Tackling the Achilles heel of spondyloarthritis

Is it an autoinflammatory or autoimmune disease?

Tessa van Kempen

Promoter:
Prof.dr T.R.D.J. (Tim) Radstake
Co-promoter:
Dr M.L. (Marianne) Boes
Date:
October 27, 2020
Time:
09:15 h

Summary

Spondyloarthritis (SpA) is a chronic inflammatory disease characterized by articular and extra-articular manifestations. SpA encompasses a heterogeneous spectrum of rheumatic diseases and includes, but not exclusively, ankylosing spondylitis (AS) and psoriatic arthritis (PsA). It is still unknown whether SpA is mainly an autoinflammatory or autoimmune-driven disease. Autoinflammation is driven by uncontrolled production of endogenous danger signals, metabolic mediators and pro-inflammatory cytokines, whereas autoimmunity involves the activation of adaptive immune cells.

In this thesis we explored whether SpA is driven by antigen-specific immunity. Firstly, we found that the CD74 processing enzyme SPPL2a in monocytes from patients with AS was often impaired. As a consequence, CD74 fragments accumulated in endosomes, which can be transported to the cell surface. These fragments can be recognized by antibodies specific to Class II MHC-associated invariant chain peptide (CD74/CLIP), which are present in most sera from patients with AS. Secondly, we set-up an in vitro model to search for putative antigen-reactive CD8+ T cells. We identified CD8+ T cell receptor sequences that are shared among patients with PsA and could be detected in psoriatic skin. Lastly, we explored whether innate lymphoid cells (ILCs) are present in synovial fluid from patients with PsA. We found that synovial fluid from patients with PsA were enriched for ILC type 3.

The studies in this thesis indicate that the adaptive immune system plays a role in the pathogenesis of SpA. Future research will show whether the aberrant adaptive immune responses are a cause or a consequence of the disease.

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