INTRICATE

Infectious triggers of chronic autoimmunity

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 Obiettivo del progetto (Objective)

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 (AAV). AAV 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 microorganisms triggers the induction or re-activation of AAV. Unraveling 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.

Introduzione (Teaser)

Researchers are investigating possible links between bacterial infections and autoimmune diseases. The study has identified novel biomarkers and opened up new opportunities for future research into therapeutics.

Descrizione progetto (Article)

Anti-neutrophil cytoplasmic antibody-associated systemic vasculitis (AAV) is a condition in which the body's immune system creates autoantibodies that destroy its own blood vessels. Researchers previously linked AAV to infections by common bacteria, and are now using it as a model to better understand mechanisms that lead to autoimmune diseases.

The studies undertaken as part of the EU-funded 'Infectious triggers of chronic autoimmunity' (http://www.intricate.eu/ (INTRICATE)) project, aim primarily to gain insight from investigating blood samples from patients with AAV and compare them to those from patients suffering from infections. Over 300 patients have consented to participate in these studies and, already, this aspect of the project has generated a number of new biomarkers that could have applications in clinical tests related to AAV management and treatment.

Further insight is expected from the generation of mice that have been genetically engineered to express the molecular targets of AAV autoantibodies. These transgenic mouse lines will be subjected to urinary tract infections with Escherichia coli and Staphylococcus aureus bacteria to gain insights into how immunity to pathogens might be misdirected and cause AAV.

In another aspect of the study, researchers are investigating the role of genetic variation in the relevant bacteria and whether they differ in patients that develop AAV. They are also trying to identify human genes that influence susceptibility to chronic infections and AAV.

The INTRICATE project is opening new avenues for investigations into bacterial infections as direct or indirect causes of autoimmunity. By understanding the underlying causes of chronic autoimmunity, researchers will be able to find new preventative and therapeutic strategies.