Biology subjects

Chudakov, D. M.

Publications and source records attributed to Chudakov, D. M..

At least 19 recordsLinked to original sources

bioRxiv2026

Towards understanding of NK cell antigenic specificity

NK cells can form clonal populations demonstrating features of adaptive immunity, including long-term memory and at least partial antigenic specificity. Given the limited individual diversity of activating receptors, the nature of NK cell antigenic specificity remains elusive. To explore this riddle, we combined scRNA-Seq of ex vivo FACS-sorted NK cell subsets expressing specific KIR receptors, single-cell cloning and bulk RNA-Seq of in vitro cultured KIR2DS4 NK cell clones, transcriptomic profiling of antigen-stimulated NK cells, and in silico modeling of glycosylated KIR2DS4-peptide-HLA complexes. scRNA-Seq resolved 12-15 clusters per KIR subset with highly heterogeneous KIR, KLRC and NCR expression patterns, consistent with clonal lineages. Notably, those clusters demonstrated over 30 differentially expressed glycosyltransferase genes, potentially involved in post-translational modification of NK cell receptors. Single-cell-derived KIR2DS4 cultures exhibited clone-specific cytotoxic, chemokine and KIR receptor genes, and transcriptional differences in > 40 glycosyltransferases. In peptide culturing autologous assays, SARS-CoV-2 (KTFPPTEPK) and EBV (CRAKFKHLL) peptides elicited NK cell proliferation and distinct transcriptional programs linking cytotoxicity genes, KIR2DS4 and glycosyltransferases. Structural modeling revealed that N-linked glycosyl residues in specific regions of KIR2DS4 may alter its contacts and interaction with MHCI and the presented peptide. We conclude that KIR human NK cells comprise clonally imprinted populations with distinct glycosyltransferase expression profiles, and site-specific KIR2DS4 glycosylation may modulate interaction with peptide-MHCI complexes, suggesting a post-translational layer of clonal NK cell diversification as a clue to their antigenic specificity.

immunology↗

bioRxiv2025

BCR repertoire analysis and cloning of antibody candidates targeting native and Asp7-isomerized beta-amyloid

Computational approaches are increasingly used to predict monoclonal antibody (mAb) candidates from BCR-seq datasets. However, the reliable identification of B cells encoding antibodies against rare antigenic epitopes remains challenging. We employed a repertoire-guided workflow combining antigen-tetramer sorting of B cells from immunized mice, followed by low-input bulk BCR-seq yielding informative clonal repertoires. Clustering and supporting somatic hypermutation (SHM) lineage analysis allowed us to identify IGH and IGK clonotypes potentially targeting {beta}-amyloid and its isoAsp7 variant (isoD7-A{beta}1-16), implicated in Alzheimers disease. We observed recurrent IGHV8-12 and IGKV1-117 usage, consistent with canonical mouse anti-A{beta} responses. Focusing on isoD7-A{beta} binders, we selected ten candidate IGH-IGK pairs for recombinant expression. One recombinant mAb demonstrated preferential binding to isoD7-A{beta} by microscale thermophoresis, supporting the feasibility of the approach but underscoring the challenge of accurate chain pairing. This highlights the potential of bioinformatic workflows to identify mAbs even under low-input conditions.

immunology↗

bioRxiv2024

Tracking antigen-specific T cell response to cancer immunotherapy

In each human or model animal, T cell receptor (TCR) of each effector/memory T cell clone recognizes from one to several cognate peptide-MHC complexes (pMHC). Limited knowledge on TCR repertoire specificities restricts our capacity to rationally interpret this information, both diagnostically and in preclinical research. Here we 1) develop cost-efficient wet lab and computational pipeline to identify mouse TCRs specific to particular peptides, 2) produce dataset of helper T cells (Th) TCR beta CDR3s specific to B16 melanoma neoantigens in the I-Ab pMHCII context, available in VDJdb, and 3) apply this dataset to track tumor-specific T cell response to the CTLA4 blocking immunotherapy on orthotopic B16 melanoma model. We show that tumor promotes clonally independent Tregs carrying tumor-specific TCRs characteristic for Th cells. We further show that CTLA4 blockade promotes Th clonal expansion and induces general, non-tumor-specific Th-to-Treg plasticity. Altogether, we provide a universal pipeline for the investigation of mouse T cell responses at the antigen-specific level, facilitating development and validation of immunotherapeutic and vaccination approaches.

immunology↗

bioRxiv2024

FCRL4 and exhausted B cell signature in tumor infiltrating B cells from lung cancer

Advances in high-dimensional flow cytometry and single-cell RNA sequencing (scRNA-seq) have enhanced our understanding of the heterogeneity of tumor-infiltrating B cells (TIBs). Subpopulations of TIBs exhibit diverse, sometimes opposing roles in tumor control, influenced by surface molecule, cytokine, and transcription factor expression. IgA and IgG expression in tumors have shown predictive value in melanoma and KRAS-mutated, but not KRAS wild-type, lung adenocarcinoma (LUAD). To investigate the functional differences between B cells producing these isotypes, we performed bulk transcriptome analysis of tumor-infiltrating surface-IgA+ (sIgA+) and sIgG+ memory B cells in LUAD. In LUAD, sIgA+ B cells overexpressed FCRL4, PDCD1, and RUNX2, suggesting an atypical chronically antigen-stimulated phenotype with features of exhaustion. Public scRNA-seq data revealed FCRL4-expressing TIBs as a distinct cluster with upregulation of genes involved in IFN{gamma} and IFN responses. sIgG+ B cells from LUAD overexpressed IL5RA, indicating a role for IL-5 in class-switch recombination to IgG. TCGA LUAD cohort analysis showed that the FCRL4/CD20 expression ratio correlates with lower survival, reinforcing FCRL4 as a marker of dysfunctional TIBs. Additionally, in renal cancer, high IGHA1/IGHG1 ratios were linked to worse survival. These findings suggest that the IgA/IgG ratio in tumors reflects not only the TME cytokine environment, but also functional differences in B cell populations, providing insights into their diverse roles in tumor progression.

immunology↗

bioRxiv2024

Splicing-aware resolution of scRNA-Seq data

Single-cell RNA sequencing (scRNA-Seq) provides invaluable insights in cell biology. Current scRNA-Seq analytic approaches do not distinguish between spliced and unspliced mRNA. RNA velocity paradigm suggests that the presence of unspliced mRNA reflects transitional cell states, informative for studies of dynamic processes such as embryogenesis or tissue regeneration. Alternatively, stable cell subsets may also maintain unspliced mRNA reservoirs for prompt initiation of transcription-independent expression. Based on the latter paradigm, we have developed a method called SANSARA (Splicing-Aware scrNa-Seq AppRoAch) for the splicing-aware analysis of scRNA-Seq data. We employed SANSARA to characterize peripheral blood regulatory T cell (Treg) subsets, revealing the complex interplay between FoxP3 and Helios master transcription factors and other unexpected splicing-informed features. For Th1 and cytotoxic CD4+ T cell subsets, SANSARA also revealed substantial splicing heterogeneity across crucial subset-specific genes. SANSARA is straightforward to implement in current data analysis pipelines and opens new dimensions in scRNA-Seq-based discoveries.

immunology↗

bioRxiv2023

Robust detection of SARS-CoV-2 exposure in population using T-cell repertoire profiling

The COVID-19 pandemic offers a powerful opportunity to develop methods for monitoring the spread of infectious diseases based on their signatures in population immunity. Adaptive immune receptor repertoire sequencing (AIRR-seq) has become the method of choice for identifying T cell receptor (TCR) biomarkers encoding pathogen specificity and immunological memory. AIRR-seq can detect imprints of past and ongoing infections and facilitate the study of individual responses to SARS-CoV-2, as shown in many recent studies. Here, we have applied a machine learning approach to two large AIRR-seq datasets with more than 1,200 high-quality repertoires from healthy and COVID-19-convalescent donors to infer TCR repertoire features that were induced by SARS-CoV-2 exposure. The new batch effect correction method allowed us to use data from different batches together, as well as combine the analysis for data obtained using different protocols. Proper standardization of AIRR-seq batches, access to human leukocyte antigen (HLA) typing, and the use of both - and {beta}-chain sequences of TCRs resulted in a high-quality biomarker database and a robust and highly accurate classifier for COVID-19 exposure. This classifier is applicable to individual TCR repertoires obtained using different protocols, paving the way to AIRR-seq-based immune status assessment in large cohorts of donors.

immunology↗

bioRxiv2023

Sort-Seq: immune repertoire-based scRNA-Seq systematization

The functional programs selected by CD4+ helper (Th) T cell clones fundamentally determine the architecture of the immune response to distinct challenges. Advances in scRNA-Seq have enhanced our understanding of the diversity of these programs, yet the correspondence between scRNA-Seq clusters and previously characterized Th subsets remains unclear. In this study, we use immune repertoires to position phenotypically sorted Th subsets within scRNA-Seq data from three healthy donors. This approach, termed TCR-Track, and accurately maps Th1, Th1-17, Th17, Th22, Th2a, Th2, Tfh, and Treg subsets, outperforming CITE-Seq-based mapping. Remarkably, the mapping is tightly focused on specific scRNA-Seq clusters despite a four-year interval between the sorting of subsets and the effector CD4+ scRNA-Seq experiment. Thus, while transient T cell plasticity is commonly observed in functionally active T cell populations, TCR-Track reveals high intrinsic program sustainability of Th clones circulating in peripheral blood. Repertoire overlap analysis at the scRNA-Seq level confirms that circulating Th1, Th2, Th2a, Th17, Th22, and Treg subsets are clonally independent. However, a prominent clonal overlap between corresponding clusters indicates that cytotoxic CD4+ T cells differentiate from Th1 clones. More specifically, we demonstrate that sorted CCR10+ Th cells correspond to a specific Th22 scRNA-Seq cluster, while CCR10-CCR6+CXCR3-CCR4+ cells, traditionally sorted as the Th17 subset, represent a mixture of bona fide Th17 and clonally unrelated CCR10low Th22 cells, which may have confounded investigators in previous studies. This clear distinction of Th17 and Th22 subsets should influence vaccine and T cell based therapies development. Additionally, we show that SARS-CoV-2 infection is associated with transient IFN type 1 activation of naive CD4+ T cells, and an increased proportion of effector IFN- induced Th cells is associated with a moderate course of the disease but remains low in critical COVID-19 cases. Using integrated scRNA-Seq, TCR-Track, and CITE-Seq data from 122 donors, we provide a comprehensive Th scRNA-Seq reference that should facilitate further investigation of Th subsets in fundamental and clinical studies.

immunology↗

bioRxiv2023

Convergence, plasticity, and tissue residence of regulatory T cell response via TCR repertoire prism

Suppressive function of regulatory T cells (Treg) is dependent on signaling of their antigen receptors triggered by cognate self, dietary or microbial antigens in the form of peptide-MHC class II complexes. However, it remains largely unknown whether distinct or shared repertoires of Treg TCRs are mobilized in response to different challenges in the same tissue or the same challenge in different tissues. Here we used a fixed TCR{beta} chain FoxP3-GFP mouse model to analyze conventional (eCD4) and regulatory (eTreg) effector TCR repertoires in response to six distinct antigenic challenges to the lung and skin. This model showed highly "digital" repertoire behavior, allowing for easy-to-track challenge-specific TCR CDR3 clusters. For both studied subsets, we observed challenge-specific clonal expansion yielding homologous TCR clusters within and across animals and exposure sites, which were also reflected in the draining lymph nodes but not systemically. Some clusters were shared across cancer challenges, suggesting response to common tumor-associated antigens. For most challenges, eCD4 and eTreg clonal response did not overlap, indicating the distinct origin of the two cell subsets. At the same time, we observed such overlap at the sites of certain tumor challenges. The overlaps included dominant responding TCR motif and characteristic iNKT TCR, suggesting the tumor-induced eCD4-eTreg plasticity. Additionally, our TCR repertoire analysis demonstrated that distinct antigenic specificities are characteristic for eTreg cells residing in particular lymphatic tissues, regardless of the challenge, revealing the homing-specific, antigen-specific resident Treg populations. Altogether, our study highlights both challenge-specific and tissue-specific responses of Treg cells associated with distinct clonal expansions. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=158 SRC="FIGDIR/small/544726v4_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@5a8353org.highwire.dtl.DTLVardef@63fef3org.highwire.dtl.DTLVardef@f7390forg.highwire.dtl.DTLVardef@c347e1_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2023

Non-canonical D1-D2 rearrangements are bimodal and represent a conservative hidden stage of VDJ recombination in TCR beta locus

T-cell receptor (TCR) diversity is generated by VDJ recombination. The classical course of TCR beta (TRB) chain production starts with D and J segment recombination and finishes with subsequent recombination between the resulting DJ junction and V segment. In this study, we performed deep sequencing of poorly explored incomplete TRBD1 to TRBD2 rearrangements in T-cell genomic DNA. We reconstructed full repertoires of human incomplete TRB DD rearrangements and validated its authenticity by detecting excision circles with RSS (recombination signal sequence) junctions for the first time. The identified rearrangements generated in compliance with the classical 12/23 rule are common for humans, rats, and mice and contain typical VDJ recombination footprints. Detected bimodal distribution of DD junctions indicates two active recombination sites producing long and short DD rearrangements. Unlike long DD rearrangements, the short ones have unusual origin resulting from non-canonical intrachromosomal RSSs junctions formation. Identified DD rearrangements lead to deleting J1 and C1 segments and creating diverse hybrid D segments, which recombine further with J2 and V segments. Resulting functional TRB VDDJ rearrangements are present in the memory T-cells subset proving its participation in antigen recognition.

immunology↗

bioRxiv2023

Systematic evaluation of intratumoral and peripheral BCR repertoires in three cancers

The current understanding of humoral immune response in cancer patients suggests that tumors may be infiltrated with diffuse B cells of extra-tumoral origin or may develop organized lymphoid structures, where somatic hypermutation and antigen-driven selection occur locally. These processes are believed to be significantly influenced by the tumor microenvironment through secretory factors and biased cell-cell interactions. To explore the manifestation of this influence, we used deep unbiased immunoglobulin profiling and systematically characterized the relationships between B cells in circulation, draining lymph nodes (draining LNs), and tumors in 14 patients with three human cancers. We demonstrated that draining LNs are differentially involved in the interaction with the tumor site, and that significant heterogeneity exists even between different parts of a single lymph node (LN). Next, we confirmed and elaborated upon previous observations regarding intratumoral immunoglobulin heterogeneity. We identified B cell receptor (BCR) clonotypes that were expanded in tumors relative to draining LNs and blood and observed that these tumor-expanded clonotypes were less hypermutated than non-expanded (ubiquitous) clonotypes. Furthermore, we observed a shift in the properties of complementarity-determining region 3 of the BCR heavy chain (CDR-H3) towards less mature and less specific BCR repertoire in tumor-infiltrating B-cells compared to circulating B-cells, which may indicate less stringent control for antibody-producing B cell development in tumor microenvironment (TME). In addition, we found repertoire-level evidence that B-cells may be selected according to their CDR-H3 physicochemical properties before they activate somatic hypermutation (SHM). Altogether, our work outlines a broad picture of the differences in the tumor BCR repertoire relative to non-tumor tissues and points to the unexpected features of the SHM process.

immunology↗

bioRxiv2023

Large-scale template-based structural modeling of T-cell receptors with known antigen specificity reveals complementarity features.

T-cell receptor (TCR) recognition of foreign peptides presented by the major histocompatibility complex (MHC) initiates the adaptive immune response against pathogens. A large number of TCR sequences specific to different antigens are known to date, however, the structural data describing the conformation and contacting residues for TCR:antigen:MHC complexes is relatively limited. In the present study we aim to extend and analyze the set of available structures by performing highly accurate template-based modeling of TCR:antigen:MHC complexes using TCR sequences with known specificity. Using the set of 29 complex templates (including a template with SARS-CoV-2 antigen) and 732 specificity records, we built a database of 1585 model structures carrying substitutions in either TCR or TCR{beta} chains with some models representing the result of different mutation pathways for the same final structure. This database allowed us to analyze features of amino acid contacts in TCR:antigen interfaces that govern antigen recognition preferences and interpret these interactions in terms of physicochemical properties of interacting residues. Our results provide a methodology for creating high-quality TCR:antigen:MHC models for antigens of interest that can be utilized to predict TCR specificity.

bioinformatics↗

bioRxiv2022

Predicting TCR-peptide recognition based on residue-level pairwise statistical potential

Prediction of TCR-peptide interactions has great importance for therapy of cancer, infectious and autoimmune diseases, but remains a major challenge, particularly for unseen epitopes. We present a structure-based method that enables scoring of TCR-peptide interactions using an energy potential (TCRen) derived from statistics of TCR-peptide contacts in existing crystal structures. We show that TCRen has high performance in discriminating cognate/unrelated peptides and can facilitate the identification of cancer neoepitopes recognized by tumor-infiltrating lymphocytes.

immunology↗

bioRxiv2022

Pinpointing the tumor-specific T-cells via TCR clusters

Adoptive T cell transfer (ACT) is a promising approach to cancer immunotherapy, but its efficiency fundamentally depends on the extent of tumor-specific T-cell enrichment within the graft. This can be estimated via activation with identifiable neoantigens, tumor-associated antigens (TAAs), or living or lyzed tumor cells, but these approaches remain laborious, time-consuming, and functionally limited, hampering clinical development of ACT. Here, we demonstrate that homology cluster analysis of T cell receptor (TCR) repertoires efficiently identifies tumor-reactive TCRs allowing to: 1) detect their presence within the pool of tumor-infiltrating lymphocytes (TILs); 2) optimize TIL culturing conditions, with IL-2low/IL-21/anti-PD-1 combination showing increased efficiency; 3) investigate surface marker-based enrichment for tumor-targeting T cells in freshly-isolated TILs (enrichment confirmed for CD4+ and CD8+ PD-1+/CD39+ subsets), or re-stimulated TILs (informs on enrichment in 4-1BB-sorted cells). We believe that this approach to the rapid assessment of tumor-specific TCR enrichment should accelerate T cell therapy development.

immunology↗

bioRxiv2022

Inhibitory IL-10-producing CD4+ T cells develop in a T-bet-dependent manner and facilitate cytomegalovirus persistence via coexpression of arginase-1

Inhibitory CD4+ T cells have been linked with suboptimal immune responses against cancer and pathogen chronicity, but the mechanisms that underpin the development of such regulatory networks in vivo have remained obscure. To address this knowledge gap, we performed a comprehensive functional, phenotypic, and transcriptomic analysis of IL-10-producing CD4+ T cells induced by chronic infection with murine cytomegalovirus (MCMV). We identified these cells as clonally expanded and highly differentiated TH1-like cells that developed at sites of viral persistence in a T-bet-dependent manner and coexpressed arginase-1 (Arg1), which promotes the catalytic breakdown of L-arginine. Mice lacking Arg1-expressing CD4+ T cells exhibited more robust antiviral immunity and were better able to control MCMV. Conditional deletion of T-bet in the CD4+ lineage suppressed the development of these inhibitory cells and also enabled better immune control of MCMV. Collectively, these data elucidated the ontogeny of IL-10-producing CD4+ T cells and revealed a previously unappreciated mechanism of immune regulation, whereby viral persistence was facilitated by the coexpression of Arg1.

immunology↗

bioRxiv2022

Memory persistence and differentiation into antibody-secreting cells accompanied by positive selection in longitudinal BCR repertoires

The stability and plasticity of B cell-mediated immune memory ensures the ability to respond to the repeated challenges. We have analyzed the longitudinal dynamics of immunoglobulin heavy chain repertoires from memory B cells, plasmablasts, and plasma cells from the peripheral blood of generally healthy volunteers. We reveal a high degree of clonal persistence in individual memory B cell subsets, with inter-individual convergence in memory and antibody-secreting cells (ASCs). ASC clonotypes demonstrate clonal relatedness to memory B cells, and are transient in peripheral blood. We identify two clusters of expanded clonal lineages with differing prevalence of memory B cells, isotypes, and persistence. Phylogenetic analysis revealed signs of reactivation of persisting memory B cell-enriched clonal lineages, accompanied by new rounds of affinity maturation during proliferation and differentiation into ASCs. Negative selection contributes to both persisting and reactivated lineages, preserving the functionality and specificity of BCRs to protect against current and future pathogens.

immunology↗

bioRxiv2021

The use of non-functional clonotypes as a natural spike-in for multiplex PCR bias correction in immune receptor repertoire profiling

High-throughput sequencing of adaptive immune receptor repertoires is a valuable tool for receiving insights in adaptive immunity studies. Several powerful TCR/BCR repertoire reconstruction and analysis methods have been developed in the past decade. However, detecting and correcting the discrepancy between real and experimentally observed lymphocyte clone frequencies is still challenging. Here we discovered a hallmark anomaly in the ratio between read count and clone count-based frequencies of non-functional clonotypes in multiplex PCR-based immune repertoires. Calculating this anomaly, we formulated a quantitative measure of V- and J-genes frequency bias driven by multiplex PCR during library preparation called Over Amplification Rate (OAR). Based on the OAR concept, we developed an original software for multiplex PCR-specific bias evaluation and correction named iROAR: Immune Repertoire Over Amplification Removal (https://github.com/smiranast/iROAR). The iROAR algorithm was successfully tested on previously published TCR repertoires obtained using both 5 RACE (Rapid Amplification of cDNA Ends)-based and multiplex PCR-based approaches and compared with a biological spike-in-based method for PCR bias evaluation. The developed approach can increase the accuracy and consistency of repertoires reconstructed by different methods making them more applicable for comparative analysis.

immunology↗

bioRxiv2021

Accounting for B cell behaviour and sampling bias yields a superior predictor of anti-PD-L1 response in bladder cancer

Tumor-infiltrating B cells and intratumorally-produced immunoglobulins (IG) play important roles in the tumor microenvironment and response to immunotherapy1-5. IgG antibodies produced by intratumoral B cells may drive antibody-dependent cellular cytotoxicity (ADCC) and enhance antigen presentation by dendritic cells6-8. Furthermore, B cells are efficient antigen-specific antigen presenters that can essentially modulate the behaviour of helper T cells9-11. Here we investigated the role of intratumoral IG isotype and clonality in bladder cancer. Our results show that the IgG1/IgA ratio offers a strong and independent prognostic indicator for the Basal squamous molecular subtype and for the whole ImVigor210 cohort in anti-PD-L1 immunotherapy. Our findings also indicate that effector B cell functions, rather than clonally-produced antibodies, are involved in the antitumor response. High IgG1/IgA ratio was associated with relative abundance of cytotoxic genes and prominence of the IL-21/IL-21R axis suggesting importance of T cell/B cell interaction. We integrated the B, NK, and T cell components, employing immFocus-like normalization to account for the stochastic nature of tumor tissue sampling. Using a random forest model with nested cross-validation, we developed a tumor RNA-Seq-based predictor of anti-PD-L1 therapy response in muscle-invasive urothelial carcinoma. The resulting PRIMUS (PRedIctive MolecUlar Signature) predictor achieves superior sensitivity compared to PD-L1 expression scores or existing gene signatures, allowing for reliable identification of responders even within the desert patient subcohort analyzed as a hold out set.

immunology↗

bioRxiv2021

HLA binding of self-peptides is biased towards proteins with specific molecular functions

Human leukocyte antigen (HLA) is highly polymorphic and plays a key role in guiding adaptive immune responses by presenting foreign and self peptides to T cells. Each HLA variant selects a minor fraction of peptides that match a certain motif required for optimal interaction with the peptide-binding groove. These restriction rules define the landscape of peptides presented to T cells. Given these limitations, one might suggest that the choice of peptides presented by HLA is non-random and there is preferential presentation of an array of peptides that is optimal for distinguishing self and foreign proteins. In this study we explore these preferences with a comparative analysis of self peptides enriched and depleted in HLA ligands. We show that HLAs exhibit preferences towards presenting peptides from certain proteins while disfavoring others with specific functions, and highlight differences between various HLA genes and alleles in those preferences. We link those differences to HLA anchor residue propensities and amino acid composition of preferentially presented proteins. The set of proteins that peptides presented by a given HLA are most likely to be derived from can be used to distinguish between class I and class II HLAs and HLA alleles. Our observations can be extrapolated to explain the protective effect of certain HLA alleles in infectious diseases, and we hypothesize that they can also explain susceptibility to certain autoimmune diseases and cancers. We demonstrate that these differences lead to differential presentation of HIV, influenza virus, SARS-CoV-1 and SARS-CoV-2 proteins by various HLA alleles. Finally, we show that the reported self peptidome preferences of distinct HLA variants can be compensated by combinations of HLA-A/HLA-B and HLA-A/HLA-C alleles in frequent haplotypes.

bioinformatics↗