Background/Purpose: One of the hallmarks of many inflammatory arthritides is their strong linkage with MHC-signalling, which is mirrored by the marked role for adaptive immunity. Accordingly, rheumatoid arthritis (RA) is characterized by the activation of auto-reactive T-cells and the development of auto-antibodies. T-cells may additionally respond to non-TCR mediated signals, which are essential in driving their effector functions. Pathways leading to the modulation of both innate and adaptive signals are therefore of marked interest to study in arthritic diseases. The paracaspase MALT1 is a key player in the activation and proliferation of immune and non-immune cells. These cells include the lymphoid, myeloid and mast cells, indicating MALT1’s crucial role in both innate and adaptive signaling. Therefore, MALT1 is regarded a promising target for the treatment of autoimmune diseases and defining its role in the pathogenesis of inflammatory arthritis is a critical first step.

Methods: To unravel MALT1’s role in inflammatory arthritis, we initially assessed MALT1-activation in mice that were challenged with collagen-induced arthritis (CIA), the prototype model for antigen-induced RA. We then addressed the role of MALT1 in the pathogenesis of inflammatory arthritis by challenging MALT1-deficient mice to distinct models of arthritis (CIA and CAIA). Additionally, CIA was induced in CD4-specific MALT1-deficient mice to determine the importance of MALT1 in T-cells. Bone homeostasis was assessed by micro-CT analysis, a 3 point bending test to test bone strength and by osteoclastogenesis assays using RANKL induced osteoclastogenesis and resorption pit assays. Immunophenotyping of T cell and regulatory T cell subsets was conducted in spleen and lymph nodes and anti-collagen II specific antibody development was measured by ELISA.

Results: We provide evidence that MALT1 plays a crucial role in the pathogenesis of RA as MALT1-deficent mice were completely protected against CIA. This complete protection was additionally observed in CD4-specific MALT1-deficient mice, indicating that the selective ablation of MALT1 in CD4-positive cells is sufficient for the observed resistance against CIA. This was reflected by markedly lower induction of anti-collagen type II antibodies. CAIA on the other hand, which is a T- and B-cell independent model of RA, did not depend on the presence of MALT1, since both MALT1+/+ and MALT1-/- mice showed comparable symptoms of RA. MALT1 deficient mice show an osteoporotic phenotype but osteoclastogenesis was normal suggesting an indirect effect. MALT1 deficient mice lack natural Tregs which could account for the osteoporotic phenotype. Accordingly, CD4-specific MALT1-deficient mice also had an osteoporotic phenotype on microCT with impaired bone strength.

Conclusion: Overall, our data highlight that MALT1 plays a crucial role in the pathogenesis of inflammatory arthritis but has a dual role on inflammation versus bone homeostasis. Our data indicate an osteoporotic phenotype in the absence of MALT1 caused by lack of Tregs.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-paracaspase-malt1-plays-a-central-role-in-the-pathogenesis-of-rheumatoid-arthritis/