Special Issue "Major Histocompatibility Complex (MHC) in Health and Disease"

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (31 May 2019).

Special Issue Editors

Dr. Jerzy K. Kulski
E-Mail Website
Guest Editor
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;
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
Prof. Takashi Shiina
E-Mail
Assistant Guest Editor
Department of Molecular Life Science, Division of Basic Medical Science and Molecular Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan
Dr. Johannes M. Dijkstra
E-Mail
Assistant Guest Editor
Institute for Comprehensive Medical Science, Fujita Health University, Dengaku-gakubo 1-98, Toyoake, 470-1192 Aichi-ken, Japan

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. Particular combinations of MHC alleles are known as MHC haplotypes.

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 also can be found in several other cell types. The term MHC stems historically from its role in graft rejection and tissue compatibility within donorrecipient 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 200 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. Also, there are thousands of putative microRNA encoding loci within HLA genes and 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.

The aim of this Special Issue is to examine further the role of the polymorphic MHC class I and class II genes, haplotypes, and molecules in health and disease in humans and other species in particular with respect to cellular functions. Analysing the structure, function, and disease associations of the MHC class I and class II genes and molecules in human and other species will improve our understanding of their role in innate and adaptive immunity, neurology and brain disease, autoimmunity, infectious diseases, cancer, and self and non-self recognition.

Dr. Jerzy K. Kulski
Prof. Takashi Shiina
Dr. Johannes M. Dijkstra
Guest Editors

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Keywords

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

Published Papers (19 papers)

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Editorial

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Open AccessEditorial
Genomic Diversity of the Major Histocompatibility Complex in Health and Disease
Cells 2019, 8(10), 1270; https://doi.org/10.3390/cells8101270 (registering DOI) - 17 Oct 2019
Abstract
The human Major Histocompatibility Complex (MHC) genes are part of the supra‐locus on
chromosome 6p21 known as the human leukocyte antigen (HLA) system [...] Full article
(This article belongs to the Special Issue Major Histocompatibility Complex (MHC) in Health and Disease)

Research

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Open AccessArticle
The Major Histocompatibility Complex of Old World Camels—A Synopsis
Cells 2019, 8(10), 1200; https://doi.org/10.3390/cells8101200 - 05 Oct 2019
Abstract
This study brings new information on major histocompatibility complex (MHC) class III sub-region genes in Old World camels and integrates current knowledge of the MHC region into a comprehensive overview for Old World camels. Out of the MHC class III genes characterized, TNFA [...] Read more.
This study brings new information on major histocompatibility complex (MHC) class III sub-region genes in Old World camels and integrates current knowledge of the MHC region into a comprehensive overview for Old World camels. Out of the MHC class III genes characterized, TNFA and the LY6 gene family showed high levels of conservation, characteristic for MHC class III loci in general. For comparison, an MHC class II gene TAP1, not coding for antigen presenting molecules but functionally related to MHC antigen presenting functions was studied. TAP1 had many SNPs, even higher than the MHC class I and II genes encoding antigen presenting molecules. Based on this knowledge and using new camel genomic resources, we constructed an improved genomic map of the entire MHC region of Old World camels. The MHC class III sub-region shows a standard organization similar to that of pig or cattle. The overall genomic structure of the camel MHC is more similar to pig MHC than to cattle MHC. This conclusion is supported by differences in the organization of the MHC class II sub-region, absence of functional DY genes, different organization of MIC genes in the MHC class I sub-region, and generally closer evolutionary relationships of camel and porcine MHC gene sequences analyzed so far. Full article
(This article belongs to the Special Issue Major Histocompatibility Complex (MHC) in Health and Disease)
Open AccessCommunication
Discovery of a Novel MHC Class I Lineage in Teleost Fish which Shows Unprecedented Levels of Ectodomain Deterioration while Possessing an Impressive Cytoplasmic Tail Motif
Cells 2019, 8(9), 1056; https://doi.org/10.3390/cells8091056 - 09 Sep 2019
Cited by 1
Abstract
A unique new nonclassical MHC class I lineage was found in Teleostei (teleosts, modern bony fish, e.g., zebrafish) and Holostei (a group of primitive bony fish, e.g., spotted gar), which was designated “H” (from “hexa”) for being the sixth lineage discovered in teleosts. [...] Read more.
A unique new nonclassical MHC class I lineage was found in Teleostei (teleosts, modern bony fish, e.g., zebrafish) and Holostei (a group of primitive bony fish, e.g., spotted gar), which was designated “H” (from “hexa”) for being the sixth lineage discovered in teleosts. A high level of divergence of the teleost sequences explains why the lineage was not recognized previously. The spotted gar H molecule possesses the three MHC class I consensus extracellular domains α1, α2, and α3. However, throughout teleost H molecules, the α3 domain was lost and the α1 domains showed features of deterioration. In fishes of the two closely related teleost orders Characiformes (e.g., Mexican tetra) and Siluriformes (e.g., channel catfish), the H ectodomain deterioration proceeded furthest, with H molecules of some fishes apparently having lost the entire α1 or α2 domain plus additional stretches within the remaining other (α1 or α2) domain. Despite these dramatic ectodomain changes, teleost H sequences possess rather large, unique, well-conserved tyrosine-containing cytoplasmic tail motifs, which suggests an important role in intracellular signaling. To our knowledge, this is the first description of a group of MHC class I molecules in which, judging from the sequence conservation pattern, the cytoplasmic tail is expected to have a more important conserved function than the ectodomain. Full article
(This article belongs to the Special Issue Major Histocompatibility Complex (MHC) in Health and Disease)
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Open AccessArticle
HLA-E Polymorphism Determines Susceptibility to BK Virus Nephropathy after Living-Donor Kidney Transplant
Cells 2019, 8(8), 847; https://doi.org/10.3390/cells8080847 - 07 Aug 2019
Abstract
Human leukocyte antigen (HLA)-E is important for the regulation of anti-viral immunity. BK polyomavirus (BKPyV) reactivation after kidney transplant is a serious complication that can result in BKPyV-associated nephropathy (PyVAN) and subsequent allograft loss. To elucidate whether HLA-E polymorphisms influence BKPyV replication and [...] Read more.
Human leukocyte antigen (HLA)-E is important for the regulation of anti-viral immunity. BK polyomavirus (BKPyV) reactivation after kidney transplant is a serious complication that can result in BKPyV-associated nephropathy (PyVAN) and subsequent allograft loss. To elucidate whether HLA-E polymorphisms influence BKPyV replication and nephropathy, we determined the HLA-E genotype of 278 living donor and recipient pairs. A total of 44 recipients suffered from BKPyV replication, and 11 of these developed PyVAN. Homozygosity of the recipients for the HLA-E*01:01 genotype was associated with the protection against PyVAN after transplant (p = 0.025, OR 0.09, CI [95%] 0.83–4.89). Considering the time course of the occurrence of nephropathy, recipients with PyVAN were more likely to carry the HLA-E*01:03 allelic variant than those without PyVAN (Kaplan–Meier analysis p = 0.03; OR = 4.25; CI (95%) 1.11–16.23). Our findings suggest that a predisposition based on a defined HLA-E genotype is associated with an increased susceptibility to develop PyVAN. Thus, assessing HLA-E polymorphisms may enable physicians to identify patients being at an increased risk of this viral complication. Full article
(This article belongs to the Special Issue Major Histocompatibility Complex (MHC) in Health and Disease)
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Open AccessArticle
A New Pedigree-Based SNP Haplotype Method for Genomic Polymorphism and Genetic Studies
Cells 2019, 8(8), 835; https://doi.org/10.3390/cells8080835 - 05 Aug 2019
Cited by 1
Abstract
Single nucleotide polymorphisms (SNPs) are usually the most frequent genomic variants. Directly pedigree-phased multi-SNP haplotypes provide a more accurate view of polymorphic population genomic structure than individual SNPs. The former are, therefore, more useful in genetic correlation with subject phenotype. We describe a [...] Read more.
Single nucleotide polymorphisms (SNPs) are usually the most frequent genomic variants. Directly pedigree-phased multi-SNP haplotypes provide a more accurate view of polymorphic population genomic structure than individual SNPs. The former are, therefore, more useful in genetic correlation with subject phenotype. We describe a new pedigree-based methodology for generating non-ambiguous SNP haplotypes for genetic study. SNP data for haplotype analysis were extracted from a larger Type 1 Diabetes Genetics Consortium SNP dataset based on minor allele frequency variation and redundancy, coverage rate (the frequency of phased haplotypes in which each SNP is defined) and genomic location. Redundant SNPs were eliminated, overall haplotype polymorphism was optimized and the number of undefined haplotypes was minimized. These edited SNP haplotypes from a region containing HLA-DRB1 (DR) and HLA-DQB1 (DQ) both correlated well with HLA-typed DR,DQ haplotypes and differentiated HLA-DR,DQ fragments shared by three pairs of previously identified megabase-length conserved extended haplotypes. In a pedigree-based genetic association assay for type 1 diabetes, edited SNP haplotypes and HLA-typed HLA-DR,DQ haplotypes from the same families generated essentially identical qualitative and quantitative results. Therefore, this edited SNP haplotype method is useful for both genomic polymorphic architecture and genetic association evaluation using SNP markers with diverse minor allele frequencies. Full article
(This article belongs to the Special Issue Major Histocompatibility Complex (MHC) in Health and Disease)
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Open AccessArticle
Genetic Association between Swine Leukocyte antigen Class II Haplotypes and Reproduction Traits in Microminipigs
Cells 2019, 8(8), 783; https://doi.org/10.3390/cells8080783 - 26 Jul 2019
Abstract
The effects of swine leukocyte antigen (SLA) molecules on numerous production and reproduction performance traits have been mainly reported as associations with specific SLA haplotypes that were assigned using serological typing methods. In this study, we intended to clarify the association between SLA [...] Read more.
The effects of swine leukocyte antigen (SLA) molecules on numerous production and reproduction performance traits have been mainly reported as associations with specific SLA haplotypes that were assigned using serological typing methods. In this study, we intended to clarify the association between SLA class II genes and reproductive traits in a highly inbred population of 187 Microminipigs (MMP), that have eight different types of SLA class II haplotypes. In doing so, we compared the reproductive performances, such as fertility index, gestation period, litter size, and number of stillbirth among SLA class II low resolution haplotypes (Lrs) that were assigned by a polymerase chain reaction-sequence specific primers (PCR-SSP) typing method. Only low resolution haplotypes were used in this study because the eight SLA class II high-resolution haplotypes had been assigned to the 14 parents or the progenitors of the highly inbred MMP herd in a previous publication. The fertility index of dams with Lr-0.13 was significantly lower than that of dams with Lr-0.16, Lr-0.17, Lr-0.18, or Lr-0.37. Dams with Lr-0.23 had significantly smaller litter size at birth than those with Lr-0.17, Lr-0.18, or Lr-0.37. Furthermore, litter size at weaning of dams with Lr-0.23 was also significantly smaller than those dams with Lr-0.16, Lr-0.17, Lr-0.18, or Lr-0.37. The small litter size of dams with Lr-0.23 correlated with the smaller body sizes of these MMPs. These results suggest that SLA class II haplotypes are useful differential genetic markers for further haplotypic and epistatic studies of reproductive traits, selective breeding programs, and improvements in the production and reproduction performances of MMPs. Full article
(This article belongs to the Special Issue Major Histocompatibility Complex (MHC) in Health and Disease)
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Open AccessArticle
HLA-DQA1 and HLA-DQB1 Alleles, Conferring Susceptibility to Celiac Disease and Type 1 Diabetes, Are More Expressed Than Non-Predisposing Alleles and Are Coordinately Regulated
Cells 2019, 8(7), 751; https://doi.org/10.3390/cells8070751 - 19 Jul 2019
Abstract
HLA DQA1*05 and DQB1*02 alleles encoding the DQ2.5 molecule and HLA DQA1*03 and DQB1*03 alleles encoding DQ8 molecules are strongly associated with celiac disease (CD) and type 1 diabetes (T1D), two common autoimmune diseases (AD). We previously demonstrated that DQ2.5 genes showed a [...] Read more.
HLA DQA1*05 and DQB1*02 alleles encoding the DQ2.5 molecule and HLA DQA1*03 and DQB1*03 alleles encoding DQ8 molecules are strongly associated with celiac disease (CD) and type 1 diabetes (T1D), two common autoimmune diseases (AD). We previously demonstrated that DQ2.5 genes showed a higher expression with respect to non-CD associated alleles in heterozygous DQ2.5 positive (HLA DR1/DR3) antigen presenting cells (APC) of CD patients. This differential expression affected the level of the encoded DQ2.5 molecules on the APC surface and established the strength of gluten-specific CD4+ T cells response. Here, we expanded the expression analysis of risk alleles in patients affected by T1D or by T1D and CD comorbidity. In agreement with previous findings, we found that DQ2.5 and DQ8 risk alleles are more expressed than non-associated alleles also in T1D patients and favor the self-antigen presentation. To investigate the mechanism causing the high expression of risk alleles, we focused on HLA DQA1*05 and DQB1*02 alleles and, by ectopic expression of a single mRNA, we modified the quantitative equilibrium among the two transcripts. After transfection of DR7/DR14 B-LCL with HLA-DQA1*05 cDNA, we observed an overexpression of the endogenous DQB1*02 allele. The DQ2.5 heterodimer synthesized was functional and able to present gluten antigens to cognate CD4+ T cells. Our results indicated that the high expression of alpha and beta transcripts, encoding for the DQ2.5 heterodimeric molecules, was strictly coordinated by a mechanism acting at a transcriptional level. These findings suggested that, in addition to the predisposing HLA-DQ genotype, also the expression of risk alleles contributed to the establishment of autoimmunity. Full article
(This article belongs to the Special Issue Major Histocompatibility Complex (MHC) in Health and Disease)
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Open AccessArticle
Intramolecular Domain Movements of Free and Bound pMHC and TCR Proteins: A Molecular Dynamics Simulation Study
Cells 2019, 8(7), 720; https://doi.org/10.3390/cells8070720 - 13 Jul 2019
Abstract
The interaction of antigenic peptides (p) and major histocompatibility complexes (pMHC) with T-cell receptors (TCR) is one of the most important steps during the immune response. Here we present a molecular dynamics simulation study of bound and unbound TCR and pMHC proteins of [...] Read more.
The interaction of antigenic peptides (p) and major histocompatibility complexes (pMHC) with T-cell receptors (TCR) is one of the most important steps during the immune response. Here we present a molecular dynamics simulation study of bound and unbound TCR and pMHC proteins of the LC13-HLA-B*44:05-pEEYLQAFTY complex to monitor differences in relative orientations and movements of domains between bound and unbound states of TCR-pMHC. We generated local coordinate systems for MHC α1- and MHC α2-helices and the variable T-cell receptor regions TCR Vα and TCR Vβ and monitored changes in the distances and mutual orientations of these domains. In comparison to unbound states, we found decreased inter-domain movements in the simulations of bound states. Moreover, increased conformational flexibility was observed for the MHC α2-helix, the peptide, and for the complementary determining regions of the TCR in TCR-unbound states as compared to TCR-bound states. Full article
(This article belongs to the Special Issue Major Histocompatibility Complex (MHC) in Health and Disease)
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Open AccessArticle
Distribution of Killer-Cell Immunoglobulin-Like Receptor Genes and Combinations of Their Human Leucocyte Antigen Ligands in 11 Ethnic Populations in China
Cells 2019, 8(7), 711; https://doi.org/10.3390/cells8070711 - 12 Jul 2019
Abstract
The aim of this study was to analyze the distribution of killer-cell immunoglobulin-like receptor (KIR) genes and their human leucocyte antigen (HLA) ligand combinations in different original ethnic populations in China, and thus, to provide relevant genomic diversity data for the future study [...] Read more.
The aim of this study was to analyze the distribution of killer-cell immunoglobulin-like receptor (KIR) genes and their human leucocyte antigen (HLA) ligand combinations in different original ethnic populations in China, and thus, to provide relevant genomic diversity data for the future study of viral infections, autoimmune diseases, and reproductive fitness. A total of 1119 unrelated individuals from 11 ethnic populations—including Hani, Jinuo, Lisu, Nu, Bulang, Wa, Dai, Maonan, Zhuang, Tu, and Yugu—from four original groups, were included. The presence/absence of the 16 KIR loci were detected, and the KIR gene’s phenotype, genotype, and haplotype A and B frequencies, as well as KIR ligand’s HLA allotype and KIR–HLA pairs for each population, were calculated. Principal component analysis and phylogenetic trees were constructed to compare the characteristics of the KIR and KIR–HLA pair distributions of these 11 populations. In total, 92 KIR genotypes were identified, including six new genotypes. The KIR and its HLA ligands had a distributed diversity in 11 ethnic populations in China, and each group had its specific KIR and KIR–HLA pair profile. The difference among the KIR–HLA pairs between northern and southern groups, but not among the four original groups, may reflect strong pressure from previous or ongoing infectious diseases, which have a significant impact on KIR and its HLA combination repertoires. Full article
(This article belongs to the Special Issue Major Histocompatibility Complex (MHC) in Health and Disease)
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Open AccessArticle
Unusual Placement of an EBV Epitope into the Groove of the Ankylosing Spondylitis-Associated HLA-B27 Allele Allows CD8+ T Cell Activation
Cells 2019, 8(6), 572; https://doi.org/10.3390/cells8060572 - 11 Jun 2019
Cited by 1
Abstract
The human leukocyte antigen HLA-B27 is a strong risk factor for Ankylosing Spondylitis (AS), an immune-mediated disorder affecting axial skeleton and sacroiliac joints. Additionally, evidence exists sustaining a strong protective role for HLA-B27 in viral infections. These two aspects could stem from common [...] Read more.
The human leukocyte antigen HLA-B27 is a strong risk factor for Ankylosing Spondylitis (AS), an immune-mediated disorder affecting axial skeleton and sacroiliac joints. Additionally, evidence exists sustaining a strong protective role for HLA-B27 in viral infections. These two aspects could stem from common molecular mechanisms. Recently, we have found that the HLA-B*2705 presents an EBV epitope (pEBNA3A-RPPIFIRRL), lacking the canonical B27 binding motif but known as immunodominant in the HLA-B7 context of presentation. Notably, 69% of B*2705 carriers, mostly patients with AS, possess B*2705-restricted, pEBNA3A-specific CD8+ T cells. Contrarily, the non-AS-associated B*2709 allele, distinguished from the B*2705 by the single His116Asp polymorphism, is unable to display this peptide and, accordingly, B*2709 healthy subjects do not unleash specific T cell responses. Herein, we investigated whether the reactivity towards pEBNA3A could be a side effect of the recognition of the natural longer peptide (pKEBNA3A) having the classical B27 consensus (KRPPIFIRRL). The stimulation of PBMC from B*2705 positive patients with AS in parallel with both pEBNA3A and pKEBNA3A did not allow to reach an unambiguous conclusion since the differences in the magnitude of the response measured as percentage of IFNγ-producing CD8+ T cells were not statistically significant. Interestingly, computational analysis suggested a structural shift of pEBNA3A as well as of pKEBNA3A into the B27 grooves, leaving the A pocket partially unfilled. To our knowledge this is the first report of a viral peptide: HLA-B27 complex recognized by TCRs in spite of a partially empty groove. This implies a rethinking of the actual B27 immunopeptidome crucial for viral immune-surveillance and autoimmunity. Full article
(This article belongs to the Special Issue Major Histocompatibility Complex (MHC) in Health and Disease)
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Open AccessArticle
Role of MHC-I Expression on Spinal Motoneuron Survival and Glial Reactions Following Ventral Root Crush in Mice
Cells 2019, 8(5), 483; https://doi.org/10.3390/cells8050483 - 21 May 2019
Abstract
Lesions to the CNS/PNS interface are especially severe, leading to elevated neuronal degeneration. In the present work, we establish the ventral root crush model for mice, and demonstrate the potential of such an approach, by analyzing injury evoked motoneuron loss, changes of synaptic [...] Read more.
Lesions to the CNS/PNS interface are especially severe, leading to elevated neuronal degeneration. In the present work, we establish the ventral root crush model for mice, and demonstrate the potential of such an approach, by analyzing injury evoked motoneuron loss, changes of synaptic coverage and concomitant glial responses in β2-microglobulin knockout mice (β2m KO). Young adult (8–12 weeks old) C57BL/6J (WT) and β2m KO mice were submitted to a L4–L6 ventral roots crush. Neuronal survival revealed a time-dependent motoneuron-like cell loss, both in WT and β2m KO mice. Along with neuronal loss, astrogliosis increased in WT mice, which was not observed in β2m KO mice. Microglial responses were more pronounced during the acute phase after lesion and decreased over time, in WT and KO mice. At 7 days after lesion β2m KO mice showed stronger Iba-1+ cell reaction. The synaptic inputs were reduced over time, but in β2m KO, the synaptic loss was more prominent between 7 and 28 days after lesion. Taken together, the results herein demonstrate that ventral root crushing in mice provides robust data regarding neuronal loss and glial reaction. The retrograde reactions after injury were altered in the absence of functional MHC-I surface expression. Full article
(This article belongs to the Special Issue Major Histocompatibility Complex (MHC) in Health and Disease)
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Open AccessArticle
Genetic Diversity and Differentiation at Structurally Varying MHC Haplotypes and Microsatellites in Bottlenecked Populations of Endangered Crested Ibis
Cells 2019, 8(4), 377; https://doi.org/10.3390/cells8040377 - 25 Apr 2019
Cited by 1
Abstract
Investigating adaptive potential and understanding the relative roles of selection and genetic drift in populations of endangered species are essential in conservation. Major histocompatibility complex (MHC) genes characterized by spectacular polymorphism and fitness association have become valuable adaptive markers. Herein we investigate the [...] Read more.
Investigating adaptive potential and understanding the relative roles of selection and genetic drift in populations of endangered species are essential in conservation. Major histocompatibility complex (MHC) genes characterized by spectacular polymorphism and fitness association have become valuable adaptive markers. Herein we investigate the variation of all MHC class I and II genes across seven populations of an endangered bird, the crested ibis, of which all current individuals are offspring of only two pairs. We inferred seven multilocus haplotypes from linked alleles in the Core Region and revealed structural variation of the class II region that probably evolved through unequal crossing over. Based on the low polymorphism, structural variation, strong linkage, and extensive shared alleles, we applied the MHC haplotypes in population analysis. The genetic variation and population structure at MHC haplotypes are generally concordant with those expected from microsatellites, underlining the predominant role of genetic drift in shaping MHC variation in the bottlenecked populations. Nonetheless, some populations showed elevated differentiation at MHC, probably due to limited gene flow. The seven populations were significantly differentiated into three groups and some groups exhibited genetic monomorphism, which can be attributed to founder effects. We therefore propose various strategies for future conservation and management. Full article
(This article belongs to the Special Issue Major Histocompatibility Complex (MHC) in Health and Disease)
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Open AccessArticle
Reproductive Strategy Inferred from Major Histocompatibility Complex-Based Inter-Individual, Sperm-Egg, and Mother-Fetus Recognitions in Giant Pandas (Ailuropoda melanoleuca)
Cells 2019, 8(3), 257; https://doi.org/10.3390/cells8030257 - 19 Mar 2019
Abstract
Few major histocompatibility complex (MHC)-based mate choice studies include all MHC genes at the inter-individual, sperm-egg, and mother-fetus recognition levels. We tested three hypotheses of female mate choice in a 17-year study of the giant panda (Ailuropoda melanoleuca) while using ten [...] Read more.
Few major histocompatibility complex (MHC)-based mate choice studies include all MHC genes at the inter-individual, sperm-egg, and mother-fetus recognition levels. We tested three hypotheses of female mate choice in a 17-year study of the giant panda (Ailuropoda melanoleuca) while using ten functional MHC loci (four MHC class I loci: Aime-C, Aime-F, Aime-I, and Aime-L; six MHC class II loci: Aime-DRA, Aime-DRB3, Aime-DQA1, Aime-DQA2, Aime-DQB1, and Aime-DQB2); five super haplotypes (SuHa, SuHaI, SuHaII, DQ, and DR); and, seven microsatellites. We found female choice for heterozygosity at Aime-C, Aime-I, and DQ and for disassortative mate choice at Aime-C, DQ, and DR at the inter-individual recognition level. High mating success occurred in MHC-dissimilar mating pairs. No significant results were found based on any microsatellite parameters, suggesting that MHCs were the mate choice target and there were no signs of inbreeding avoidance. Our results indicate Aime-DQA1- and Aime-DQA2-associated disassortative selection at the sperm-egg recognition level and a possible Aime-C- and Aime-I-associated assortative maternal immune tolerance mechanism. The MHC genes were of differential importance at the different recognition levels, so all of the functional MHC genes should be included when studying MHC-dependent reproductive mechanisms. Full article
(This article belongs to the Special Issue Major Histocompatibility Complex (MHC) in Health and Disease)
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Review

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Open AccessReview
Avian MHC Evolution in the Era of Genomics: Phase 1.0
Cells 2019, 8(10), 1152; https://doi.org/10.3390/cells8101152 - 26 Sep 2019
Abstract
Birds are a wonderfully diverse and accessible clade with an exceptional range of ecologies and behaviors, making the study of the avian major histocompatibility complex (MHC) of great interest. In the last 20 years, particularly with the advent of high-throughput sequencing, the avian [...] Read more.
Birds are a wonderfully diverse and accessible clade with an exceptional range of ecologies and behaviors, making the study of the avian major histocompatibility complex (MHC) of great interest. In the last 20 years, particularly with the advent of high-throughput sequencing, the avian MHC has been explored in great depth in several dimensions: its ability to explain ecological patterns in nature, such as mating preferences; its correlation with parasite resistance; and its structural evolution across the avian tree of life. Here, we review the latest pulse of avian MHC studies spurred by high-throughput sequencing. Despite high-throughput approaches to MHC studies, substantial areas remain in need of improvement with regard to our understanding of MHC structure, diversity, and evolution. Recent studies of the avian MHC have nonetheless revealed intriguing connections between MHC structure and life history traits, and highlight the advantages of long-term ecological studies for understanding the patterns of MHC variation in the wild. Given the exceptional diversity of birds, their accessibility, and the ease of sequencing their genomes, studies of avian MHC promise to improve our understanding of the many dimensions and consequences of MHC variation in nature. However, significant improvements in assembling complete MHC regions with long-read sequencing will be required for truly transformative studies. Full article
(This article belongs to the Special Issue Major Histocompatibility Complex (MHC) in Health and Disease)
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Open AccessReview
An RNA Metabolism and Surveillance Quartet in the Major Histocompatibility Complex
Cells 2019, 8(9), 1008; https://doi.org/10.3390/cells8091008 - 30 Aug 2019
Abstract
At the central region of the mammalian major histocompatibility complex (MHC) is a complement gene cluster that codes for constituents of complement C3 convertases (C2, factor B and C4). Complement activation drives the humoral effector functions for immune response. Sandwiched between the genes [...] Read more.
At the central region of the mammalian major histocompatibility complex (MHC) is a complement gene cluster that codes for constituents of complement C3 convertases (C2, factor B and C4). Complement activation drives the humoral effector functions for immune response. Sandwiched between the genes for serine proteinase factor B and anchor protein C4 are four less known but critically important genes coding for essential functions related to metabolism and surveillance of RNA during the transcriptional and translational processes of gene expression. These four genes are NELF-E (RD), SKIV2L (SKI2W), DXO (DOM3Z) and STK19 (RP1 or G11) and dubbed as NSDK. NELF-E is the subunit E of negative elongation factor responsible for promoter proximal pause of transcription. SKIV2L is the RNA helicase for cytoplasmic exosomes responsible for degradation of de-polyadenylated mRNA and viral RNA. DXO is a powerful enzyme with pyro-phosphohydrolase activity towards 5′ triphosphorylated RNA, decapping and exoribonuclease activities of faulty nuclear RNA molecules. STK19 is a nuclear kinase that phosphorylates RNA-binding proteins during transcription. STK19 is also involved in DNA repair during active transcription and in nuclear signal transduction. The genetic, biochemical and functional properties for NSDK in the MHC largely stay as a secret for many immunologists. Here we briefly review the roles of (a) NELF-E on transcriptional pausing; (b) SKIV2L on turnover of deadenylated or expired RNA 3′→5′ through the Ski-exosome complex, and modulation of inflammatory response initiated by retinoic acid-inducible gene 1-like receptor (RLR) sensing of viral infections; (c) DXO on quality control of RNA integrity through recognition of 5′ caps and destruction of faulty adducts in 5′→3′ fashion; and (d) STK19 on nuclear protein phosphorylations. There is compelling evidence that a dysregulation or a deficiency of a NSDK gene would cause a malignant, immunologic or digestive disease. Full article
(This article belongs to the Special Issue Major Histocompatibility Complex (MHC) in Health and Disease)
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Open AccessReview
The Cynomolgus Macaque MHC Polymorphism in Experimental Medicine
Cells 2019, 8(9), 978; https://doi.org/10.3390/cells8090978 - 26 Aug 2019
Cited by 1
Abstract
Among the non-human primates used in experimental medicine, cynomolgus macaques (Macaca fascicularis hereafter referred to as Mafa) are increasingly selected for the ease with which they are maintained and bred in captivity. Macaques belong to Old World monkeys and are phylogenetically [...] Read more.
Among the non-human primates used in experimental medicine, cynomolgus macaques (Macaca fascicularis hereafter referred to as Mafa) are increasingly selected for the ease with which they are maintained and bred in captivity. Macaques belong to Old World monkeys and are phylogenetically much closer to humans than rodents, which are still the most frequently used animal model. Our understanding of the Mafa genome has progressed rapidly in recent years and has greatly benefited from the latest technical advances in molecular genetics. Cynomolgus macaques are widespread in Southeast Asia and numerous studies have shown a distinct genetic differentiation of continental and island populations. The major histocompatibility complex of cynomolgus macaque (Mafa MHC) is organized in the same way as that of human, but it differs from the latter by its high degree of classical class I gene duplication. Human polymorphic MHC regions play a pivotal role in allograft transplantation and have been associated with more than 100 diseases and/or phenotypes. The Mafa MHC polymorphism similarly plays a crucial role in experimental allografts of organs and stem cells. Experimental results show that the Mafa MHC class I and II regions influence the ability to mount an immune response against infectious pathogens and vaccines. MHC also affects cynomolgus macaque reproduction and impacts on numerous biological parameters. This review describes the Mafa MHC polymorphism and the methods currently used to characterize it. We discuss some of the major areas of experimental medicine where an effect induced by MHC polymorphism has been demonstrated. Full article
(This article belongs to the Special Issue Major Histocompatibility Complex (MHC) in Health and Disease)
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Open AccessFeature PaperReview
Long Noncoding RNA HCP5, a Hybrid HLA Class I Endogenous Retroviral Gene: Structure, Expression, and Disease Associations
Cells 2019, 8(5), 480; https://doi.org/10.3390/cells8050480 - 20 May 2019
Cited by 1
Abstract
The HCP5 RNA gene (NCBI ID: 10866) is located centromeric of the HLA-B gene and between the MICA and MICB genes within the major histocompatibility complex (MHC) class I region. It is a human species-specific gene that codes for a long noncoding RNA [...] Read more.
The HCP5 RNA gene (NCBI ID: 10866) is located centromeric of the HLA-B gene and between the MICA and MICB genes within the major histocompatibility complex (MHC) class I region. It is a human species-specific gene that codes for a long noncoding RNA (lncRNA), composed mostly of an ancient ancestral endogenous antisense 3′ long terminal repeat (LTR, and part of the internal pol antisense sequence of endogenous retrovirus (ERV) type 16 linked to a human leukocyte antigen (HLA) class I promoter and leader sequence at the 5′-end. Since its discovery in 1993, many disease association and gene expression studies have shown that HCP5 is a regulatory lncRNA involved in adaptive and innate immune responses and associated with the promotion of some autoimmune diseases and cancers. The gene sequence acts as a genomic anchor point for binding transcription factors, enhancers, and chromatin remodeling enzymes in the regulation of transcription and chromatin folding. The HCP5 antisense retroviral transcript also interacts with regulatory microRNA and immune and cellular checkpoints in cancers suggesting its potential as a drug target for novel antitumor therapeutics. Full article
(This article belongs to the Special Issue Major Histocompatibility Complex (MHC) in Health and Disease)
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Open AccessReview
Major Histocompatibility Complex (MHC) Genes and Disease Resistance in Fish
Cells 2019, 8(4), 378; https://doi.org/10.3390/cells8040378 - 25 Apr 2019
Cited by 2
Abstract
Fascinating about classical major histocompatibility complex (MHC) molecules is their polymorphism. The present study is a review and discussion of the fish MHC situation. The basic pattern of MHC variation in fish is similar to mammals, with MHC class I versus class II, [...] Read more.
Fascinating about classical major histocompatibility complex (MHC) molecules is their polymorphism. The present study is a review and discussion of the fish MHC situation. The basic pattern of MHC variation in fish is similar to mammals, with MHC class I versus class II, and polymorphic classical versus nonpolymorphic nonclassical. However, in many or all teleost fishes, important differences with mammalian or human MHC were observed: (1) The allelic/haplotype diversification levels of classical MHC class I tend to be much higher than in mammals and involve structural positions within but also outside the peptide binding groove; (2) Teleost fish classical MHC class I and class II loci are not linked. The present article summarizes previous studies that performed quantitative trait loci (QTL) analysis for mapping differences in teleost fish disease resistance, and discusses them from MHC point of view. Overall, those QTL studies suggest the possible importance of genomic regions including classical MHC class II and nonclassical MHC class I genes, whereas similar observations were not made for the genomic regions with the highly diversified classical MHC class I alleles. It must be concluded that despite decades of knowing MHC polymorphism in jawed vertebrate species including fish, firm conclusions (as opposed to appealing hypotheses) on the reasons for MHC polymorphism cannot be made, and that the types of polymorphism observed in fish may not be explained by disease-resistance models alone. Full article
(This article belongs to the Special Issue Major Histocompatibility Complex (MHC) in Health and Disease)
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Other

Open AccessCommentary
MHC Genomics and Disease: Looking Back to Go Forward
Cells 2019, 8(9), 944; https://doi.org/10.3390/cells8090944 - 21 Aug 2019
Abstract
Ancestral haplotypes are conserved but extremely polymorphic kilobase sequences, which have been faithfully inherited over at least hundreds of generations in spite of migration and admixture. They carry susceptibility and resistance to diverse diseases, including deficiencies of CYP21 hydroxylase (47.1) and complement components [...] Read more.
Ancestral haplotypes are conserved but extremely polymorphic kilobase sequences, which have been faithfully inherited over at least hundreds of generations in spite of migration and admixture. They carry susceptibility and resistance to diverse diseases, including deficiencies of CYP21 hydroxylase (47.1) and complement components (18.1), as well as numerous autoimmune diseases (8.1). The haplotypes are detected by segregation within ethnic groups rather than by SNPs and GWAS. Susceptibility to some other diseases is carried by specific alleles shared by multiple ancestral haplotypes, e.g., ankylosing spondylitis and narcolepsy. The difference between these two types of association may explain the disappointment with many GWAS. Here we propose a pathway for combining the two different approaches. SNP typing is most useful after the conserved ancestral haplotypes have been defined by other methods. Full article
(This article belongs to the Special Issue Major Histocompatibility Complex (MHC) in Health and Disease)
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