Infectious triggers of chronic autoimmunity

This proposal builds on existing expertise and collaborations of a multidisciplinary Consortium of basic scientists and clinical investigators each of whom has made a substantial individual contribution to understanding the links between infection and autoimmunity. The aim of the INTRICATE Consortium is to prosecute a programme of Translational Research that deliniates the role of infection in the induction and perpetuation of severe systemic autoimmune disease with the ultimate object of identifying new therapeutic strategies based on knowledge of pathogenesis. Our strategy will systematically analyse the complex and diverse processes involved in a model human disease: - Anti-neutrophil cytoplasmic antibody (ANCA) associated systemic vasculitis (AASV).

AASV is ideally suited because it is known to be caused by autoantibodies of defined specificity and second because it is strongly linked to infection to infection. INTRICATE will use mouse models to answer the specific question whether infection with clinically relevant bacteria induces autoimmune disease in transgenic mice that express the human autoantigen. The use of novel high-throughput antigen array technology in well-characterized patient cohorts and analysis of microbial and host specific mechanisms combined with genome wide association study (GWAS) will determine whether dysbiosis or infection with specific micro-organisms triggers the induction or re-activation of AASV. Unravelling the pathogenic processes that are responsible for this chronic autoimmune disease and the knowledge gained will lead to the development of novel preventive and therapeutic strategies.