Background 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.

Objectives 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 (1). 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) or by backcrossing MALT1-deficient mice to TNF^DARE mice, representing an SpA-like model. Additionally, CIA was induced in CD4-specific MALT1-deficient mice to determine the importance of MALT1 in T-cells.

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. 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. Interestingly, TNF^DARE mice that were deficient for MALT1 also showed a reduced enthesitis and ileitis phenotype, although TNF-concentration in the serum of these mice was higher compared to MALT1^+/+xTNF^DARE mice.

Conclusions Overall, our data highlight that MALT1 plays a crucial role in the pathogenesis of inflammatory arthritis and represents an interesting candidate to target therapeutically.

References

1. Thome M. Multifunctional roles for MALT1 in T-cell activation. Nat Rev Immunol 2008; 8 (7): 495–500.

References

Acknowledgements We thank Chris Vercruysse (Department of Basic Medical Sciences, University of Ghent, Belgium) for exerting the three-point-bending tests of the femurs and the lab of Prof. Dr. Luc Van Hoorebeke (Department of Physics and Astronomy) for the use of the μCT-scanner.

Disclosure of Interest None declared