Autoimmunity and Epitopes and Peptides, oh my!

Type I Diabetes (TID) and Rheumatoid Arthritis (RA) are two autoimmune disorders with clear HLA associations.  Often, these are reported as allele associations - for example, RA is commonly associated with HLA-DRB1*04:01.  Functionally, an MHC association with autoimmunity makes sense - self antigens presented on certain MHC that do not elicit a strong T cell:MHC interaction do not cause the elimination of the autoreactive T cells in the thymus.  It follows from this that only an MHC that binds the antigen in a particular conformation will cause this effect.  Below is a summary of three methods of antigen processing and presentation on MHC class II molecules:

  Pippa Marrack and John Kappler, 2012

With increasing power in bioinformatics and larger sample sizes, additional alleles from the major ones have been found that is also associated with RA (and TID, and other autoimmune diseases).  This led to the observation that each of these alleles had a shared epitope, or a pattern of either one or more amino acids that was associated with the disease.  In our lab, this observation led to the creation of a computer program that could identify these associations - and it is quite powerful!  In RA for example, given HLA data from controls and patients we used the program to examine over 2 million potential epitopes.  The most significantly associated with the disease, is the well known LA(67,74) epitope, which is of course, present in HLA-DRB1*04:01, as well as the other alleles that have been identified.  Another neat aspect of this program, it also identifies resistant epitopes, which in RA is an aspartic acid at position 70.  The diagram below details the peptide binding in the groove of the MHC for both the susceptible allele (left) and the resistant allele (right).    

Freed et. al., 2011

The presence of shared epitopes among disease associated alleles indicates the importance of the peptide binding chemistry in the development of autoimmunity.  In the same article, our lab performed peptide binding studies comparing the resistant and susceptible allele and found that the RA self antigen citrullinated vimentin bound to the susceptible allele better than the resistant.  Finally, in recent unpublished results we found that people who had BOTH the resistant and susceptible allele were less likely to have the disease.  We are currently in the midst of developing a quicker peptide binding assay, with our big question being how important is the shared epitope in peptide binding of self antigens?  

Some things to think about:

Which method of antigen processing shown in the first diagram do you think contributes most in autoimmune development?

Why do you think that people who have a copy of both the resistant and susceptible alleles have a lower chance of developing the disease?  What functionality could be going on there?

References:

Marrack, P., Kappler, J. 2012.  Do MHCII-Presented Neoantigens Drive Type 1 

Diabetes and Other Autoimmune Diseases?  Perspectives in Medicine 2:a007765 

Freed, B.M., Schluyer, R. P., Aubrey, M.T. 2011.  Association of the HLA–DRB1 Epitope LA67, 74 With Rheumatoid Arthritis and Citrullinated Vimentin Binding.  Arthritis and Rheumatism 63:3733–3739