Cracking tolerance Examining tissue microenvironments in early arthritis

The study of human biopsies provides great insights into the specialized tissue environments that maintain immune homeostasis in the body. Direct comparisons between healthy and diseased tissues enhance our understanding of the mechanisms underlying disease onset and progression. Rheumatoid Arthritis (RA) is a chronic autoimmune disease of unknown origin which is characterized by synovial joint inflammation which if left untreated leads to pannus formation causing pain, swelling and bone damage. In this thesis we first explored immune perturbations in the lymph node and synovium in both preclinical and established RA. The findings in this thesis revealed an enrichment of neutrophils within the lymph node of established arthritis patients. Lymph node analysis of RA patients and individuals at risk of developing disease (RA-risk) and uncovered a type I interferon signature in RA-risk individuals and a T follicular helper cell profile in RA patients. Synovial tissue analysis of RA-risk individuals and RA patients revealed increased DNA damage and a reduced capacity for DNA repair in synovial fibroblasts. The final chapters focused on the crosstalk between lymph node fibroblasts and T cells and its impact on immunological tolerance. Lymph node fibroblasts were shown to uniquely maintain regulatory T cells in a HLA-DR dependent manner. This mechanism was not perturbed in RA patients and RA-risk individuals despite a reduced expression of HLA-DR on ex-vivo LN fibroblasts. Collectively, the chapters of this thesis present compelling evidence for alterations in the immunological landscape of the lymph node and synovium during the earliest phases of autoimmunity.