Several hypotheses have been suggested to explain how variation in HLA class I genes could trigger autoimmunity. HLA class I molecules play a role in presenting endogenous antigens, including those derived from viruses and/or bacteria, which have been proposed to be key enviromental trigger for autoimmune disease. Viral/bacteria antigens may trigger autoimmun disease through molecular mimicry and via acting as superantigens HLA class I molecules could also be associated with autoimmune disease due to their role in inhibiting natural killer cell activity. Non-viral mechanism have also been proposed including:
- Protein misfolding causing specific molecules to accumulate in the RER, where they are degraded, potentially causing a pro-inflammatory unfolded protein stress response or misfolded proteins themselves to become autoantigenic
- Conversion of HLA class I molecules into peptides which could then be presented by HLA class II molecules to the immune system and an immune respones mounted as has been pr0posed in ankylosing spondylitis with B*27
- Peptide binding and presentation by specific HLA molecules as suggested earlier for HLA class II molecules with mechanisms including selection of antigen-specific CD8 T cells during thymic education, and positive or negative selection of a strong CD8 T suppressor population
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