Human leukocyte antigen

HLA genes are highly polymorphic, which means that they have many different alleles, allowing them to fine-tune the adaptive immune system.HLAs corresponding to MHC class II (DP, DM, DO, DQ, and DR) present antigens from outside of the cell to T-lymphocytes.Predicting which (fragments of) antigens will be presented to the immune system by a certain HLA type is difficult, but the technology involved is improving.Diversity of HLAs in the human population is one aspect of disease defense, and, as a result, the chance of two unrelated individuals with identical HLA molecules on all loci is extremely low.HLA genes have historically been identified as a result of the ability to successfully transplant organs between HLA-similar individuals.Proteins from the pathogen are digested into small pieces (peptides) and loaded on to HLA antigens (to be specific, MHC class II).[10] The image off to the side shows a piece of a poisonous bacterial protein (SEI peptide) bound within the binding cleft portion of the HLA-DR1 molecule.It has been shown that high resolution HLA typing (HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1 and HLA-DPB1) may be relevant in transplantation to identify a full match, even when the donor is related.More often, however, HLA molecules play a protective role, recognizing increases in antigens that are not tolerated because of low levels in the normal state.The genes of the class II combine to form heterodimeric (αβ) protein receptors that are typically expressed on the surface of antigen-presenting cells.For class II (DR, DP and DQ), amino acid variants within the receptor's peptide-binding cleft tend to produce molecules with different binding capability.However, the gene frequencies of the most common alleles (>5%) of HLA-A, -B, -C and HLA-DPA1, -DPB1, -DQA1, -DQB1, and -DRB1 from South America have been reported from the typing and sequencing carried out in genetic diversity studies and cases and controls.Number of variant alleles at class I loci according to the IMGT-HLA database, last updated October 2018: Number of variant alleles at class II loci (DM, DO, DP, DQ, and DR): The large extent of variability in HLA genes poses significant challenges in investigating the role of HLA genetic variations in diseases.[28] A tool to convert HLA alleles into their component SFVTs can be found on the Immunology Database and Analysis Portal (ImmPort) website.It is possible to predict based on 'square root','maximum-likelihood' method, or analysis of familial haplotypes to account for adequately typed alleles.A representative cellular assay is the mixed lymphocyte culture (MLC) and used to determine the HLA class II types.[34] Minor reactions to subregions that show similarity to other types can be observed to the gene products of alleles of a serotype group.Allelic diversity makes it necessary to use broad antigen typing followed by gene sequencing because there is an increased risk of misidentifying by serotyping techniques.(By serotyping A3-Cw7-B7-DR15-DQ6 or the older version "A3-B7-DR2-DQ1") These haplotypes can be used to trace migrations in the human population because they are often much like a fingerprint of an event that has occurred in evolution.Studies of humans and animals imply a heterozygous selection mechanism operating on these loci as an explanation for this variability.[39] One proposed mechanism is sexual selection in which females are able to detect males with different HLA relative to their own type.Studies of the variable positions of DP, DR, and DQ reveal that peptide antigen contact residues on class II molecules are most frequently the site of variation in the protein primary structure.This diversity enhances the survival of such groups, and thwarts evolution of epitopes in pathogens, which would otherwise be able to be shielded from the immune system.HLA antibodies are typically not naturally occurring, and with few exceptions are formed as a result of an immunologic challenge to a foreign material containing non-self HLAs via blood transfusion, pregnancy (paternally inherited antigens), or organ or tissue transplant.[41] Donor-specific HLA antibodies have been found to be associated with graft failure in renal, heart, lung, and liver transplantation.These donor-specific HLA antibodies can exist pretransplant as consequence of sensitization to prior transplants or through pregnancies, but also occur de novo post-transplantation.[42] In some diseases requiring hematopoietic stem cell transplantation, preimplantation genetic diagnosis may be used to give rise to a sibling with matching HLA, although there are ethical considerations.