Delighted to share our latest work on defining the effects of the HLA on an intermediate phenotype: the T cell repertoire with @Kazu_Ishigaki medrxiv.org/content/10.110… #genetics #type1diabetes #rheumatoidarthritis
HLA influence autoimmune risk. 2 non-exclusive hypotheses: i) the peripheral hypothesis, where HLA risk alleles increase binding to antigens ii) the central hypothesis, where HLA risk alleles influence thymic selection to select for antigen reactive T cell receptors (TCRs). 
The CDR3 region of TCR recognizes antigens. CDR3 diversity in the repertoire gives the immune system its ability to respond to many antigens. If central hypothesis plays a role in HLA mediated risk, then the HLA alleles might influence CDR3 composition during thymic selection.
In an examination of public data, we observed that the central positions of the CDR3 were highly random with little mutual information between positions.
Testing for HLA association to CDR3 composition. we see HLA-DRB1 position 13 explained as much as 10% of amino acid residue frequencies within CDR3 sites. This HLA position mediates risk for multiple autoimmune diseases, including rheumatoid arthritis and type I diabetes.
In structural analysis of TCR-peptide-MHC complexes, we observed that HLA-DRB1 position 13 does not interact directly with CDR3, but is proximate to antigenic peptide residues that are also close to CDR3.
We identified CDR3 amino acid profiles enriched by HLA risk alleles. Specific sequences are favored by alleles for different diseases. These sequences offer a way to identifying T cells driving autoimmunity. These results provide evidence supporting central hypothesis.
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