- The Quest for Better Understanding of HLA-Disease Association: Scenes from a Road Less Travelled By
- Human leukocyte antigen
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- HLA variation and disease
The HLA region encodes several molecules that play key roles in the immune system. The advances being made in determining the primary associations within the HLA region and AIDs will not only increase our understanding of the mechanisms behind disease pathogenesis but may also aid in the development of novel therapeutic targets in the future. These diseases are often chronic and debilitating and, although treatments are available, many are inadequate [ 1 ] providing the impetus for a greater understanding of the disease mechanisms and the development of novel therapeutic agents.
Antigen presentation and T cell activation appear to be key to triggering an autoimmune response [ 2 ] prompting investigation of many genes within this pathway for association with AID including several within the major histocompatibility complex MHC.
It also exhibits the most dense linkage disequilibrium LD [ 5 ], extending up to kb, which compares with distances of between kb seen in the rest of the genome [ 6 , 7 ]. The extent of LD within the region has proved challenging when trying to tease out the exact location of etiological variants.
Exogenous antigen is imported into the cell and then enters the endosytic pathway encompassing the early endosome, late endosome and lysosome where the antigen is degraded.
This molecule forms a critical residue in peptide binding pocket nine P9 of the DQB1 binding pocket involved in antigen presentation and T cell receptor TCR interaction.
Further verification of this hypothesis, re-defining the shared epitope, is required.
The Quest for Better Understanding of HLA-Disease Association: Scenes from a Road Less Travelled By
Exogenous peripheral antigens are internalized via antigen presenting cells APC and are degraded into amino acid residue peptides, preferentially bound by HLA class II molecules, in the increasingly acidic compartments of the endocytic pathway.
HLA class II molecules are synthesized in the rough endoplasmic reticulum RER where they associate with the invariant chain Ii to prevent endogenous peptide binding. This could affect thymic T cell education, causing incomplete thymic tolerance and a Th and T regulatory Treg cell population that does not recognize all self molecules.
It has been proposed that the protective effects seen with specific HLA molecules could be due to the generation of Treg cells that are able to keep autoreactive T cells in check and prevent autoimmunity [ 39 ].
Studies in RA have shown Treg populations to be compromised [ 40 ], suggesting that RA could be associated with a failure to protect rather than a predisposition to disease. Promiscuous restriction where some TCRs will use a series of different restriction elements to bind to and, therefore, interact with a wider variety of different peptides.
Although class II molecules traditionally present exogenous antigens and class I present endogenous antigens see Fig.
This could alter how these antigens are presented to the immune system and the response triggered. These hypotheses suggest a series of potential mechanistic pathways by which the HLA class II molecules could be involved in disease onset by altering the Th and Treg cell repertoire or through changes in how the antigen is recognized in the periphery.
The utilization of larger datasets and the development of more advanced statistical analysis, has enabled re-investigation of the HLA class I region as an independent general AID locus.
Work in T1D identified a microsatellite D6S 4. Although this study did not find any support for independent HLA-A effects, they could not rule out an effect at this locus [ 60 ]. HLA class I molecules present endogenous antigens, such as those derived from viruses and intracellular bacteria, for recognition by the immune system see Fig.
Human leukocyte antigen
This process involves ubiquitination of endogenous cytosolic proteins and then degradation into short amino acid peptides, optimal for HLA class I binding. They act as one of the first lines of innate immune defence by producing lymphokines, including interferons, which aid in the recruitment of additional cells to the site of inflammation [ 61 ] and also produce cytokines and chemokines that have a cytolytic activity aiding cell destruction.
Several hypotheses have been suggested to explain how variation in HLA class I genes could trigger autoimmunity. Molecular mimicry occurs when microbial antigens that are sufficiently similar to self-antigens activate autoreactive T-cells that can cross react with self antigen triggering autoimmunity.
During viral infection soluble HLA levels, involved in regulating the immune response, have also been shown to be increased in RA patients, the level of which is dependent on HLA allele present [ 74 , 75 ].
NK cell cytotoxic activity is controlled by a balance between activating and inhibitory receptors on their surface [ 76 ]. Activation signals are blocked by inhibitory signals produced through interaction of killer immunoglobulin-like receptors KIR with a variety of HLA class I molecules loaded with peptide [ 76 , 77 ].
MHC Made Simple! Also HLA disease Coorelations
Groups C1 and C2 are distinguished by the presence of Ser at position 77 and asparagine Asn at position 80 of the 1 helix or Asp at position 77 and a lysine Lys at position 80, respectively. Strong association of HLA-C with psoriasis was detected and presumed to be the etiological variant, until further studies suggested that the true etiological variant actually lies 60kb outside of the HLA-C molecule [ 85 , 86 ].
Further work is required to determine if these genes are true AID etiological variants [ 87 , 88 ], using techniques, for example, which utilise the development of tag SNPs to screen the HLA region [ 89 ]. With our increased understanding of the complexity within the HLA region and the development of new statistical methodologies to help decipher the unique LD structure therein, progress has been made in starting to disentangle the associations present [ 89 , 90 ], providing valuable insights into AID mechanisms.
Novel therapeutic treatments based on these discoveries have already been proposed. The development of protease inhibitors designed to alter the antigen presenting properties of HLA molecules, by blocking the presentation of potentially auto-antigenic peptides, could direct the immune system away from a particular antigenic motif and in turn the autoimmune disease process [ 37 ].
Although clinical use may be some way off, continued research on the whole HLA region is vital to increase our understanding of the key mechanisms behind AID and ultimately the provision of new therapeutic targets. The authors would like to thank Dr Joanne Heward for her helpful comments on the manuscript and the Wellcome Trust for funding.
National Center for Biotechnology Information , U. Journal List Curr Genomics v. Curr Genomics. L Gough and M. Author information Article notes Copyright and License information Disclaimer. This article has been cited by other articles in PMC.
Abstract The HLA region encodes several molecules that play key roles in the immune system. Open in a separate window.
Both allelic and haplotype associations have been shown. GD [ ] Complement component C4 Class III Plays a role in both the classical and lectin pathways of complement activation which leads to several outcomes including activating inflammation, secretion of immunoregulatory molecules that fine tune the immune response, clearance of immune complexes, opsoniza-tion aiding antibodies to enhance the ability of phagocytic cells to attack bacteria and lysis of bacteria, viruses and cells.
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Human Leukocyte Antigen Disease Association
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Hla disease association pdf merge
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HLA variation and disease
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