Pathogen diversity drives the evolution of generalist MHC-II alleles in human populations

Abstract

Central players of the adaptive immune system are the groups of proteins encoded in the major histocompatibility complex (MHC), which shape the immune response against pathogens and tolerance to self-peptides. The corresponding genomic region is of particular interest, as it harbors more disease associations than any other region in the human genome, including associations with infectious diseases, autoimmune disorders, cancers, and neuropsychiatric diseases. Certain MHC molecules can bind to a much wider range of epitopes than others, but the functional implication of such an elevated epitope-binding repertoire has remained largely unclear. It has been suggested that by recognizing more peptide segments, such promiscuous MHC molecules promote immune response against a broader range of pathogens. If so, the geographical distribution of MHC promiscuity level should be shaped by pathogen diversity. Three lines of evidence support the hypothesis. First, we found that in pathogen-rich geographical regions, humans are more likely to carry highly promiscuous MHC class II DRB1 alleles. Second, the switch between specialist and generalist antigen presentation has occurred repeatedly and in a rapid manner during human evolution. Third, molecular positions that define promiscuity level of MHC class II molecules are especially diverse and are under positive selection in human populations. Taken together, our work indicates that pathogen load maintains generalist adaptive immune recognition, with implications for medical genetics and epidemiology.

Combinatorial mutagenesis of rapidly-evolving residues yields super-restrictor antiviral proteins

“…Our findings suggest that, under threat by multiple viruses, antiviral genes such as MxA appear to be under evolutionary pressure to harbor more broadly active alleles even at the expense of more potent, specific antiviral activity. This result is reminiscent of a recent study, which reported that generalist (promiscuous) MHC class II alleles are selected for in human populations in response to high pathogen diversity [22]. Similar breadth-specificity tradeoffs have also been invoked in the case of cytochrome p450 detoxification genes that protect herbivorous insects from plant counterdefenses [23] and in plant disease resistance (R) genes encoded by the Leucine Rich Repeat (LRR) gene family [24].…”

Diversity of HLA Class I and Class II blocks and conserved extended haplotypes in Lacandon Mayans

“…www.nature.com/scientificreports www.nature.com/scientificreports/ by extension, in mixed populations with high proportions of Native American ancestry) might result from the frequency increase of some alleles that provide efficient immune protection against highly prevalent extracellular pathogens in specific populations 6,7,15,19,72 .…”

“…The class II HLA evolutionary mechanisms proposed by Sanchez-Mazas et al 6 apply particularly to HLA-DQA1 and HLA-DQB1, whereas as noted previously the Lacandon also exhibit relatively low diversity in HLA-DRB1. Certain HLA alleles appear to be promiscuous and are capable of binding an exceptionally large set of epitope peptide segments 15 . Since the HLA class II alleles commonly found in Native Americans (except for HLA-DRB1*16:02), and specifically those reported here for Lacandon Mayans, do not fall within the category of "promiscuous alleles" established by Manczinger et al 15 , we can in principle hypothesize that selection events happening in recent times may have driven this genetic structure.…”

“…The genetic diversity of MHC genes results from selective pressures including functional adaptation to pathogens [2][3][4][5][6][7][8] with some peptide-HLA complexes being more effective in eliciting an immune response than others 4 . It seems likely that individuals with greater diversity at their HLA loci would have a greater chance of survival in pathogen-enriched environments 5 , but there is debate as to whether simple heterozygote advantage or more complex host-pathogen co-evolutionary processes are responsible for the diversity of human HLA alleles generally [9][10][11][12][13][14][15] . In addition to their direct role in immune responses against pathogens, HLA molecules are crucial genetic markers to study the genetic diversity of populations in the context of disease susceptibility and allotransplantation [3][4][5][16][17][18][19][20] .…”

Immunpathogenesis and genetics of skin diseases

“…A humán leukocita antigén (HLA) molekulákat kódoló gének bioinformatikai vizsgálatával kimutattuk, hogy bizonyos HLA variánsok a többinél sokkal több, eltérő epitópot képesek megkötni (31). Ezek olyan területeken terjedtek el, ahol sok eltérő kórokozó faj található, így az ott élők immunrendszere képessé válik a környezetben található mikrobák hatékony felismerésére és elpusztítására (32).…”