Human Leukocyte Antigen Polymorphisms Research Articles

Human Leukocyte Antigen Polymorphism and Blood Biomarker Profiles in Parkinson’s Disease: A Pilot Study in a Latvian Cohort

Background: Parkinson’s disease (PD) is a neurodegenerative disorder characterised by a high prevalence of sporadic cases. Various molecular mechanisms are involved in its pathogenesis. This pilot study aimed to identify potential risk and protective human leukocyte antigen (HLA) alleles in PD, discover candidate alleles for further research, and evaluate potential blood biomarkers. Methods: A total of 43 PD patients and 79 unrelated sex-matched controls were enrolled in this study. We analysed the polymorphism of HLA-DRB1, HLA-DQA1, and HLA-DQB1 alleles and the blood levels of biomarkers such as S100 calcium-binding protein A9 (S1000A9), kynurenic acid (KYNA), neurofilament light chain (NfL), and glutamate decarboxylase (GAD1). Results: We found that the frequencies of the HLA-DRB1*04, -DQA1*02:01, and -DQA1*03:01 alleles were significantly higher in the PD patients than in the controls, suggesting that these alleles are potential risk factors. Furthermore, the HLA-DQA1*02:01 allele was detected more frequently in the PD group when the disease onset was at 60 years or older. On the contrary, the HLA-DRB1*01 and HLA-DQA1*05:01 alleles were less common in the PD patients, indicating a possible protective effect. Regarding biomarkers, the blood levels of S100 calcium-binding protein A9 were significantly higher, and the kynurenic acid levels were significantly lower in the PD group. The NfL levels were also higher in the PD group but did not reach statistical significance, possibly due to the sensitivity limitations of the ELISA method used. The GAD1 levels showed no significant differences between the two groups. Conclusions: Our findings indicate that the HLA-DRB1*01 and -DRB1*04 alleles and the HLA-DQA1*02:01, -DQA1*03:01, and -DQA1*05:01 alleles are associated with PD. Moreover, S100 calcium-binding protein A9 and kynurenic acid can be considered potential blood biomarkers for PD. These findings contribute to the growing body of knowledge on PD and offer new directions for further research in Latvian cohorts.

Comparison of HBV-specific T cell reactivity across the pregnant, postpartum and non-pregnant women with chronic HBV infection.

To investigate the features of HBV-specific T cell reactivity across the pregnant, postpartum or non-pregnant women with chronic HBV infection. A total of 283 patients with chronic HBV infection were enrolled in this study, including 129 patients during pregnancy, 58 patients during postpartum less than 6 months and 96 non-pregnant patients at childbearing age. A universal ELISpot assay was set up using a broad-spectrum T-cell epitope peptide library which containing 103 functionally validated CD8+ T-cell epitopes derived from overall HBsAg, HBc/eAg, HBx and HBpol proteins and fitting to the human leukocyte antigen polymorphisms of Chinese population. Then, The functional HBV-specific T cells in peripheral blood were detected. The spot-forming units (SFUs) of HBV-specific T cells in the pregnant group showed no statistical difference from the postpartum group, but significantly less than that in the non-pregnant group (p = 0.046). In the untreated patients, the pregnant group displayed HBe/cAg-specific T cells (SFUs) less than the non-pregnant group (P = 0.025) and the postpartum group (P = 0.045). Meanwhile, in the NUCs-treated patients, the three groups presented similar HBV-specific T cell reactivity. Furthermore, the SFUs in the NUCs-treated pregnant group were similar to that in the NUCs-untreated pregnant group. Importantly, ROC analysis demonstrated that the HBV-specific T cells (SFUs) (AUC = 0.742) and combined with HBsAg levels (AUC = 0.775) or with HBeAg level (AUC = 0.78) had a good predictive performance for hepatitis progression during pregnancy group. Pregnancy can reduce HBV-specific T cell reactivity in the women with chronic HBV infection, and NUCs treatment cannot improve their HBV-specific T cells reactivity. Routine monitoring of HBV-specific T cells during pregnant and postpartum period can provide precise evaluation for immune function and valuable guidance for treatments.

An archaic HLA class I receptor allele diversifies natural killer cell-driven immunity in First Nations peoples of Oceania

Genetic variation in host immunity impacts the disproportionate burden of infectious diseases that can be experienced by First Nations peoples. Polymorphic human leukocyte antigen (HLA) class I and killer cell immunoglobulin-like receptors (KIRs) are key regulators of natural killer (NK) cells, which mediate early infection control. How this variation impacts their responses across populations is unclear. We show that HLA-A∗24:02 became the dominant ligand for inhibitory KIR3DL1 in First Nations peoples across Oceania, through positive natural selection. We identify KIR3DL1∗114, widespread across and unique to Oceania, as an allele lineage derived from archaic humans. KIR3DL1∗114+NK cells from First Nations Australian donors are inhibited through binding HLA-A∗24:02. The KIR3DL1∗114 lineage is defined by phenylalanine at residue 166. Structural and binding studies show phenylalanine 166 forms multiple unique contacts with HLA-peptide complexes, increasing both affinity and specificity. Accordingly, assessing immunogenetic variation and the functional implications for immunity are fundamental toward understanding population-based disease associations.

HLA Genetic Variants in COVID-19 Susceptibility: Assessing Diversity in Indian and Global Populations

Background: The rapid spread of the SARS-CoV-2 virus has had a global impact on various ethnic groups. In order to assess the genetic predisposition of the Indian population towards COVID-19, a comparative analysis was conducted using the Human Leukocyte Antigen (HLA) to investigate the frequencies of polymorphisms directly or potentially associated with COVID-19 susceptibility, severity, immune response, and fatal outcomes in comparison to other major populations. Objectives: The objective of this study is to evaluate the genetic predisposition of the Indian population to COVID-19 by analyzing the frequencies and associations of Human Leukocyte Antigen (HLA) polymorphisms. In addition, by delineating the role of specific HLA variants in the Indian context, the study seeks to enhance our understanding of genetic factors influencing COVID-19 impact and contribute to personalized approaches for disease management and prevention across diverse ethnic groups. Methods: We collected allelic information for DRB1 gene from 653 populations globally, as documented in The Allele Frequency Net Database (AFND). Data on COVID-19 susceptibility, severity, mortality, and protective factors were obtained from a previous global study. This study aimed to compare the specific frequencies of HLA-DRB1* in different ethnic groups, including other Indian populations with COVID-19-associated alleles and protective factors. Results: HLA-DRB1*01 was identified as a significant determinant of COVID-19 susceptibility among patients in 28 states of Mexico, whereas DRB1*08 in Saudi Arabian populations, DRB1*09:01 in Japanese populations, and DRB1*15:01 in Italian populations also showed this association. Likewise, DRB1*04 in the Iranian population played a role in disease severity, and DRB1*08 in the Italian population was associated with mortality in COVID-19 patients. In addition, alleles DRB1*01:01 and DRB1*04:01 were found to exhibit a protective role in Northeast England, whereas DRB1*04 demonstrated protective effects in Saudi Arabian populations. Conclusion: The involvement of HLA in COVID-19 requires further investigation, and epidemiological studies should focus on HLA profiles as determinants of the host immune system. Prolonged homozygosity in particular genomic regions could potentially increase susceptibility to COVID-19 infection. Therefore, prudent management strategies are recommended for this pandemic in isolated communities in India and worldwide.

Frequencies of Human Leukocyte Antigen Alleles in Turkish Children with Kawasaki Disease

Abstract Objective Kawasaki disease (KD) is an acute systemic vasculitis that is one of the major causes of acquired heart disease especially in young children. The pathogenesis of KD is still unclear. The increased incidence of the disease among Japanese children and siblings of affected patients suggests a genetic component to KD susceptibility. Several reports have studied human leukocyte antigen (HLA) polymorphisms in different populations with KD and found various results. In the present study, we aimed to evaluate the association of HLA-A, -B, -C, -DRB1, and -DQB1 allele frequencies in Turkish children with KD. Methods The study was conducted between January 2016 and February 2018. HLA Class I (A, B, and C) and Class II (DRB1 and DQB1) alleles of patients and healthy controls were studied using the low-resolution DNA-based sequence-specific oligonucleotide method. Results Fifty children with KD and 500 healthy controls were included in this study. In the analysis of HLA-A, HLA-B, HLA-C, and HLA-DRB1 alleles, no statistical difference was found in the frequency of alleles between the patients with KD and the control group. However, a significantly lower frequency of the HLA-DQB1*03 allele was observed in the KD group than in the control group (p < 0.001, odds ratio [OR]: 0.29, 95% confidence interval [CI]: 0.15–0.55). When the patients with KD were divided into two subgroups with or without coronary artery lesions (CALs), the frequency of the HLA-DQB1*03 allele was also found lower in the KD group with CALs than the KD group without CALs (p = 0.008, OR: 0.19, 95% CI: 0.05–0.68). Conclusion The study may guide future studies on HLA-DQB1*03 whether it is a protective allele for KD and CALs in Turkish children.

Associations between end stage renal disease and HLA polymorphisms in the Guangxi Zhuang population

To investigate the genetic relationship between end stage renal disease (ESRD) and human leukocyte antigen (HLA) alleles in the Guangxi Zhuang population. We performed polymerase chain reaction reversed sequence-specific oligonucleotide (PCR-rSSO) in 325 patients with ESRD and genotyped the HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 loci. The direct counting method was used to determine the frequencies of HLA alleles, and Arlequin software (version 3.5.2.2) was used for haplotypic frequency analyses to compare the included ESRD patients with 350 healthy donors from the Guangxi Zhuang population. In our study, 120 HLA alleles, 284 HLA-A-B-DRB1 haplotypes, and 332 HLA-A-C-B-DRB1-DQB1 haplotypes were detected. We found that only A*11:01-B*15:02-DRB1*12:02 had a positive association with ESRD (P = 0.001, Pc = 0.020, OR = 3.106, 95% CI = 1.497–6.446) after Bonferroni correction; thus, individuals with this haplotype may be susceptible to ESRD. A*11:01-B*15:02-DRB1*12:02 is a potentially valuable haplotype for evaluating the risk of ESRD in the Guangxi Zhuang population.

The influence of HLA genetic variation on plasma protein expression

Genetic variation in the human leukocyte antigen (HLA) loci is associated with risk of immune-mediated diseases, but the molecular effects of HLA polymorphism are unclear. Here we examined the effects of HLA genetic variation on the expression of 2940 plasma proteins across 45,330 Europeans in the UK Biobank, with replication analyses across multiple ancestry groups. We detected 504 proteins affected by HLA variants (HLA-pQTL), including widespread trans effects by autoimmune disease risk alleles. More than 80% of the HLA-pQTL fine-mapped to amino acid positions in the peptide binding groove. HLA-I and II affected proteins expressed in similar cell types but in different pathways of both adaptive and innate immunity. Finally, we investigated potential HLA-pQTL effects on disease by integrating HLA-pQTL with fine-mapped HLA-disease signals in the UK Biobank. Our data reveal the diverse effects of HLA genetic variation and aid the interpretation of associations between HLA alleles and immune-mediated diseases.

Orthanq: transparent and uncertainty-aware haplotype quantification with application in HLA-typing

BackgroundIdentification of human leukocyte antigen (HLA) types from DNA-sequenced human samples is important in organ transplantation and cancer immunotherapy and remains a challenging task considering sequence homology and extreme polymorphism of HLA genes.ResultsWe present Orthanq, a novel statistical model and corresponding application for transparent and uncertainty-aware quantification of haplotypes. We utilize our approach to perform HLA typing while, for the first time, reporting uncertainty of predictions and transparently observing mutations beyond reported HLA types. Using 99 gold standard samples from 1000 Genomes, Illumina Platinum Genomes and Genome In a Bottle projects, we show that Orthanq can provide overall superior accuracy and shorter runtimes than state-of-the-art HLA typers.ConclusionsOrthanq is the first approach that allows to directly utilize existing pangenome alignments and type all HLA loci. Moreover, it can be generalized for usages beyond HLA typing, e.g. for virus lineage quantification. Orthanq is available under https://orthanq.github.io.

Association between human leukocyte antigen alleles and COVID-19 disease severity

Backgroundthe human leukocyte antigen (HLA) loci have been widely characterized to be associated with viral infectious diseases. Several studies including various ethnic groups and populations suggested associations between certain HLA alleles and SARS-CoV-2 infection. Despite the numerous associations identified, the role of HLA polymorphisms in determining the individual response to SARS-CoV-2 infection is controversial among different Saudi populations. MethodHere, we performed HLA typing by next-generation sequencing to investigate if variations in polymorphic HLA genes are linked to COVID-19 severity in the Saudi population. Namely, we analyzed HLA loci at allele level in 575 Saudi patients with SARS-CoV-2 infection. HLA class I and class II frequencies in patients were compared with allele frequency data from healthy Saudi population. Resultsin our cohort HLA-A* 02:01:01 G was associated with mild disease but was not associated with moderate and severe disease. HLA-B* 51:01:01 G was protective from severe disease while HLA-B* 50:01:01 G, HLA-C* 06:02:01 G and HLA-DRB1 * 07:01:01 G were associated with risk to severe disease as well as the total COVID-19 cohort. HLA-DRB1 * 15:01:01 G was associated with risk to all severity groups. Conclusionin conclusion, we found significant associations between HLA alleles and COVID-19 disease severity in Saudis. Further studies are warranted to include HLA typing in the workup for any new COVID-19 patients.

Uncommon HLA Alleles Observed in a Population of Istanbul Province

Objective: New polymorphisms are formed in human leucocyte antigen (HLA) genes with point mutations, gene conversions, and duplication, and the diversity continues to increase. Various new HLA alleles have significant roles in transplantation, and epidemiologic and population studies. The aim of our study was to determine the status of HLA alleles in the Turkish population, which is uncommon, well-defined, and non-defined in the world population according to the international ImMunoGeneTics information system® (IMGT) database. Methods: We performed HLA-A, -B, -C, -DQB1, and DRB1 loci at the four-field resolution level, using Sanger- sequence-based typing (SBT) for 5592 healthy, unrelated bone marrow donor volunteers from Istanbul Province. The uncommon alleles were also confirmed using high-throughput next-generation sequencing (NGS). Results: Uncommon alleles were determined at five loci as follows: HLA-A*01:155, 02:66, 02:90, 02:110, 02:343, 03:82, 24:28, 24:146, 24:276, 24:356, 31:23,33:33, 68:38; HLA-B *07:240, 18:19, 35:193, 40:303, 51:69, 51:169; HLA-C*04:39, 06:40, 07:93, 12:149, 15:73; HLA-DRB1*11:149, 13:14:02 and HLA-DQB1*03:27. All alleles were arranged according to the common and well‐documented (CWD) 3.0.0 catalog. Conclusion: This is the first study to show uncommon alleles in our population. These reported data increase the knowledge of HLA polymorphisms in the Turkish population and provide a basis for further studies in population genetics. This information may also be useful in determining whether a matched, unrelated donor is unlikely to be found so that a mismatch strategy, an extended family search, or alternate therapy, can be pursued, thus saving time and cost for patients.

Elucidating the Mechanisms Underlying Interindividual Differences in the Onset of Adverse Drug Reactions.

Idiosyncratic drug toxicities (IDTs) pose a significant challenge; they are marked by life-threatening adverse reactions that emerge aftermarket release and are influenced by intricate genetic and environmental variations. Recent genome-wide association studies have highlighted a strong correlation between specific human leukocyte antigen (HLA) polymorphisms and IDT onset. This review provides an overview of current research on HLA-mediated drug toxicities. In the last six years, HLA-transgenic (Tg) mice have been instrumental in advancing our understanding of these underlying mechanisms, uncovering systemic immune reactions that replicate human drug-induced immune stimulation. Additionally, the potential role of immune tolerance in shaping individual differences in adverse effects highlights its relevance to the interplay between HLA polymorphisms and IDTs. Although HLA-Tg mice offer valuable insights into systemic immune reactions, further exploration is essential to decipher the intricate interactions that lead to organ-specific adverse effects, especially in organs such as the skin or liver. Navigating the intricate interplay of HLA, which may potentially trigger intracellular immune responses, this review emphasizes the need for a holistic approach that integrates findings from both animal models and molecular/cellular investigations. The overarching goal is to enhance our comprehensive understanding of HLA-mediated IDTs and identify factors shaping individual variations in drug reactions. This review aims to facilitate the development of strategies to prevent severe adverse effects, address existing knowledge gaps, and provide guidance for future research initiatives in the field of HLA-mediated IDTs.

Pharmacogenomics as a Tool in Addressing Genetic VariationDependent Adverse Drug Reactions

Adverse drug reactions (ADRs) are a cause of discontinuing drug development and withdrawal from market, as well as a very common source of morbidity and mortality. Genetic variables may be the primary predictor of drug response for certain medications, but they are estimated to account for 15– 30% of the variability in drug response. Many factors can contribute to adverse drug reactions, including genetics and drug targeting/delivery. Genetic markers, such as single nucleotide polymorphisms (SNPs) in drug-metabolizing enzymes, drug targets, and human leukocyte antigen (HLA) genotypes, have been associated with an increased risk of ADRs. Pharmacogenomics is the study of the genetic variation in the way that different people react to different pharmaceuticals, including variations in the risk of adverse drug reactions, dose requirements, and efficacy. The implementation of genetic data for predicting responses to medications and ADRs is becoming a reality in clinical practice, offering the potential to reduce the incidence of ADRs and improve patient outcomes. As pharmacogenomic research continues to advance, it holds great promise for enhancing drug safety and efficacy, ultimately leading to more tailored and effective therapeutic interventions.

HLA variations in patients with diffuse large B-cell lymphoma and association with disease risk and prognosis: a case-control study.

Human leukocyte antigen (HLA) polymorphisms have been associated with the development of various autoimmune diseases, as well as malignant neoplasms. Non-Hodgkin lymphomas (NHLs) are a heterogenous group of lymphoid malignancies in which a genetic substrate has been established and is deemed to play a crucial role in disease pathogenesis. This study aimed to identify whether variations in the HLA gene region were associated with diffuse large B-cell lymphoma (DLBCL) risk and prognosis. We defined HLA class I (HLA-A, HLA-B, HLA-C) and class II (HLA-DRB1, HLA-DQB1) alleles in 60 patients with DLBCL and compared the results to those found by 236 healthy adult donors from the bone marrow bank of Northern Greece. HLA typing was performed by two molecular methods, Sequence - Specific Oligonucleotide HLA typing (SSO) and Sequence - Specific Primer HLA typing (SSP), from white blood cells recovered from peripheral blood. The phenotypic frequencies of HLA-A, HLA-B, HLA-C, HLA-DRB1 and HLA-DQB1 between patients and controls were compared with the 2-sided Fisher's exact test. Results with p-value <0.05 were considered statistically significant. Odds Ratios with 95% Confidence Intervals were calculated to further strengthen the results. The 2-sided Fisher's exact test was also applied to alleles found only in one of the two groups, while the odds ratios together with the confidence intervals were corrected with Haldane-Anscombe method. Among the studied HLA polymorphisms, the frequency HLA-C*12 allele was significantly lower in patients with DLBCL compared with control subjects (6.7% vs. 34.7%, OR = 0.16, 95% CI: 0.04-0.44). Frequency of HLA-B*39 was significantly lower in patients with DLBCL compared with controls, but due to the low frequency of this polymorphism in the studied population and small sample size, determinations regarding the significance of this findings were limited. Survival analysis revealed that the presence of HLA-C*12 was not associated with improved or worsened overall and progression-free survival. No statistically significant associations were observed in the phenotypic frequencies of HLA-A, HLA-DQB1, HLA-DRB1 and the rest of HLA-B alleles between the control and DLBCL groups. Collectively, our results provide valuable insight regarding the role of HLA variations on DLBCL risk. Further studies are required to consolidate our findings and ascertain the clinical implications of these genetic variations on DLBCL management and prognosis.

HLA-B*57:01-dependent intracellular stress in keratinocytes triggers dermal hypersensitivity reactions to abacavir.

Specific human leukocyte antigen (HLA) polymorphisms combined with certain drug administration strongly correlate with skin eruption. Abacavir hypersensitivity (AHS), which is strongly associated with HLA-B*57:01, is one of the most representative examples. Conventionally, HLA transmits immunological signals via interactions with T cell receptors on the cell surface. This study focused on HLA-mediated intracellular reactions in keratinocytes that might determine the onset of skin immunotoxicity by drug treatments. Abacavir exposure resulted in keratinocytes expressing HLA-B*57:01 exhibiting endoplasmic reticulum (ER) stress responses, such as immediate calcium release into the cytosol and enhanced HSP70 expression. In contrast, keratinocytes expressing HLA-B*57:03 (closely related to HLA-B*57:01) did not show these changes. This indicated that HLA-B*57:01 has a specific intracellular response to abacavir in keratinocytes in the absence of lymphocytes. Furthermore, abacavir exposure in HLA-B*57:01-expressing keratinocytes elevated the expression of cytokines/chemokines such as interferon-γ, interleukin-1β, and CCL27, and induced T lymphoblast migration. These effects were suppressed by ER stress relief using 4-phenylbutyrate (4-PB). HLA-B*57:01-transgenic mice also exhibited ER stress in epidermal areas following abacavir administration, and abacavir-induced skin toxicity was attenuated by the administration of 4-PB. Moreover, abacavir bound to HLA-B*57:01 within cells and its exposure led to HLA-B*57:01 protein aggregation and interaction with molecular chaperones in the ER of keratinocytes. Our results underscore the importance of HLA-mediated intracellular stress responses in understanding the onset of HLA-B*57:01-mediated AHS. We provide the possibility that the intracellular behavior of HLA is crucial for determining the onset of drug eruptions.

Differences in F pocket impact on HLA I genetic associations with autoimmune diabetes.

Human leukocyte antigen (HLA) I molecules present antigenic peptides to activate CD8+ T cells. Type 1 Diabetes (T1D) is an auto-immune disease caused by aberrant activation of the CD8+ T cells that destroy insulin-producing pancreatic β cells. Some HLA I alleles were shown to increase the risk of T1D (T1D-predisposing alleles), while some reduce this risk (T1D-protective alleles). Here, we compared the T1D-predisposing and T1D-protective allotypes concerning peptide binding, maturation, localization and surface expression and correlated it with their sequences and energetic profiles using experimental and computational methods. T1D-predisposing allotypes had more peptide-bound forms and higher plasma membrane levels than T1D-protective allotypes. This was related to the fact that position 116 within the F pocket was more conserved and made more optimal contacts with the neighboring residues in T1D-predisposing allotypes than in protective allotypes. Our work uncovers that specific polymorphisms in HLA I molecules potentially influence their susceptibility to T1D.

Routine evaluation of HBV-specific T cell reactivity in chronic hepatitis B using a broad-spectrum T-cell epitope peptide library and ELISpot assay

BackgroundThe clinical routine test of HBV-specific T cell reactivity is still limited due to the high polymorphisms of human leukocyte antigens (HLA) in patient cohort and the lack of universal detection kit, thus the clinical implication remains disputed.MethodsA broad-spectrum peptide library, which consists of 103 functionally validated CD8+ T-cell epitopes spanning overall HBsAg, HBeAg, HBx and HBpol proteins and fits to the HLA polymorphisms of Chinese and Northeast Asian populations, was grouped into eight peptide pools and was used to establish an ELISpot assay for enumerating the reactive HBV-specific T cells in PBMCs. Totally 294 HBV-infected patients including 203 ones with chronic hepatitis B (CHB), 13 ones in acute resolved stage (R), 52 ones with liver cirrhosis (LC) and 26 ones with hepatocellular carcinoma (HCC) were detected, and 33 CHB patients were longitudinally monitored for 3 times with an interval of 3–5 months.ResultsThe numbers of reactive HBV-specific T cells were significantly correlated with ALT level, HBsAg level, and disease stage (R, CHB, LC and HCC), and R patients displayed the strongest HBV-specific T cell reactivity while CHB patients showed the weakest one. For 203 CHB patients, the numbers of reactive HBV-specific T cells presented a significantly declined trend when the serum viral DNA load, HBsAg, HBeAg or ALT level gradually increased, but only a very low negative correlation coefficient was defined (r = − 0.21, − 0.21, − 0.27, − 0.079, respectively). Different Nucleotide Analogs (NUCs) did not bring difference on HBV-specific T cell reactivity in the same duration of treatment. NUCs/pegIFN-α combination led to much more reactive HBV-specific T cells than NUCs monotherapy. The dynamic numbers of reactive HBV-specific T cells were obviously increasing in most CHB patients undergoing routine treatment, and the longitudinal trend possess a high predictive power for the hepatitis progression 6 or 12 months later.ConclusionThe presented method could be developed into an efficient reference method for the clinical evaluation of cellular immunity. The CHB patients presenting low reactivity of HBV-specific T cells have a worse prognosis for hepatitis progression and should be treated using pegIFN-α to improve host T-cell immunity.

Drug-induced autoimmune-like liver injury

Drug-induced liver injury (DILI) is arare yet potentially life-threatening disease. Besides intrinsic DILI, which is mainly caused by paracetamol overdosing and which is dose-dependent and predictable, there is idiosyncratic DILI-an unpredictable and dose-independent injury of the liver caused by certain medications that only occurs in aminority of patients taking this drug. The reason why some patients react with DILI towards aspecific drug is still unknown. However, the immune system plays acentral role, which is underlined by the association of certain human leukocyte antigen (HLA) polymorphisms and DILI caused by specific drug classes. Due to the immunological processes that lead to the liver injury in DILI, there are great overlaps regarding laboratory and histological parameters between DILI and autoimmune hepatitis (AIH). Differentiating DILI and AIH can therefore be challenging, especially at the time of presentation. In addition, there are other immunologically mediated DILI phenotypes, in particular the newly defined drug-induced autoimmune-like hepatitis (DI-ALH) and liver injuries caused by checkpoint inhibitors (CPI). DI-ALH is characterized by autoimmune features and good responses towards corticosteroids, with the difference that DI-ALH mostly does not relapse after discontinuation of corticosteroids. CPI-induced liver injury has become more frequent with the rising use of those drugs and is characterized by adistinct histopathological pattern with granulomatous hepatitis and infiltration dominated by cytotoxic Tcells. Similarly, the recently recognized liver injury following vaccinations also shows an autoimmune phenotype; however, in contrast to AIH, cytotoxic Tcells seem to dominate the inflammatory infiltrates in the liver.

HLA class I peptide polymorphisms contribute to class II DQβ0603:DQα0103 antibody specificity

Antibodies reactive to human leukocyte antigens (HLA) represent a barrier for patients awaiting transplantation. Based on reactivity patterns in single-antigen bead (SAB) assays, various epitope matching algorithms have been proposed to improve transplant outcomes. However, some antibody reactivities cannot be explained by amino acid motifs, leading to uncertainty about their clinical relevance. Antibodies against the HLA class II molecule, DQβ0603:DQα0103, present in some candidates, represent one such example. Here, we show that peptides derived from amino acids 119-148 of the HLA class I heavy chain are bound to DQβ0603:DQα0103 proteins and contribute to antibody reactivity through an HLA-DM-dependent process. Moreover, antibody reactivity is impacted by the specific amino acid sequence presented. In summary, we demonstrate that polymorphic HLA class I peptides, bound to HLA class II proteins, can directly or indirectly be part of the antibody binding epitope. Our findings have potential important implications for the field of transplant immunology and for our understanding of adaptive immunity.

HLA Polymorphisms and Clinical Manifestations in IgA Vasculitis.

Studies concerning the genetic background of IgA vasculitis (IgAV), a small-vessel vasculitis occurring predominantly in childhood, have confirmed that the HLA-DRB1 gene showed a strong association with disease susceptibility. The objective was to investigate human leukocyte antigen (HLA) polymorphisms among Croatian patients with IgAV and their influence on disease susceptibility and clinical heterogeneity. Thus, 130 children with IgAV and 202 unrelated healthy individuals were enrolled in the study. Genomic DNA was extracted from whole peripheral blood, and HLA-A, -B, -DRB1 and -DQB1 gene polymorphism analysis was performed. HLA-A*03 (21.4% vs. 12.38%, p = 0.0092), HLA-B*37 (2.9% vs. 0.2%, p = 0.0054) and HLA-DRB1*12 (3.1% vs. 0.7%, p = 0.0216) alleles were significantly more frequent in IgAV patients than in controls. High-resolution typing revealed significantly higher frequency of HLA-DRB1*10:01 and -DRB1*11:03 among IgAV patients with gastrointestinal manifestations of the disease in comparison to controls (p = 0.0021 and p = 0.0301, respectively), while HLA-DRB1*14:01P occurred significantly more often in the group of patients who developed nephritis during the course of the disease (17.5% vs. 4.5%, p = 0.0006). Our results demonstrated that there is an association of HLA-A*03, HLA-B*37 and HLA-DRB1*12 alleles with susceptibility to IgAV in the examined Croatian pediatric population. Studies which aim to determine the HLA profile may contribute to the elucidation of the genetic background of autoimmune diseases, including IgAV.

Human leukocyte antigen-DQA1*04:01 and rs2040406 variants are associated with elevated risk of childhood Burkitt lymphoma

Burkitt lymphoma (BL) is responsible for many childhood cancers in sub-Saharan Africa, where it is linked to recurrent or chronic infection by Epstein-Barr virus or Plasmodium falciparum. However, whether human leukocyte antigen (HLA) polymorphisms, which regulate immune response, are associated with BL has not been well investigated, which limits our understanding of BL etiology. Here we investigate this association among 4,645 children aged 0-15 years, 800 with BL, enrolled in Uganda, Tanzania, Kenya, and Malawi. HLA alleles are imputed with accuracy >90% for HLA class I and 85-89% for class II alleles. BL risk is elevated with HLA-DQA1*04:01 (adjusted odds ratio [OR] = 1.61, 95% confidence interval [CI] = 1.32-1.97, P = 3.71 × 10−6), with rs2040406(G) in HLA-DQA1 region (OR = 1.43, 95% CI = 1.26-1.63, P = 4.62 × 10−8), and with amino acid Gln at position 53 versus other variants in HLA-DQA1 (OR = 1.36, P = 2.06 × 10−6). The associations with HLA-DQA1*04:01 (OR = 1.29, P = 0.03) and rs2040406(G) (OR = 1.68, P = 0.019) persist in mutually adjusted models. The higher risk rs2040406(G) variant for BL is associated with decreased HLA-DQB1 expression in eQTLs in EBV transformed lymphocytes. Our results support the role of HLA variation in the etiology of BL and suggest that a promising area of research might be understanding the link between HLA variation and EBV control.