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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.

SUBMITTER: Manczinger M

PROVIDER: S-EPMC6372212 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Human leukocyte antigen (HLA) class I and II are known to have association with severe cutaneous adverse reactions (SCARs) when exposing to certain drug treatment. Due to genetic differences at population level, drug hypersensitivity reactions are varied, and thus common pharmacogenetics markers for one country might be different from another country, for instance, HLA-A*31:01 is associated with carbamazepine (CBZ)-induced SCARs in European and Japanese while HLA-B*15:02 is associated with CBZ-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) among Taiwanese and Southeast Asian. Such differences pose a major challenge to prevent drug hypersensitivity when pharmacogenetics cannot be ubiquitously and efficiently translated into clinic. Therefore, a population-wide study of the distribution of HLA-pharmacogenetics markers is needed. This work presents a study of Thai HLA alleles on both HLA class I and II genes from 470 unrelated Thai individuals by means of polymerase chain reaction sequence-specific oligonucleotide (PCR-SSO) in which oligonucleotide probes along the stretches of HLA-A, -B, -C, -DRB1, -DQA1, and -DQB1 genes were genotyped. These 470 individuals were selected according to their regional locations, which were from North, Northeast, South, Central, and a capital city, Bangkok. Top ranked HLA alleles in Thai population include HLA-A*11:01 (26.06%), -B*46:01 (14.04%), -C* 01:02 (17.13%), -DRB1*12:02 (15.32%), -DQA1*01:01 (24.89%), and -DQB1*05:02 (21.28%). The results revealed that the distribution of HLA-pharmacogenetics alleles from the South had more HLA-B75 family that a typical HLA-B*15:02 pharmacogenetics test for SJS/TEN screening would not cover. Besides the view across the nation, when compared HLA alleles from Thai population with HLA alleles from both European and Asian countries, the distribution landscape of HLA-associated drug hypersensitivity across many countries could be observed. Consequently, this pharmacogenetics database offers a comprehensive view of pharmacogenetics marker distribution in Thailand that could be used as a reference for other Southeast Asian countries to validate the feasibility of their future pharmacogenetics deployment.

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

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