Human Leukocyte Antigen Profiles Research Articles

HLA-DR3 ~ DQ2 associates with sensory neuropathy in paraneoplastic neurological syndromes with Hu antibodies.

To investigate the association between human leukocyte antigen (HLA) and paraneoplastic neurological syndromes (PNS) with Hu antibodies, and potential specificities according to clinical presentation and cancer status. HLA genotypes at four-digit resolution were imputed from available genome-wide association data. Allele carrier frequencies were compared between patients (whole cohort, n = 100, and according to clinical presentation and cancer status) and matched healthy controls (n = 508) using logistic regression controlled by the three main principal components. The clinical presentation of 100 anti-Hu patients involved the central nervous system (28, 28%), the peripheral nervous system (36, 36%) or both combined (36, 36%). Cancer diagnosis was certain in 75 (75%). HLA association analyses revealed that anti-Hu PNS patients were more frequently carriers of DQA1*05:01 (39% vs. 19%, OR = 2.8 [1.74-4.49]), DQB1*02:01 (39% vs. 18%, OR = 2.88 [1.79-4.64]) and DRB1*03:01 (41% vs. 19%, OR = 2.92 [1.80-4.73]) than healthy controls. Remarkably, such DR3 ~ DQ2 association was absent in patients with pure central involvement, but more specific to those manifesting with peripheral involvement: DQA1*05:01 (OR = 3.12 [1.48-6.60]), DQB1*02:01 (OR = 3.35 [1.57-7.15]) and DRB1*03:01 (OR = 3.62 [1.64-7.97]); being even stronger in cases with sensory neuropathy, DQA1*05:01 (OR = 4.41 [1.89-10.33]), DQB1*02:01 (OR = 4.85 [2.04-11.53]) and DRB1*03:01 (OR = 5.79 [2.28-14.74]). Similarly, DR3 ~ DQ2 association was only observed in patients with cancer. Patients with anti-Hu PNS show different HLA profiles according to clinical presentation and, probably, cancer status, suggesting pathophysiological differences.

The impact of ageing on the distribution of preformed anti-HLA and anti-MICA antibody specificities in recipients from eastern China prior to initial HSCT

BackgroundWith the development of Hematopoietic Stem Cell Transplantation (HSCT) technology, increasing numbers of elderly patients were undergoing allogeneic HSCT and elderly patients with hematologic malignancies could benefit most from it. Preformed donor-specific human leukocyte antigen (HLA) antibodies (DSA) were associated with graft failure in HLA-mismatched allogeneic HSCT and the absence of DSA was the main criterion of selecting the donor. Except for sensitization events such as transfusion, pregnancy or previous transplantation, ageing affects the humoral immune response both quantitatively and qualitatively. To evaluate the prevalence and distribution of anti-HLA and antibodies of MHC class I chain related antigens A (MICA) specificities in different age groups before initial HSCT would provide HLA and MICA specific antibody profiles under the impact of ageing, which could provide meaningful information in the process of selecting suitable HLA-mismatched donors by avoiding preformed DSA.ResultsThere were no significant differences in the distribution of anti-HLA class I, class II and anti-MICA antibodies among the three age groups in this study except that a significant lower negative ratio of anti-HLA class I, class II antibodies and higher positive rate of MICA antibodies with maximum mean fluorescent intensity (MFI) > 5000 in the elderly than in young age group. The distribution of antibody specificities against HLA -A, -B, -C, -DR, -DQ, -DP and MICA antigens in the three age groups were generally consistent. The anti-HLA class I antibody specificities with higher frequencies were A80,A68;B76,B45;Cw17, which were unlikely to become DSA in Chinese. Anti-HLA class II antibody specificities were more likely to become potential DSA than class I.DR7, DR9, DQ7, DQ8 and DQ9 were most likely to become potential DSA.ConclusionsThe prevalence of anti-HLA and anti-MICA antibodies increased slightly as age increased. While ageing had a small impact on the distribution of antibody specificity frequencies against HLA-A, -B, -C, -DR,-DQ, -DP and MICA antigens in recipients awaiting initial HSCT from East China. The risk of developing preformed DSA was basically consistent in the three age groups and the elderly group might be more favorable in HLA-mismatched HSCT due to higher positive rate of anti-MICA antibody.

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.

Diversity of HLA-A, -B, -C, -DRB1, and -DQB1 alleles and haplotypes in Kazakhstani Tatar population and genetic relatedness to other populations

BackgroundKazakhstan is a transcontinental former Soviet Union republic whose present-day population comprises more than 100 ethnic groups. Insofar as Human Leukocyte Antigen (HLA) genotyping is useful for anthropological studies, data on the HLA profile of Kazakhstani Tatars are lacking. ObjectiveWe extend our earlier findings on the unique HLA profile of distinct Kazakhstani populations by examining HLA class I and class II loci in Kazakhstani (Volga) Tatar minority population and its relatedness to those of bordering and worldwide communities. MethodsHLA class I and class II genotypes of the Kazakhstan Tatar minority were analyzed by PCR-SSP and were compared to neighboring populations using Neighbor-Joining (NJ) trees and standard genetic distances (SGD) analysis. ResultsIn total, 132 HLA alleles were identified in a sample of 103 Kazakhstani Tatars, of which HLA-A*02:01 (20.1 %), -B*07:02 (12.1 %), -C*07:02 (12.7 %), -DRB1*07:01 (18.1 %), and -DQB1*02:01 (19.6 %) were the most frequent. The most frequent two-locus haplotypes were B*07:02 ∼ C*07:02 (10.6 %) B*07:02 ∼ DRB1*15:01 (06.1 %), B*07:02 ∼ DQB1*06:02 (07.1 %), and DRB1*15:01 ∼ DQB1*06:02 (11.6 %). ConclusionsConsidering historical data, the close relatedness of Kazakhstani Tatars to European Russians (including Russian Tatars) suggests that Kazakhstani Tatars may be Russian Tatars, who originated from the Volga region, following their massive migrations to central Asia.

Deregulation of HLA-Class I and Class II Genes in Chip, MDS, and Acute Leukemia and Similarity between Chip and MDS in HLA Profile

Introduction: Human leukocyte antigen (HLA) plays a major role in the interaction between the immune system and oncogenic process in various types of tumors. Emerging data suggests that the HLA system may have profound effects on response to immunotherapy and other types of therapy. Structural defects in HLA genes and variation in methylation have been reported to play a role in the expression of various HLA-I and HLA-II genes. Furthermore, an association between the expression of specific HLA-I or HLA-II genes and prognosis and outcome has been reported in some types of leukemia. Since HLA-I is expressed on all cells while HLA-II is expressed mainly in antigen presenting cells, we hypothesized that profiling the expression levels of both HLA-I and HLA-II in the bone marrow of patients with various myeloid neoplasms may provide information on the interaction between the microenvironment and the leukemic cell in these diseases. We used next generation sequencing to evaluate the expression level of HLA-I and HLA-II genes in myeloid neoplasms and compared these levels to normal bone marrow control. We used targeted next generation sequencing (NGS) for quantification of the RNA expression of 15 HLA-I and HLA-II genes. Methods: RNA was extracted from fresh bone marrow aspiration samples from 115 acute myeloid leukemia (AML), 196 clonal hematopoiesis of indeterminate potential (CHIP), 84 myeloproliferative neoplasm (MPN), 177 myelodysplastic syndrome (MDS), 40 acute lymphoblastic leukemia (ALL), and 279 normal bone marrow cases. RNA sequencing was performed using a targeted hybrid capture panel. The sequenced HLA-I genes were HLA-A, HLA-B, HLA-C, HLA-E, HLA-F, and HLA-H. The sequenced HLA-II genes were: HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1, HLA-DQB2, HLA-DRA, HLA-DRB1, HLA-DRB5, and HLA-DRB6. Salmon v1.4.0 software was used for expression quantification (TPM). To evaluate the depth of the significance in variation of the expression profiles between diseases we tested machine learning algorithm (random forest) incorporating the expression of all 15 genes in blindly classifying diseases. Two thirds of samples were used for training the random forest algorithm and one third was used for testing. Results: Bone marrow samples with CHIP showed no significant difference from normal bone marrow in level of expression of HLA-I genes but showed significantly (P <0.001) lower level of most HLA-II markers (DMB, DQA1, DQB2, DRB1, and DRB5). The same pattern was observed in MDS samples. In contrast, AML showed significant (P < 0.001) increase in the expression of both HLA-1 genes (A, C, and F) and HLA-II genes (DQA1, DPA1, DQB1, DRB6, and DPB1). Bone marrow samples from ALL patients showed significantly (P< 0.001) higher expression levels in DRB1 and DQA1 as compared with normal bone marrow. MPN samples showed no statistically significant difference from normal BM in any of the HLA-I or HLA-II genes, after adjusting for multiple testing. Machine leaning algorithm poorly classified MDS and AML and suggests complex overlap between the two diseases in HLA response. In contrast, the machine learning algorithm showed significant difference between MPN, MDS, and AML, and ability to distinguish all MPN cases with AUC of 0.738 (95% CI : 0.546-0.930) in the testing set (see figure). Conclusions: These findings show that the bone marrow microenvironment immune profile in MDS and CHIP likely plays a major role in the disease. Furthermore, this data suggests that this immune microenvironment is critical in CHIP and perhaps that therapeutic approaches supporting this immune microenvironment may help in preventing CHIP from progressing to MDS. The data also supports that AML is a disease that completely overwhelms the HLA immune system. In contrast, MPN appears to evade the HLA system and perhaps activating this system may help in the therapy of MPN.

Honduras HIV cohort: HLA class I and CCR5-Δ32 profiles and their associations with HIV disease outcome.

We identify both canonical and novel human leukocyte antigen (HLA)-HIV associations, providing a first step toward improved understanding of HIV immune control among the understudied Honduras Mestizo population. Our results are relevant to understanding the protective or detrimental effects of HLA subtypes in Latin America because their unique HLA diversity poses challenges for designing vaccines against HIV and interpreting results from such vaccine trials. Likewise, the description of the HLA profile in an understudied population that shows a unique HLA immunogenetic background is not only relevant for HIV immunology but also relevant in population genetics, molecular anthropology, susceptibility to other infections, autoimmune diseases, and allograft transplantation.

Inflammatory human leucocyte antigen genotypes are not a risk factor in chronic subdural hematoma development.

Chronic subdural hematoma (CSDH) pathophysiology has undergone a paradigm shift from being regarded as solely traumatic to be driven mainly by inflammation. Human leucocyte antigen (HLA) is a gene complex involved in antigen processing and presentation to T lymphocytes, thereby mediating the adaptive immune responses. As specific HLA profiles are associated with inflammatory diseases, patients with a specific HLA profile may have a lower threshold for subdural inflammation, and therefore are predisposed for CSDH development. We hypothesized that (1) CSDH patients have a specific HLA profile compared to a Danish background population, and (2) patients with recurrent CSDH have a specific HLA profile compared to CSDH patients without recurrent CSDH. Three specific HLA class II haplotypes known to drive inflammatory-mediated diseases were determined in 68 patients with CSDH. The distribution of these three haplotypes in our CSDH population was compared to a Danish population of blood donors using Monte Carlo Pearson's chi-square test. Furthermore, the distribution of the haplotypes was compared between CSDH patients with and without recurrent CSDH. We found no significant association between either of the haplotypes and the risk of CSDH, and neither of the haplotypes were associated with increased risk of CSDH recurrence. This study did not show an association between selected HLA class II haplotypes and the risk of CSDH or recurrence of CSDH compared with a healthy background population.

Matching for HLA-DR excluding diabetogenic HLA-DR3 and HLA-DR4 predicts insulin independence after pancreatic islet transplantation.

In pancreatic islet transplantation, the exact contribution of human leukocyte antigen (HLA) matching to graft survival remains unclear. Islets may be exposed to allogenic rejection but also the recurrence of type 1 diabetes (T1D). We evaluated the HLA-DR matching, including the impact of diabetogenic HLA-DR3 or HLA-DR4 matches. We retrospectively examined the HLA profile in 965 transplant recipients and 2327 islet donors. The study population was obtained from patients enrolled in the Collaborative Islet Transplant Registry. We then identified 87 recipients who received a single-islet infusion. Islet-kidney recipients, 2nd islet infusion, and patients with missing data were excluded from the analysis (n=878). HLA-DR3 and HLA-DR4 were present in 29.7% and 32.6% of T1D recipients and 11.6% and 15.8% of the donors, respectively. We identified 52 T1D islet recipients mismatched for HLA-DR (group A), 11 with 1 or 2 HLA-DR-matches but excluding HLA-DR3 and HLA- DR4 (group B), and 24 matched for HLA-DR3 or HLA-DR4 (group C). Insulin-independence was maintained in a significantly higher percentage of group B recipients from year one through five post-transplantation (p<0.01). At five-year post-transplantation, 78% of group B was insulin-independent compared to 24% (group A) and 35% (group C). Insulin-independence correlated with significantly better glycemic control (HbA1c <7%), fasting blood glucose, and reduced severe hypoglycemic events. Matching HLA-A-B-DR (≥3) independently of HLA- DR3 or HLA-DR4 matching did not improve graft survival. This study suggests that matching HLA-DR but excluding the diabetogenic HLA-DR3 and/or 4 is a significant predictor for long-term islet survival.

Immunogenetic Profiles and Associations of Breast, Cervical, Ovarian, and Uterine Cancers.

It is increasingly recognized that the human immune response influences cancer risk, progression, and survival; consequently, there is growing interest in the role of human leukocyte antigen (HLA), genes that play a critical role in initiating the immune response, on cancer. Recent evidence documented clustering of cancers based on immunogenetic profiles such that breast and ovarian cancers clustered together as did uterine and cervical cancers. Here we extend that line of research to evaluate the HLA profile of those 4 cancers and their associations. Specifically, we evaluated the associations between the frequencies of 127 HLA alleles and the population prevalences of breast, ovarian, cervical, and uterine cancer in 14 countries in Continental Western Europe. Factor analysis and hierarchical clustering were used to evaluate groupings of cancers based on their immunogenetic profiles. The results documented highly similar immunogenetic profiles for breast and ovarian cancers that were characterized predominantly by protective HLA effects. In addition, highly similar immunogenetic profiles for cervical and uterine cancers were observed that were, conversely, characterized by susceptibility effects. In light of the role of HLA in host immune system protection against non-self antigens, these findings suggest that certain cancers may be associated with similar contributory factors such as viral oncoproteins or neoantigens.

O-312 Does infertility relate to Human Leucocyte Antigen similarity? – a genetic analysis based on 609 couples

Abstract Study question Do infertile couples differ from the average population in Human Leukocyte Antigen (HLA) similarity? Summary answer Infertile couples share a significantly higher number of genes than expected by chance in four out of six HLA loci. What is known already HLA genes encode the peptides for the formation of the innate immune system and are highly polymorphic. To allow increased variability of the innate immune system for the offspring, it is necessary that the parental alleles of the HLA complex are dissimilar. In animal studies, such mechanisms have been shown to play a role in mate choice. While some large studies show that humans in Western cultures do not engage in HLA-based mate choice, it has also long been hypothesized that a couple's fertility and pregnancy outcome is influenced by the degree of HLA similarity. Study design, size, duration A multicenter study including a total number of 609 couples was performed between May 2020 and November 2021 at a private fertility center and a department of reproductive medicine of a university clinic. All couples were diagnosed with primary infertility prior to assisted reproductive techniques. Buccal swab samples were provided by both partners to determine HLA profiles. Participants/materials, setting, methods Primary infertile couples (mean age women: 34.35 years, men: 37.59 years) were recruited before undergoing IVF or ICSI therapy. Couples with former pregnancies, tubal factor, azoospermia or donor therapies were excluded. Six different HLA genes (HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1) were analysed using next-generation sequencing. Subsequently the number of HLA similarities was determined per couple. Comparison against chance level was performed using a random permutation approach with 100,000 repetitions. Main results and the role of chance Our analysis revealed a higher degree of HLA similarity in infertile couples, than expected by chance, for the loci HLA-C, -DPB1, -DRB1 and HLA-DQB1, but not for the loci HLA-A and HLA-B. A priori power analysis was performed to statistically ensure a small effect size at a � = 0.05 ������������ 1 − � = 0.95 and resulted in a number of 536 couples. Limitations, reasons for caution Conclusions are limited due to the inclusion of predominantly Caucasian couples. Wider implications of the findings This study adds new evidence to former publications with small study groups. HLA similarities may be a contributing factor to primary infertility. Further on, we will examine whether HLA similarities relate to success rates of infertility treatment and outcome of pregnancies. Trial registration number not applicable

Association of Human Leukocyte Antigen Genotypes with Severe Acute Respiratory Syndrome Coronavirus 2 Vaccine-Induced Subacute Thyroiditis.

Background: Despite mass vaccination, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine-induced subacute thyroiditis (SAT) is rarely seen as a complication. The reason why some individuals are susceptible to developing vaccine-induced SAT is not known. SAT develops in genetically predisposed individuals who carry specific human leukocyte antigen (HLA) haplotypes. It is unknown whether specific HLA alleles are associated with SARS-CoV-2 vaccine-induced SAT. Objective: This study compared the HLA profiles of patients with SARS-CoV-2 vaccine-induced SAT to controls, to assess whether there is an association between specific HLA genotypes and development of SAT. The relationship between HLA genotypes and the clinical course of SARS-CoV-2 vaccine-induced SAT was also evaluated. Methods: A case-control study was conducted in a Turkish tertiary care center. Fourteen patients with SARS-CoV-2 vaccine-induced SAT and 100 healthy controls were included. HLA-A, HLA-B, HLA-C, HLA-DQB1, and HLA-DRB1 frequencies were analyzed by next-generation sequencing. Results: The frequencies of HLA-B*35 and HLA-C*04 alleles were significantly higher in SARS-CoV-2 vaccine-induced SAT cohort when compared with controls (HLA-B*35: 13 [93%] vs. 40 [40%], p < 0.001; HLA-C*04: 13 [93%] vs. 43 [43%], p < 0.001, respectively). More severe thyrotoxicosis was seen in patients having HLA-B*35 and HLA-C*04 homozygous alleles (free thyroxine: 4.47 ng/dL [3.77-5.18] vs. 1.41 ng/dL [1.22-2.63], p = 0.048). Inflammation tended to be more severe in homozygous patients (C-reactive protein: 28.2 mg/dL [13.6-42.9] vs. 4.8 [1.2-10.5], p = 0.07). Conclusions: The frequencies of HLA-B*35 and HLA-C*04 alleles were higher in SARS-CoV-2 vaccine-induced SAT compared with controls. Homozygosity for HLA-B*35 and HLA-C*04 was associated with thyrotoxicosis and a greater inflammatory reaction. Our findings should be confirmed in studies of other populations.

T Cell Epitope Discovery in the Context of Distinct and Unique Indigenous HLA Profiles

CD8+ T cells are a pivotal part of the immune response to viruses, playing a key role in disease outcome and providing long-lasting immunity to conserved pathogen epitopes. Understanding CD8+ T cell immunity in humans is complex due to CD8+ T cell restriction by highly polymorphic Human Leukocyte Antigen (HLA) proteins, requiring T cell epitopes to be defined for different HLA allotypes across different ethnicities. Here we evaluate strategies that have been developed to facilitate epitope identification and study immunogenic T cell responses. We describe an immunopeptidomics approach to sequence HLA-bound peptides presented on virus-infected cells by liquid chromatography with tandem mass spectrometry (LC-MS/MS). Using antigen presenting cell lines that stably express the HLA alleles characteristic of Indigenous Australians, this approach has been successfully used to comprehensively identify influenza-specific CD8+ T cell epitopes restricted by HLA allotypes predominant in Indigenous Australians, including HLA-A*24:02 and HLA-A*11:01. This is an essential step in ensuring high vaccine coverage and efficacy in Indigenous populations globally, known to be at high risk from influenza disease and other respiratory infections.

Relationship between pediatric celiac disease and chromatin remodeling gene expressions

Celiac disease (CD) is an immune-dependent systemic disorder that occurs in genetically predisposed individuals resulting in damage in the small intestine. It is known that chromatin remodeling, an epigenetic mechanism, is associated with gastrointestinal diseases associated with chronic inflammation. However, no information is available on the link between CD and chromatin remodeling. For this purpose, the expression profiles of chromatin remodeling group genes in children diagnosed with CD according to Marsh classification and HLA profile were evaluated and their relationship with CD was investigated. Endoscopic biopsies embedded in the paraffin block of 40 children with CD diagnosis and 30 healthy children were included in the study. The most common four mutations (DQA1*05, DQB1*02, DQA1*03, and DQB1*03:02) related to CD on human leukocyte antigen (HLA) gene were screened. Intestinal biopsy samples were used for mRNA isolations and cDNA synthesis. Expressions of total seven genes in the chromatin remodeling groups (SWI/SNF Complex Group: ARID1A, Polycomb Group: CTBP1, Nucleosome-Remodeling &amp; Histone Deacetylase (NuRD) Complex Group: MTA1, Chromobox/Heterochromatin Protein 1 (HP1) Homologs Group: CBX3 and CBX7, Homeodomain (PHD) Protein Group: NSD1, Inhibitor of Growth (ING) family group: ING 5) were analyzed by Real-Time qPCR. Data analysis was performed online using the software provided by the manufacturer. Overexpression in ARID1A, CTBP1, and NSD1 genes was detected when the CD group was compared against the control group, however they were not significant (p=0.31, 0.33, and 0.33). When CD group who had diarrhea symptom (typical) were compared to the CD group without diarrhea symptom (atypical), statistically significant under-expression was found in CBX3 and CTBP1 genes (p=0.04 and p=0.004). Statistically significant CTB1 overexpression was detected in Marsh 2 CD cases (p=0.03). In the comparison of HLA DQ2/DQ8 positive CD patient group with the control group, the NSD1, CBX3, and EED (p=0.75, 0.75, and 0.78) genes were over-expressed and the CBX7, MTA1, ARID1A, and CTBP1 genes (p=0.74, 0.75, 0.75, and 0.75) were under-expressed. This is the first study to report that expression of chromatin remodeling genes may have roles in the development and progression of CD. The results of this case-control study are open to confirmation by future studies with larger number of subjects to obtain statistically significant results.

The similarity of class II HLA genotypes defines patterns of autoreactivity in idiopathic bone marrow failure disorders

AbstractIdiopathic aplastic anemia (IAA) is a rare autoimmune bone marrow failure (BMF) disorder initiated by a human leukocyte antigen (HLA)-restricted T-cell response to unknown antigens. As in other autoimmune disorders, the predilection for certain HLA profiles seems to represent an etiologic factor; however, the structure-function patterns involved in the self-presentation in this disease remain unclear. Herein, we analyzed the molecular landscape of HLA complexes of a cohort of 300 IAA patients and almost 3000 healthy and disease controls by deeply dissecting their genotypic configurations, functional divergence, self-antigen binding capabilities, and T-cell receptor (TCR) repertoire specificities. Specifically, analysis of the evolutionary divergence of HLA genotypes (HED) showed that IAA patients carried class II HLA molecules whose antigen-binding sites were characterized by a high level of structural homology, only partially explained by specific risk allele profiles. This pattern implies reduced HLA binding capabilities, confirmed by binding analysis of hematopoietic stem cell (HSC)-derived self-peptides. IAA phenotype was associated with the enrichment in a few amino acids at specific positions within the peptide-binding groove of DRB1 molecules, affecting the interface HLA-antigen-TCR β and potentially constituting the basis of T-cell dysfunction and autoreactivity. When analyzing associations with clinical outcomes, low HED was associated with risk of malignant progression and worse survival, underlying reduced tumor surveillance in clearing potential neoantigens derived from mechanisms of clonal hematopoiesis. Our data shed light on the immunogenetic risk associated with IAA etiology and clonal evolution and on general pathophysiological mechanisms potentially involved in other autoimmune disorders.

Immunogenetic Epidemiology of Motor Neuron Diseases in 14 Continental Western European Countries

Very few studies have evaluated associations of human leukocyte antigen (HLA) with motor neuron diseases (MND). Using an immunogenetic epidemiological approach, we identified a population-level HLA profile for MND by evaluating the correlations between the population frequencies of 127 HLA Class I and II alleles and the population prevalence of MND in 14 Continental Western European countries. The results demonstrated that significantly more HLA alleles, particularly for Class I, were negatively associated with the population prevalence of MND, suggesting a preponderance of protective vs susceptibility effects. The findings add to the limited literature implicating HLA in MND and considering the role of HLA in immune system responses to pathogens, suggest a potential influence of pathogens in MND.

Immunogenetic Epidemiology of Type 1 Diabetes in 14 Continental Western European Countries

Human leukocyte antigen (HLA) is widely recognized to influence individual Type 1 diabetes (T1D) risk. Here we utilized an immunogenetic epidemiological approach to evaluate the influence of HLA on T1D at the population level. Specifically, we evaluated the correlations between the population frequencies of 127 HLA Class I and II alleles and the population prevalence of T1D in 14 Continental Western European countries to identify a population-level HLA profile for T1D. The results of these analyses generally corroborated prior findings regarding the influence of HLA on T1D risk and protection and revealed several novel HLA-T1D associations. The findings, discussed within the context of the role of HLA in pathogen elimination and autoimmunity, point to a contributory role of exposure to pathogens in the absence of protective HLA in underlying the autoimmune destruction of pancreatic beta cells in T1D.

Abstract 3020: Human leukocyte antigen (HLA) typing of a broad panel of cancer patient-derived xenograft (PDX) models for immune therapies

Abstract Background In immuno-oncology research, an appropriate microenvironment for both human tumor cells and human immune cells is an important but challenging factor for successful development of relevant preclinical models. Humanized patient-derived xenograft (PDX) models can support establishment of such an environment based on matching human leukocyte antigen (HLA) profiles of PDX and compatible human immune cell populations. In this study, we determined the individual HLA types of a broad panel of 291 established PDX models from 18 different tumor entities. Furthermore, we performed comprehensive HLA matching analyses of all PDX models and 13 peripheral blood mononuclear cell (PBMC) donors to enable personalized studies with HLA-matched PDX. Methods The HLA profile of each PDX was determined comprising HLA class I, II and non-class types in 4-digit resolution. Matching analyses were performed according to donor-recipient HLA matching criteria recommended by the Blood and Marrow Transplant Clinical Trials Network (BMT CTN). For comparative HLA profile analyses, allele frequencies of 8862 German stem cell donors provided by The Allele Frequency Net Database were downloaded. Results The individual HLA profiles of all PDX models were generated comprising HLA-A, -B and -C (class I), HLA-DQA1, -DQB1, -DRB1, -DPA1 and -DPB1 (class II) as well as HLA-H (non-class) types. Comparative analyses of HLA profiles revealed that obtained frequencies of PDX HLA alleles are comparable with frequencies of a representative population of 8862 German stem cell donors. HLA profile matching analyses performed for all PDX models and PBMC donors resulted in 15 matches regarding PDX from head and neck, lung, mammary and pancreatic carcinoma as well as from endometrial cancer, glioma, lymphoma, melanoma and sarcoma. Dependence of immune therapy efficacy on matched HLA profiles was shown exemplarily for a head and neck squamous cell cancer (HNSCC) PDX. The HNSCC PDX was humanized with PBMC from 5 donors representing different degrees of HLA matching (33 - 100 %). Treatment with the checkpoint inhibitor Nivolumab caused a more powerful tumor growth inhibition in matched HLA profiles compared to non-matched profiles. This indicated a relation between antitumoral immune therapy effect and HLA matching in preclinical models. Conclusions We generated a comprehensive HLA profile portfolio containing information of a broad panel of PDX models. Matched HLA profiles of PDX models and PBMC donors enable personalized, preclinical immune-oncology studies to support the development of novel therapeutic strategies. Citation Format: Theresia Conrad, Annika Wulf-Goldenberg, Maria Stecklum, Michael Becker, Konrad Klinghammer, Jens Hoffmann. Human leukocyte antigen (HLA) typing of a broad panel of cancer patient-derived xenograft (PDX) models for immune therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3020.

Human Leukocyte Antigen Profile Predicts Severity of Autoimmune Liver Disease in Children of European Ancestry.

Genetic predisposition to autoimmune hepatitis (AIH) in adults is associatedwith possession of human leukocyte antigen (HLA) class I (A*01,B*08) and class II (DRB1*03,-04, -07, or-13) alleles,depending on geographic region. Juvenile autoimmune liver disease (AILD) comprises AIH-1, AIH-2, and autoimmune sclerosing cholangitis (ASC), which are phenotypically different from their adult counterparts. We aimed to define the relationship between HLA profile and disease course, severity, and outcome in juvenile AILD. We studied 236 children of European ancestry (152 female [64%], median age 11.15 years, range 0.8-17), including 100 with AIH-1, 59 with AIH-2, and 77 with ASC. The follow-up period was from 1977 to June 2019 (median 14.5 years). Class I and II HLA genotyping was performed using PCR/sequence-specific primers.HLAB*08, -DRB1*03, and theA1-B8-DR3haplotype impart predisposition to all three forms of AILD. Homozygosity forDRB1*03represented the strongest risk factor (8.8). HLADRB1*04,which independently confers susceptibility to AIH in adults, was infrequent in AIH-1 and ASC, suggesting protection; and DRB1*15 (DR15)was protective against all forms of AILD. Distinct HLA class II alleles predispose to the different subgroups of juvenile AILD:DRB1*03to AIH-1,DRB1*13to ASC, andDRB1*07to AIH-2. Possession of homozygousDRB1*03 or of DRB1*13 isassociated with fibrosis at disease onset, and possession of these two genes in addition toDRB1*07is associated with a more severe disease in all three subgroups. Unique HLA profiles are seen in each subgroup of juvenile AILD. HLA genotype might be useful in predictingresponsiveness to immunosuppressive treatment and course.

Immunogenetic Epidemiology of Dementia and Parkinson’s Disease in 14 Continental European Countries: Shared Human Leukocyte Antigen (HLA) Profiles

Human leukocyte antigen (HLA), which is critically involved in immune response to foreign antigens and in autoimmunity, has been implicated in dementia and Parkinson’s disease. Here we report on the correlations between the population frequencies of 127 HLA Class I and II alleles and the population prevalence of dementia and Parkinson’s disease in 14 Continental Western European countries, extending previous work1,2. We used these correlations to construct and compare HLA profiles for each disease3. We found that (a) the HLA profiles of the two diseases were significantly correlated across both HLA Class I and Class II alleles, (b) negative (“protective”) HLA-disease correlations did not differ significantly for either HLA class, but (c) positive (“susceptibility”) HLA-disease correlations were significantly higher in dementia than in Parkinson’s disease for both HLA classes of alleles. These findings indicate that (a) dementia and Parkinson’s disease share immunogenetic HLA-related mechanisms, (b) HLA-related protective mechanisms (presumably against pathogens) do not differ between the two diseases, but (c) HLA-related susceptibility mechanisms (presumably underlying autoimmunity) are significantly stronger in dementia than in Parkinson’s disease.

HLA Class II Genotype Does Not Affect the Myelin Responsiveness of Multiple Sclerosis Patients.

Background: When aiming to restore myelin tolerance using antigen-specific treatment approaches in MS, the wide variety of myelin-derived antigens towards which immune responses are targeted in multiple sclerosis (MS) patients needs to be taken into account. Uncertainty remains as to whether the myelin reactivity pattern of a specific MS patient can be predicted based upon the human leukocyte antigen (HLA) class II haplotype of the patient. Methods: In this study, we analyzed the reactivity towards myelin oligodendrocyte glycoprotein (MOG), myelin basic protein (MBP) and proteolipid protein (PLP) peptides using direct interferon (IFN)-γ enzyme-linked immune absorbent spot (ELISPOT). Next, the HLA class II haplotype profile was determined by next-generation sequencing. In doing so, we aimed to evaluate the possible association between the precursor frequency of myelin-reactive T cells and the HLA haplotype. Results: Reactivity towards any of the analyzed peptides could be demonstrated in 65.0% (13/20) of MS patients and in 60.0% (6/10) of healthy controls. At least one of the MS risk alleles HLA-DRB1*15:01, HLA-DQA1*01:02 and HLA-DQB1*06:02 was found in 70.0% (14/20) of patients and in 20.0% (2/10) of healthy controls. No difference in the presence of a myelin-specific response, nor in the frequency of myelin peptide-reactive precursor cells could be detected among carriers and non-carriers of these risk alleles. Conclusion: No association between HLA haplotype and myelin reactivity profile was present in our study population. This complicates the development of antigen-specific treatment approaches and implies the need for multi-epitope targeting in an HLA-unrestricted manner to fully address the wide variation in myelin responses and HLA profiles in a heterogeneous group of MS patients.