|Professor Richard Kitching|
Professor Richard Kitching is a head of the Autoimmune Kidney Disease and Vasculitis research group at Monash School of Clinical Sciences and a leading Nephrologist at Monash Health.
Professor Kitching will be discussing "A new mechanism determining the risk of autoimmune disease". Abstract:
The highly polymorphic HLA system is critical to foreign and self-protein recognition by the immune system. A key question in autoimmune disease is how this HLA system, genetically linked to almost all autoimmune diseases, mediates disease risk. Furthermore, conditions such as type I diabetes mellitus, multiple sclerosis and Goodpasture’s disease (GPD) not only feature risk MHC Class II (HLA) alleles, but also exhibit dominant HLA-mediated protection, i.e. some HLA alleles are protective, even when inherited with a risk allele. We used GPD that causes life-threatening glomerulonephritis and pulmonary haemorrhage, to address this fundamental question. GPD is caused by autoimmunity to the non-collagenous domain of the α3 chain of type IV collagen, α3(IV)NC1, found in glomerular and pulmonary basement membranes, with the dominant CD4+ T cell epitope being the α3135-145 peptide. HLA-DR15+ people have a relative risk of GPD of 8.5, but HLA-DR1+ only 0.3. This HLA-DR15-associated risk is abrogated by HLA-DR1 co-inheritance.
We used in vitro and in vivo systems in HLA-DR15, DR1 and DR15/DR1 transgenic mice, together with samples from both GPD patients and from fully HLA-typed health donors. CD4+ α3135-145-specific T helper cells are central to disease and α3135-145 responses define HLA-DR1’s dominant protection. The molecular structure of the α3135-145-HLA-DR complex differs markedly between HLA-DR15 and of HLA-DR1, resulting in different α3135-145-specific T cell selection. Furthermore, most α3135-145-specific CD4+ T cells in HLA-DR15+ mice and humans are conventional T cells (with the potential to become autoreactive pro-inflammatory cells). However, when educated by HLA-DR1, the resultant α3135-145-specific CD4+ cells are anti-inflammatory regulatory T cells (Tregs) that maintain tolerance to α3(IV)NC1. Even in the presence of HLA-DR15, it is these α3135-145-specific specific Tregs, generated by HLA-DR1-peptide interactions, that potently protect from autoimmunity and GPD.
These findings answer a central question in autoimmune disease, providing a mechanistic basis for understanding HLA-mediated susceptibility and protection. Peptide-HLA/T cell interactions could be used in disease diagnosis and risk stratification, and the potency of Tregs specific for immunodominant autoepitopes mean that they may be more specific therapies for autoimmune diseases.
Translational Research Symposium
- Date: Monday 31 July, 2017
- Time: 8:30 for 9:00am start - 7:00pm close
- RSVP here