Work package 4.  Rheumatoid Arthritis (RA)

Work package leader: Prof. dr. Rikard Holmdahl.


Research question: What is the precise role of the GCR in RA pathogenesis?

Rheumatoid Arthritis (RA) is an autoimmune disease characterised by chronic inflammation of the synovium and subsequent joint damage. Most RA patients are seropositive for autoantibodies, such as anti-citrullinated protein antibodies (ACPA) and rheumatoid factor (RF) that are produced by germinal center (GC) experienced B cells, and are arthritogenic if they cross-react to joint cartilage. The antibodies critical for both the origin of the disease and the later clinical onset are isotype-switched and most likely somatic mutated and, therefore, likely originate from the GC.

COSMIC aims to understand the contribution of the GCR and underlying molecular networks to the onset and pathogenesis of RA. This requires a better understanding of the connection between autoantigen-specificity, GC-dependent clonal expansion of autoreactive B cells, and B-cell receptor (BCR) repertoire against specific antigenic epitopes. It also requires in-depth characterisation of GC-associated tolerance immune-checkpoints, and the assessment of effects of pathogenic and regulatory antibodies. In this investigation we include clinically relevant high-risk pre-RA patients for which we will identify RA-specific GC-related (molecular) parameters, and determine the clonal and cellular composition in different tissues (blood, synovium, lymph nodes) at different disease stages.

Expected results: a better understanding of the role of the GCR and associated molecular mechanisms underlying the GCR disturbance in RA. Prognostic antibody biomarkers, diagnostic parameters, and new drug targets for RA therapies.

Go to Work package overview 


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