NHMRC Research Fellowship: Understanding the basis of autoimmunity in rheumatoid arthritis and type 1 diabetes to underpin the implementation of antigen-specific therapies (2015-2020)

Autoimmune diseases are chronic diseases in which organ-specific or systemic inflammation has devastating and destructive consequences. Rheumatoid arthritis (RA) is a currently incurable systemic autoimmune disease predominantly affecting synovial joints, in 1% of adults worldwide. Type 1 diabetes (T1D) is an organ-specific autoimmune disease, with inflammatory destruction of the insulin-producing beta cells leading to progressive decline in insulin production in response to glucose. In each case, HLA-class II genes underlie the major genetic susceptibility. Development of autoimmunity is marked by the appearance of autoantibodies (AB) ¿ directed against beta-cells in T1D and citrullinated antigens in RA (known as anti-citrullinated peptide antibodies, ACPA). In both diseases, AB precede expression of clinical symptoms and are present in first-degree relatives. AB are associated with carriage of HLA-class II susceptibility genes and severe outcome. This proposal underpins my vision for the development and commercialization of antigen-specific immunotherapy in RA and T1D. Theme 1 will examine how the interaction between autoantigenic peptide and HLA molecule affects the response of T cells to promote or regulate disease. We recently discovered novel inflammatory biomarkers predicting high-risk first degree relatives with multiple AB and that AB+ children could be segregated into sub-groups dominated either by ¿metabolic¿ or ¿inflammatory¿ serum biomarker signatures. Theme 2 will determine whether ¿metabolic¿ and ¿inflammatory¿ signatures we have identified 1. predict risk of progression to T1D in AB+ first degree relative progressors and non-progressors to T1D in longitudinal studies of the natural history study of T1D, 2. predict response to immunotherapies in recent-onset T1D and 3. how these signatures relate to HLA risk.