Multiple sclerosis: doubling down on MHC

Genes of the human leukocyte antigen (HLA)-DR15 haplotype show a strong association with disease risk for multiple sclerosis (MS).Current genotyping tools failed to pinpoint second HLA-DR allele, DRB5*01:01, besides well-known DRB1*15:01 gene, despite their close 100% linkage disequilibrium (LD).Functional studies illustrate complex mechanisms how both DR15 alleles shape CD4+ T cell repertoire that is selected and maintained by peptides from molecules but reacts more strongly MS-associated infectious organisms autoantigens.The roles disease-associated include serving as antigen-presenting structure source antigen.The cooperativity between two same likely applies other HLA-disease associations well should be examined. Human (HLA)-encoded surface present antigenic lymphocytes play key role in adaptive immune responses. Besides physiological defending host against pathogens, specific serve genetic factors autoimmune diseases. For (MS), an affects brain spinal cord, HLA-DR15 was described early 1970s. This short opinion piece discusses difficulties disentangling details this recent observations about functional involvement not only one, also gene haplotype. information important understanding pathomechanism MS, antigen-specific therapies. MHC, called HLA humans, describes set proteins central recognition lymphocytes. The genes coding are located on 3.6 Mb stretch arm chromosome 6 (6p21) (Figure 1A, Key figure ). In order understand deciphering different diseases (AIDs), we briefly summarize organization locus, which code proteins, these form membrane involved recognition. There three class I HLA-A, -B, -C, encoded respective genes. consist domains (α1, α2, α3) heterodimers together invariant β2 microglobulin 1B). Their membrane-distal α1 α2 groove, bind recognized receptors (TCRs) CD8+ binding grooves closed at either end length nine or ten amino acids. All nucleated cells platelets express molecules, perhaps exception intact neurons, cornea, sperm, some trophoblast privileged sitesi [1.Hewitt E.W. MHC presentation pathway: strategies viral evasion.Immunology. 2003; 110: 163-169Crossref PubMed Scopus (243) Google Scholar,2.Boegel S. et al.HLA proteasome expression body map.BMC Med. Genet. 2018; 11: 36Google Scholar]. A codes II HLA-DR, -DQ, -DP. α β chains, pair build molecules. β1 chains binds TCRs Different antigen-binding groove open can up 25 However, number acids inside ten. expressed presentation, so-called (APCs) [3.Ting J.P. Trowsdale J. Genetic control expression.Cell. 2002; 109: S21-S33Abstract Full Text PDF (429) inflammatory conditions they types, example, thyroid epithelial [4.Pujol-Borrell R. al.Lectin-induced DR cultured follicular cells.Nature. 1983; 304: 71-73Crossref (177) Scholar] astrocytes [5.Fontana A. al.Astrocytes myelin basic protein encephalitogenic T-cell lines.Nature. 1984; 307: 273-276Crossref (642) oligodendrocytes [6.Falcao A.M. al.Disease-specific oligodendrocyte lineage arise sclerosis.Nat. 24: 1837-1844Crossref (146) HLA-DQ -DP polymorphic HLA-DQA1, -DPA1, -DQB1, -DPB1 formed nonpolymorphic chain (DRα), HLA-DRA highly (DRβ) four genes, HLA-DRB1, -DRB3, -DRB4, -DRB5. belongs most regions genome [7.Leen G. al.The diversity Anthony Nolan register.HLA. 2021; 97: 15-29Crossref (3) all except HLA-DRA, polymorphic. To complexity, so far, than 2400 known HLA-DRB1 alone, resulting enormous diversityii (see Glossary) [8.Dendrou C.A. variation disease.Nat. Rev. Immunol. 18: 325-339Crossref (220) fact, it expected no individuals completely matching types found population, monozygotic twins. Considering -DRB1 currently typed molecular methods, estimated possible genotypes 9 × 1025, although real will considerably lower due (LD) [9.Kröger N. Allogene Stammzelltherapie - Grundlagen, Indikationen und Perspektiven.4th edn. UNI-MED Science, 2015Google Certain combinations particular HLA-DRB proximity, usually inherited referred Most haplotypes makes heterodimer HLA-DRα, -DRB5, forms HLA-DRα 1A,C). Exceptions HLA-DR1, -8, -10 haplotypes, encode (Table 1).Table 1Discovery evolution HLA-D region its correlation antigens DRB genes1st β-chain2nd β-chainantigenSerological splitCellular splitHTCaAbbreviation: HTC, homozygous typing cell.DRB geneantigenDRB geneRefsDR1–Dw1DRB1*01:01--DR2DR15Dw2PGFDRB1*15:01DRw51DRB5*01:01[16.Lee B.S. al.HLA-DR2 subtypes additional supertypic family beta alleles.Proc. Natl. Acad. Sci. 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