Leader
Dr. Elisabeth Brouwer, Akademisch Ziekenhuis Groningen

Description of the tasks

Ageing is associated with profound changes in immune cell distribution and function and an increased incidence of autoimmune diseases. This suggests that age associated changes in the immune system predispose to autoimmunity and their co-morbidities. The exact underlying mechanisms are unknown.
The overall purpose of this work package is to identify common age-associated immune cell signatures that predispose to autoimmune disease and its relapses.

This Work Package is based on the hypothesis that age-associated changes in the immune system are linked to increased susceptibility for autoimmune diseases and their relapses. The focus will be on anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV), Giant-cell arteritis (GCA) and Polymyalgia rheumatica (PMR) as chronic autoimmune diseases that preferentially affect the elderly and of which approximately 50% of patients experience disease relapses resulting in progressive loss of organ function and increased burden of co-morbidities. Clinical studies in these patient cohorts will address the question whether age related changes in the immune system, either numerically and/or functionally, predispose to autoimmunity and co-morbidities and aim to identify immune signatures that are common to these age associated autoimmune diseases. The clinical studies will be complemented with mouse studies in established models of AAV induced by autoimmunity to MPO that will i) explore the effect of ageing on the nature of anti-MPO autoimmunity ii) examine the effect of chronic CMV infection on autoreactivity to MPO in aged mice and iii) determine whether anti-MPO mediated disease is aggravated in aged mice.

The work will primarily be undertaken by Partner UMCG and Partner Monash but will involve synergistic collaboration with Partners MUW and UCAM as well as the transfer of data and materials to Partners KTH and SME Partner. The results will provide comprehensive insight into whether and how an ageing  immune system contributes to increased susceptibility for autoimmune diseases and their co-morbidities.
    

Objectives of this work package

• Determine immune cell signatures of immune cell exhaustion and senescence by surface marker analysis and transcriptome analysis in leukocyte subsets from patients with AAV, GCA and PMR in comparison with those obtained from healthy young and elderly individuals to identify disease specific and overlapping immune signatures.
• Analyse the expression of immune checkpoint molecules on circulating and lesional leukocyte subsets from patients with small and large vessel vasculitis in comparison with those obtained from healthy young and elderly individuals to clarify their role in immune tolerance and (re)activation of autoimmune responses.
• Examine the role of ageing of the immune system in the nature and severity of anti-MPO autoimmunity in mouse models, including loss of tolerance in the thymus and peripheral tolerance.