OP0176 The paracaspase MALT1 plays a central role in the pathogenesis of rheumatoid arthritis

Abstract

BackgroundOne 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.ObjectivesThe 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.MethodsTo 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 TNFDARE 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.ResultsWe 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, TNFDARE 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+/+xTNFDARE mice.ConclusionsOverall, our data highlight that MALT1 plays a crucial role in the pathogenesis of inflammatory arthritis and represents an interesting candidate to target therapeutically.References Thome M. Multifunctional roles for MALT1 in T-cell activation. Nat Rev Immunol 2008; 8 (7): 495–500. AcknowledgementsWe 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 InterestNone declared

Compendium of Synovial Signatures Identifies Pathologic Characteristics for Predicting Treatment Response in Rheumatoid Arthritis

“…Interestingly, DEG-driven models outperformed models that were relying on pathways as features. Among 7 featured genes in SVM model, HMMR (Hyaluronan-mediated motility receptor, also known as RHAMM) exacerbated collagen-induced arthritis by supporting cell migration and up-regulating genes involved with inflammation (52) and MATL1 (Mucosa associated lymphoid tissue lymphoma translocation gene 1) was recently identified to play a crucial role in the pathogenesis of RA as MATL1-deficient mice were completely resistant to collage-induced arthritis (53). Direct connection to RA was not revealed for the rest of the identified informative genes so far and it remains to be investigated how and why these features are indicative of drug response.…”