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I'm going to try and explain what I think I know

From what I understand, MHC/HLA molecules present peptides to T cells. To be able to present peptides from a wide variety of pathogens, they need to have diversity in their peptide binding domains. My lecture handout tell me that MHC diversity comes due to polygeny and polymorphism. Polygeny refers to there being 3/6 (handout says 3, textbook says 6) MHC class I loci leading to 3/6 class I isotypes, and 3/5 MHC class II loci leading to 3/5 class II isotypes. Polymorphism refers to multiple alleles of each gene, meaning a variety of allotypes produced from each gene. These processes lead to the generation of a wide variety of isoforms of MHC proteins in the human population. The textbook also states that there is no rearrangement or structural change of the genes encoding the MHC proteins.

So I get that in the population, there is huge diversity of MHC molecules. But in each human, since there is no rearrangement of genes as in the case of antibodies to generate antibody diversity, is there therefore only one type of MHC protein being encoded? So by MHC diversity, we are not referring to diversity in each human, rather in the entire population? And if so, how do our MHC molecules become capable of binding to any antigen from any pathogen?

Please could someone clarify for me if I've misunderstood something, and also if my above explanation is factually correct, with the appropriate use of terminology?

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You're right that both polygeny and polymorphism contribute to the diversity of a given gene in the population correctly described what they mean individually.

However, you missed that the polygeny of MHC means that the human genome has 3 different loci/genes (called MHC-I A,B & C) in the haploid genome, meaning that any given human as actually 6 copies of the gene (i.e. 3 copies from each parent). All of these copies perform the same function of presenting peptides to CD8+ cells, but will have slightly different binding preferences for the peptides that they load. This is where the MHC diversity in a single human comes from.

Additionally each of the 3 MHC-I loci/isoforms is polymorphic, meaning that for each of them multiple alleles/variants exist in the human population. Since the number of these variants is pretty big (hundreds to thousands), most humans have different alleles on their paternal & maternal chromosomes and end up with 6 unique MHC-I genes.

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  • $\begingroup$ Ah yes, okay. So is the diversity produced from just those 6 genes enough to allow peptides from potentially any pathogen to be recognised and bound, and then presented to T cells? And does that mean the variation in MHC alleles between individuals produces only a very small difference in phenotype? I.e. are there large or only small differences in the types of antigen/peptide that each individual's MHC molecules can recognise? I just can't get my head around how such a few number of MHC molecule isoforms can bind such a wide variety of peptides $\endgroup$ – Alex Sep 2 at 14:58
  • $\begingroup$ @Alex Yes, individual diversity just comes from having 6 different MHC-I genes. Generally they all bind broadly ~8-12aa pepdites with a few additional requirements, but still a big variety. Discussing the specificities, differences etc of peptide binding between the different subtypes & alleles is outside of the scope of this question/comment though - I'd recommend you read up about that in a proper textbook. $\endgroup$ – Nicolai Sep 2 at 15:47

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