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Major Histocompatibility Complex (MHC) in Health and Disease 2022

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Immunology".

Deadline for manuscript submissions: closed (30 April 2023) | Viewed by 26577

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Special Issue Editors

Dr. Johannes M. Dijkstra

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Guest Editor

Institute for Comprehensive Medical Science, Fujita Health University, Dengaku-gakubo 1-98, Toyoake, 470-1192 Aichi-ken, Japan
Interests: immunogenetics and biology of the major histocompatibility complex; genomics; retroelements

Dr. Jerzy K. Kulski

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Guest Editor

1. Department of Molecular Life Science, Division of Basic Medical Science and Molecular Medicine, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1143, Japan
2. School of Psychiatry and Clinical Neurosciences, The University of Western Australia, Crawley, WA 6009, Australia
Interests: immunogenetics and biology of the major histocompatibility complex; genomics; retroelements
Special Issues, Collections and Topics in MDPI journals

Dr. Nianzhi Zhang

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Department of Microbiology and Immunology, College of Veterinary Medicine, China Agricultural University, Haidian District, Beijing 100094, China
Interests: MHC; structure; peptide presentation; CTL epitope

Special Issue Information

Dear Colleagues,

The major histocompatibility complex (MHC) antigen presenting molecules consist of two primary classes of glycoproteins that bind peptides derived from intracellular or extracellular antigens and play an integral role in adaptive and innate immune defense systems. They are present in all classes of jawed vertebrates. The MHC genes are polygenic and encode a set of MHC molecules with different ranges of peptide-binding specificities that can be divided into MHC class I and MHC class II depending on their structure and phylogeny. Typically, species have several highly polymorphic genes of both class I and class II, so that there are multiple variants of those genes within the population. MHC haplotypes are extended ancestral blocks of particular combinations of MHC alleles that provide coherent genetic information concerning diversity, inheritance of traits, disease susceptibility/severity, and responses to vaccines and therapy.

The MHC classical class I molecules are expressed on the cell surface of all nucleated cells including neuronal cells in the brain, and they can present peptides derived from intracellular proteins or cellular-infected viral proteins to circulating CD8+ cytotoxic T-cells. The MHC class I molecules can also serve as inhibitory ligands for natural killer (NK) cells. In comparison, the MHC class II genes encode for cell-surface glycoproteins that bind extracellular peptides and present them to circulating CD4+ T helper cells. The expression of MHC class II genes is a characteristic of professional antigen-presenting cells such as dendritic cells, macrophages, and B cells, but expression can also be found in several other cell types. The term MHC stems historically from its role in graft rejection and tissue compatibility within donor–recipient pairs. The extensive polymorphism between the MHC molecules probably protects populations from different invading pathogens, and yet, in the clinic, it adds to the difficulty of finding matched pairs for successful transplantation outcomes.

The MHC genes, haplotypes, and polymorphic molecules are investigated continuously due to their crucial role in the regulation of innate and adaptive immune responses; the pathogenesis of numerous infectious and/or autoimmune diseases; brain development and plasticity; olfaction; therapeutic vaccinations and T cell-based immunotherapy; and the compatibility of grafted tissue, which also concerns potential graft-versus-host disease involving hematopoietic stem cell transplants. Recent reports describe a role for neuronal MHC-I in synaptic plasticity, brain development, axonal regeneration, neuroinflammatory processes, and immune-mediated neurodegeneration. In humans, the MHC (HLA) genes are part of the supra-locus on chromosome 6p21 known as the human leukocyte antigen (HLA) system. This genomic complex consists of more than 300 genes, some located closely together as haplotype blocks and involved in inflammatory and immune-response, heat shock, and complement cascade systems; cytokine signalling; and the regulation of various aspects of cellular development, differentiation, and apoptosis. Additionally, there are many putative microRNA and long-noncoding RNA loci within the HLA genomic region that may be expressed by different cell types and play a role in the regulation of immune-response genes and in the etiology of numerous diseases.

This proposed Special Issue of the MHC in Health and Disease is a follow-up to our first edition in 2019 where we published eighteen articles including one commentary, five reviews, eleven research articles, and one communication covering a broad range of topics on the genomic diversity of the MHC regulatory system in various vertebrate species in health and disease including structure and function; MHC class I, II, and III genes; antigen presentation; innate and adaptive immunity; neurology; transplantation; haplotypes; alleles; infectious and autoimmune diseases; fecundity; conservation; lineage and evolution. Taken together, these articles helped to further demonstrate the immense complexity and diversity of the MHC structure and function within and between different vertebrate species in regulating innate and adaptive immunity. [https://www.mdpi.com/journal/cells/special_issues/major_histocompatibility_complex].

The aim of this second edition is to continue and expand our examination of the polymorphic MHC class I and class II genes, haplotypes, and molecules with an added focus on their cellular functions, molecular interactions and immunity-related networks in health and disease, together with self and non-self recognition, and their role in the susceptibility and resistance to SARS-CoV-2 infections and associated COVID-19 symptoms.

Dr. Johannes M. Dijkstra
Dr. Jerzy K. Kulski
Dr. Nianzhi Zhang
Guest Editors

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Keywords

MHC
HLA
function
structure
innate and adaptive immunity
autoimmunity
antigen presentation
disease

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Published Papers (7 papers)

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Research

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23 pages, 2301 KiB

Open AccessArticle

Large-Scale Polymorphism Analysis of Dog Leukocyte Antigen Class I and Class II Genes (DLA-88, DLA-12/88L and DLA-DRB1) and Comparison of the Haplotype Diversity between Breeds in Japan

by Jiro Miyamae, Masaharu Okano, Fumihiko Katakura, Jerzy K. Kulski, Tadaaki Moritomo and Takashi Shiina

Cells 2023, 12(5), 809; https://doi.org/10.3390/cells12050809 - 6 Mar 2023

Cited by 4 | Viewed by 2548

Abstract

Polymorphisms of canine leukocyte antigen (DLA) class I (DLA-88 and DLA-12/88L) and class II (DLA-DRB1) genes are important for disease susceptibility studies, but information on the genetic diversity among dog breeds is still lacking. To better elucidate the polymorphism and genetic diversity between breeds, we genotyped DLA-88, DLA-12/88L, and DLA-DRB1 loci using 829 dogs of 59 breeds in Japan. Genotyping by Sanger sequencing identified 89, 43, and 61 alleles in DLA-88, DLA-12/88L, and DLA-DRB1 loci, respectively, and a total of 131 DLA-88–DLA-12/88L–DLA-DRB1 haplotypes (88-12/88L-DRB1) were detected more than once. Of the 829 dogs, 198 were homozygotes for one of the 52 different 88-12/88L-DRB1 haplotypes (homozygosity rate: 23.8%). Statistical modeling suggests that 90% of the DLA homozygotes or heterozygotes with one or other of the 52 different 88-12/88L-DRB1 haplotypes within somatic stem cell lines would benefit graft outcome after 88-12/88L-DRB1-matched transplantation. As previously reported for DLA class II haplotypes, the diversity of 88-12/88L-DRB1 haplotypes varied remarkably between breeds but was relatively conserved within most breeds. Therefore, the genetic characteristics of high DLA homozygosity rate and poor DLA diversity within a breed are useful for transplantation therapy, but they may affect biological fitness as homozygosity progresses. Full article

(This article belongs to the Special Issue Major Histocompatibility Complex (MHC) in Health and Disease 2022)

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25 pages, 4060 KiB

Open AccessArticle

The Parallel Presentation of Two Functional CTL Epitopes Derived from the O and Asia 1 Serotypes of Foot-and-Mouth Disease Virus and Swine SLA-2*HB01: Implications for Universal Vaccine Development

by Lei Feng, Yong-Yu Gao, Mingwei Sun, Zi-Bin Li, Qiang Zhang, Jie Yang, Cui Qiao, Hang Jin, Hong-Sheng Feng, Yu-Han Xian, Jianxun Qi, George F. Gao, William J. Liu and Feng-Shan Gao

Cells 2022, 11(24), 4017; https://doi.org/10.3390/cells11244017 - 12 Dec 2022

Cited by 1 | Viewed by 2208

Abstract

Foot-and-mouth disease virus (FMDV) poses a significant threat to the livestock industry. Through their recognition of the conserved epitopes presented by the swine leukocyte antigen (SLA), T cells play a pivotal role in the antiviral immunity of pigs. Herein, based on the peptide binding motif of SLA-2*HB01, from an original SLA-2 allele, a series of functional T-cell epitopes derived from the dominant antigen VP1 of FMDV with high binding capacity to SLA-2 were identified. Two parallel peptides, Hu64 and As64, from the O and Asia I serotypes, respectively, were both crystallized with SLA-2*HB01. Compared to SLA-1 and SLA-3, the SLA-2 structures showed the flexibility of residues in the P4, P6, and P8 positions and in their potential interface with TCR. Notably, the peptides Hu64 and As64 adopted quite similar overall conformation when bound to SLA-2*HB01. Hu64 has two different conformations, a more stable ‘chair’ conformation and an unstable ‘boat’ conformation observed in the two molecules of one asymmetric unit, whereas only a single ‘chair’ conformation was observed for As64. Both Hu64 and As64 could induce similar dominant T-cell activities. Our interdisciplinary study establishes a basis for the in-depth interpretation of the peptide presentation of SLA-I, which can be used toward the development of universal vaccines. Full article

(This article belongs to the Special Issue Major Histocompatibility Complex (MHC) in Health and Disease 2022)

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14 pages, 1836 KiB

Open AccessArticle

Genetic Association between Farrowing Rates and Swine Leukocyte Antigen Alleles or Haplotypes in Microminipigs

by Asako Ando, Tatsuya Matsubara, Shingo Suzuki, Noriaki Imaeda, Masaki Takasu, Atsuko Shigenari, Asuka Miyamoto, Shino Ohshima, Yoshie Kametani, Takashi Shiina, Jerzy K. Kulski and Hitoshi Kitagawa

Cells 2022, 11(19), 3138; https://doi.org/10.3390/cells11193138 - 5 Oct 2022

Cited by 1 | Viewed by 1602

Abstract

We have previously reported specific swine leukocyte antigen (SLA) haplotype associations with significant effects on several reproduction performance traits in a highly inbred miniature pig population of Microminipigs (MMPs). In this study, to clarify the effects on farrowing rates of SLA similarity between mating partners in the MMP population, we compared the farrowing rates as a measure of reproductive success after 1063-cumulative matings among the following three groups of mating partners: (1) completely sharing SLA class I or class II haplotypes or alleles between partners (CS), (2) only one sharing the haplotypes or alleles (OS), and (3) non-sharing the haplotypes or alleles (NS). Average farrowing rates in CS groups consisting of completely sharing SLA class II haplotypes or DRBI and DQB1 alleles were lowest in the three groups. Moreover, lower farrowing rates were indicated in mating pairs with smaller amino acid pairwise genetic distances of SLA-1, SLA-3, DRB1 and DQB1 alleles between the pairs. These results suggested that the dissimilarity of SLA class I and class II alleles between mating partners markedly improved reproductive performance; therefore, SLA alleles or haplotypes are potentially useful genetic markers for the selection of mating pairs in breeding programs and epistatic studies of reproductive traits of MMPs. Full article

(This article belongs to the Special Issue Major Histocompatibility Complex (MHC) in Health and Disease 2022)

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8 pages, 714 KiB

Open AccessArticle

Contribution from MHC-Mediated Risk in Schizophrenia Can Reflect a More Ethnic-Specific Genetic and Comorbid Background

by Lekshmy Srinivas, Neetha N. Vellichirammal, Indu V. Nair, Chandrasekharan M. Nair and Moinak Banerjee

Cells 2022, 11(17), 2695; https://doi.org/10.3390/cells11172695 - 30 Aug 2022

Cited by 3 | Viewed by 2581

Abstract

The immune system seems to play a significant role in the development of schizophrenia. This becomes more evident with the emerging role of MHC complex and cytokines in schizophrenia. In the recent past, several GWAS have implied that the 6p21 region was associated with schizophrenia. However, the majority of these studies were performed in European populations. Considering tremendous variations in this region and the probability of South Indian populations being quite different from the European gene-pool from an immunogenetic point, the present study was initiated to screen SNPs in the 2.28 MB region, spanning the extended MHC locus, in 492 cases and controls from a South Indian population. We found a very strong association of rs3815087 with schizophrenia at both allelic and genotypic levels with a 7.3-fold increased risk in the recessive model. Interestingly, the association of none of the earlier reported GWAS hits, such as rs3130375, rs3131296, rs9272219, or rs3130297 were found to be replicable in our study population. rs3815087 lies in the 5′UTR region of the psoriasis susceptibility 1 candidate 1 (PSORS1C1) gene, which further suggests that inflammatory processes might be an important common pathogenic pathway leading to both schizophrenia and psoriasis. The study hints at ethnic specific gene–environment interaction in determining the critical threshold for disease initiation and progression. Full article

(This article belongs to the Special Issue Major Histocompatibility Complex (MHC) in Health and Disease 2022)

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22 pages, 2870 KiB

Open AccessReview

MHC Class II Presentation in Autoimmunity

by Irina A. Ishina, Maria Y. Zakharova, Inna N. Kurbatskaia, Azad E. Mamedov, Alexey A. Belogurov, Jr. and Alexander G. Gabibov

Cells 2023, 12(2), 314; https://doi.org/10.3390/cells12020314 - 14 Jan 2023

Cited by 27 | Viewed by 10748

Abstract

Antigen presentation by major histocompatibility complex class II (MHC-II) molecules is crucial for eliciting an efficient immune response by CD4⁺ T cells and maintaining self-antigen tolerance. Some MHC-II alleles are known to be positively or negatively associated with the risk of the development of different autoimmune diseases (ADs), including those characterized by the emergence of autoreactive T cells. Apparently, the MHC-II presentation of self-antigens contributes to the autoimmune T cell response, initiated through a breakdown of central tolerance to self-antigens in the thymus. The appearance of autoreactive T cell might be the result of (i) the unusual interaction between T cell receptors (TCRs) and self-antigens presented on MHC-II; (ii) the posttranslational modifications (PTMs) of self-antigens; (iii) direct loading of the self-antigen to classical MHC-II without additional nonclassical MHC assistance; (iv) the proinflammatory environment effect on MHC-II expression and antigen presentation; and (v) molecular mimicry between foreign and self-antigens. The peculiarities of the processes involved in the MHC-II-mediated presentation may have crucial importance in the elucidation of the mechanisms of triggering and developing ADs as well as for clarification on the protective effect of MHC-II alleles that are negatively associated with ADs. Full article

(This article belongs to the Special Issue Major Histocompatibility Complex (MHC) in Health and Disease 2022)

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16 pages, 6006 KiB

Open AccessBrief Report

Crystal Structure of a Classical MHC Class I Molecule in Dogs; Comparison of DLA-88*0 and DLA-88*5 Category Molecules

by Yujiao Sun, Lizhen Ma, Shen Li, Yawen Wang, Ruiqi Xiao, Junqi Yang, Johannes M. Dijkstra and Chun Xia

Cells 2023, 12(7), 1097; https://doi.org/10.3390/cells12071097 - 6 Apr 2023

Cited by 2 | Viewed by 1978

Abstract

DLA-88 is a classical major histocompatibility complex (MHC) class I gene in dogs, and allelic DLA-88 molecules have been divided into two categories named “DLA-88*0” and “DLA-88*5.” The defining difference between the two categories concerns an LQW motif in the α2 domain helical region of the DLA-88*5 molecules that includes the insertion of an extra amino acid compared to MHC class I consensus length. We here show that this motif has been exchanged by recombination between different DLA-88 evolutionary lineages. Previously, with pDLA-88*508:01, the structure of a molecule of the DLA-88*5 category was elucidated. The present study is the first to elucidate a structure, using X-ray crystallography, of the DLA-88*0 category, namely DLA-88*001:04 complexed with β2m and a nonamer peptide derived from canine distemper virus (CDV). The LQW motif that distinguishes DLA-88*5 from DLA-88*0 causes a shallower peptide binding groove (PBG) and a leucine exposed at the top of the α2 domain helix expected to affect T cell selection. Peptide ligand amino acid substitution and pMHC-I complex formation and stability analyses revealed that P2 and P3 are the major anchor residue positions for binding to DLA-88*001:04. We speculate that the distribution pattern of the LQW motif among canine classical MHC class I alleles represents a strategy to enhance allogeneic rejection by T cells of transmissible cancers such as canine transmissible venereal tumor (CTVT). Full article

(This article belongs to the Special Issue Major Histocompatibility Complex (MHC) in Health and Disease 2022)

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8 pages, 260 KiB

Open AccessBrief Report

HLA Allele Frequencies and Association with Severity of COVID-19 Infection in Northern Italian Patients

by Franca Rosa Guerini, Elisabetta Bolognesi, Agata Lax, Luca Nicola Cesare Bianchi, Antonio Caronni, Milena Zanzottera, Cristina Agliardi, Maria Paola Albergoni, Paolo Innocente Banfi, Jorge Navarro and Mario Clerici

Cells 2022, 11(11), 1792; https://doi.org/10.3390/cells11111792 - 30 May 2022

Cited by 7 | Viewed by 1999

Abstract

HLA allelic distribution was analysed in a cohort of 96 Northern Italian subjects (53M/43F) (mean age 59.9 ± 13.3 years) from Lombardy who developed COVID-19 during the first two pandemic waves to investigate possible correlations between HLA molecules and disease severity. An important role of HLA- B and HLA-C loci in modulating the clinical severity of COVID-19 disease was identified. In particular, the HLA-B07 supertype was observed to be associated with a significant risk for severe disease; conversely, the HLA-B27 supertype and C*12:02 allele played a protective role as they were associated with milder disease. These associations were confirmed after applying a multinomial regression analysis to adjust the correlation for age, gender and comorbidities with COVID-19 severity. Though the power of results is limited by the small sample size, data herein contribute to shedding light on the role played by genetic background in COVID-19 infection. Full article

(This article belongs to the Special Issue Major Histocompatibility Complex (MHC) in Health and Disease 2022)

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