following concepts: HLA, renal failure and genetic association. A total of 245 papers were identified and assessed for eligibility; 35 of these were included in the final study.ResultsA total of 95 HLA types and 14 three‐locus haplotypes were reported to be associated with either increased or decreased renal function. A number of these findings were replicated by independent studies that reported 16 types were protective against renal dysfunction and 15 types were associated with reduced renal function. A total of 20 HLA types were associated with both increased risk of renal disease and decreased risk by independent studies.DiscussionThere is very little consensus on which HLA types have a protective or deleterious effect on renal function. Ethnicity may play a role, with HLA types possibly having different effects among different populations, and it is possible that the different primary diseases that lead to ESRD may have different HLA associations. Some of the studies may contain type I and type II errors caused by insufficient sample sizes, cohort selection and statistical methods. Although we have compiled a comprehensive list of published associations between renal function and HLA, in many cases, it is unclear which associations are reliable. Further studies are required to confirm or refute these findings.

Association of High-Affinity Autoantibodies With Type 1 Diabetes High-Risk HLA Haplotypes.

Electrochemiluminescence (ECL) assays are high-affinity autoantibody (Ab) tests that are more specific than Abs detected by traditional radiobinding assays (RBA) for risk screening and prediction of progression to type 1 diabetes. We sought to characterize the association of high-risk human leukocyte antigen (HLA) haplotypes and genotypes with ECL positivity and levels in relatives of individuals with type 1 diabetes. We analyzed 602 participants from the TrialNet Pathway to Prevention Study who were positive for at least 1 RBA diabetes-related Ab [glutamic acid decarboxylase autoantibodies (GADA) or insulin autoantibodies (IAA)] and for whom ECL and HLA data were available. ECL and RBA Ab levels were converted to SD units away from mean (z-scores) for analyses. Mean age at initial visit was 19.4 ± 13.7 years; 344 (57.1%) were female and 104 (17.3%) carried the high-risk HLA-DR3/4*0302 genotype. At initial visit 424/602 (70.4%) participants were positive for either ECL-GADA or ECL-IAA, and 178/602 (29.6%) were ECL negative. ECL and RBA-GADA positivity were associated with both HLA-DR3 and DR4 haplotypes (all Ps < 0.05), while ECL and RBA-GADA z-score titers were higher in participants with HLA-DR3 haplotypes only (both Ps < 0.001). ECL-IAA (but not RBA-IAA) positivity was associated with the HLA-DR4 haplotype (P < 0.05). ECL-GADA positivity is associated with the HLA-DR3 and HLA-DR4 haplotypes and levels are associated with the HLA-DR3 haplotype. ECL-IAA positivity is associated with HLA-DR4 haplotype. These studies further contribute to the understanding of genetic risk and islet autoimmunity endotypes in type 1 diabetes.

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.

Severe delayed hypersensitivity reactions to IL-1 and IL-6 inhibitors link to common HLA-DRB1*15 alleles

ObjectivesDrug reaction with eosinophilia and systemic symptoms (DRESS) is a severe, delayed hypersensitivity reaction (DHR). We observed DRESS to inhibitors of interleukin 1 (IL-1) or IL-6 in a small group...