Evolution and molecular interactions of major histocompatibility complex (MHC)-G, -E and -F genes

Abstract

Classical HLA (Human Leukocyte Antigen) is the Major Histocompatibility Complex (MHC) in man. HLA genes and disease association has been studied at least since 1967 and no firm pathogenic mechanisms have been established yet. HLA-G immune modulation gene (and also -E and -F) are starting the same arduous way: statistics and allele association are the trending subjects with the same few results obtained by HLA classical genes, i.e., no pathogenesis may be discovered after many years of a great amount of researchers’ effort. Thus, we believe that it is necessary to follow different research methodologies: (1) to approach this problem, based on how evolution has worked maintaining together a cluster of immune-related genes (the MHC) in a relatively short chromosome area since amniotes to human at least, i.e., immune regulatory genes (MHC-G, -E and -F), adaptive immune classical class I and II genes, non-adaptive immune genes like (C2, C4 and Bf) (2); in addition to using new in vitro models which explain pathogenetics of HLA and disease associations. In fact, this evolution may be quite reliably studied during about 40 million years by analyzing the evolution of MHC-G, -E, -F, and their receptors (KIR—killer-cell immunoglobulin-like receptor, NKG2—natural killer group 2-, or TCR-T-cell receptor—among others) in the primate evolutionary lineage, where orthology of these molecules is apparently established, although cladistic studies show that MHC-G and MHC-B genes are the ancestral class I genes, and that New World apes MHC-G is paralogous and not orthologous to all other apes and man MHC-G genes. In the present review, we outline past and possible future research topics: co-evolution of adaptive MHC classical (class I and II), non-adaptive (i.e., complement) and modulation (i.e., non-classical class I) immune genes may imply that the study of full or part of MHC haplotypes involving several loci/alleles instead of single alleles is important for uncovering HLA and disease pathogenesis. It would mainly apply to starting research on HLA-G extended haplotypes and disease association and not only using single HLA-G genetic markers.

Maternal HLA class II alleles and haplotypes associated with altered risk of recurrent pregnancy loss: A case‐control study

“…The HLA complex is characterized by its highly polymorphic and gene‐dense nature and is broadly divided into three major regions 12,13 . Classical HLA‐A, ‐B, and ‐C genes encode class I antigens, while HLA‐E, ‐F, and ‐G genes encode class 1b antigens 13,14 . Moreover, class II genes encode DR, DQ, and DP antigens.…”

“…In contrast, the class III region comprises genes encoding heat shock protein HSP-70, proinflammatory cytokines, including TNFα, lymphotoxin (LT)-α, and LT-β, and a few components of the complement system. 12,14,15 Functionally, Class I proteins form heterodimers with βmicroglobulin on the surfaces of nucleated cells and are notably absent from erythrocytes and trophoblasts. In contrast, heterodimeric Class II proteins exist on antigen-presenting cells.…”

“…12,13 Classical HLA-A, -B, and -C genes encode class I antigens, while HLA-E, -F, and -G genes encode class 1b antigens. 13,14 Moreover, class II genes encode DR, DQ, and DP antigens. In contrast, the class III region comprises genes encoding heat shock protein HSP-70, proinflammatory cytokines, including TNFα, lymphotoxin (LT)-α, and LT-β, and a few components of the complement system.…”

Long-read single-cell sequencing reveals expressions of hypermutation clusters of isoforms in human liver cancer cells

“…These mutations may alter the interaction with T lymphocytes ( Chan et al, 2018 ; Kondo et al, 2004 ). There was a broad spectrum of somatic mutations that affected the HLA gene since both cytosolic and endocytic pathways of antigen presentation may be blocked ( Arnaiz-Villena et al, 2022 ; Manoury et al, 2022 ). Interestingly, the expression levels of the mutated HLA molecules also increased in comparison with wild-type alleles from the benign hepatocytes.…”

Human leukocyte antigen and tumor immunotherapy (Review)

“…In recent years, greater attention has been paid to HLA-G and HLA-E, which belong to the group of non-classical HLA-I molecules and are located at chromosome 6p21.3 (19,20). During embryonic development, HLA-G is secreted by amniotic cells, erythroid precursor cells and cytotrophoblasts (21); its main role is to inhibit the function of maternal natural killer (NK) cells and to prevent NK cells from attacking allogeneic fetuses with antigenicity (22).…”