Objective. Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT-1) plays a crucial role in innate and adaptive immune signaling by modulating the threshold for activation of immune cells, including Treg cells. Therefore, MALT-1 is regarded to be an interesting therapeutic target in several immune-mediated diseases. The goal of this study was to examine the role of MALT-1 in experimental animal models of rheumatoid arthritis (RA).Methods. MALT-1 activation was assessed by measuring cleavage of the deubiquitinase CYLD in lymphocytes from mice with collagen-induced arthritis (CIA). Furthermore, the impact of MALT-1 deficiency on arthritis was evaluated in Malt1 KO mice with CIA or with collagen antibody-induced arthritis (CAIA). T cell-specific MALT-1 deficiency was measured in mice with deletion of T cell-specific MALT-1 (Malt1 TcellKO ), and the timedependent effects of MALT-1 deficiency were assessed in mice with deletion of tamoxifen-inducible T cellspecific MALT-1 (Malt1 iTcellKO ). Bone density was determined in MALT-1-deficient mice using micro-computed tomography and femur-bending tests. Reconstitution of Treg cells was performed using adoptive transfer experiments.Results. MALT-1 activation was observed in the lymphocytes of mice with CIA. T cell-specific MALT-1 deletion in the induction phase of arthritis (incidence of arthritis, 25% in control mice versus 0% in Malt1 iTcellKO mice; P < 0.05), but not in the effector phase of arthritis, completely protected mice against the development of CIA. Consistent with this finding, MALT-1 deficiency had no impact on CAIA, an effector phase model of RA. Finally, mice with MALT-1 deficiency showed a spontaneous decrease in bone density (mean ± SEM trabecular thickness, 46.3 ± 0.7 μm in control mice versus 40 ± 1.1 μm in Malt1 KO mice; P < 0.001), which was linked to the loss of Treg cells in these mice.Conclusion. Overall, these data in murine models of RA highlight MALT-1 as a master regulator of T cell activation, which is relevant to the pathogenesis of autoimmune arthritis. Furthermore, these findings show that MALT-1 deficiency can lead to spontaneous osteoporosis, which is associated with impaired Treg cell numbers.
Spondyloarthritis (SpA) encompasses a group of diseases characterized by an inflammatory arthritis involving both joints and entheses. However, extraarticular symptoms constitute a large element of the pathology and should not be underestimated. Microscopic gut inflammation is observed in 50% of patients with SpA and has been linked to disease activity, underscoring the effect of gut inflammation in SpA. In this review, we discuss the influence of gut microbiota on SpA pathogenesis. A change in microbiota composition has been linked to the development of various inflammatory arthritides, and dysbiosis is a potential factor in the pathogenesis of multiple inflammatory diseases. In this context, several groups have reported the modulatory effects of gut microbiota-derived metabolites on the effect of immune cells. The gut mucosa is populated by several types of regulatory T cells, but also some specialized unconventional innate-like T cells. These cells are predominantly found at mucosal and epithelial barrier sites, where they serve an essential role in modulating host-microbial interplay. Apart from the close association between the composition of the microbiota and inflammatory diseases, the therapeutic value of dysbiosis needs further investigation, and the identification of a causal inflammatory pathway between gut dysbiosis and musculoskeletal inflammation could revolutionize the therapeutic approach in SpA.
Objective Divergent therapeutic outcomes on different disease domains have been noted with interleukin (IL)-23 and IL-17A-blockade in psoriatic arthritis (PsA). Therefore, elucidating the role of RORγt, the master regulator of type 17 immune responses, is of potential therapeutic interest. To this end, RORγt inhibition was assessed in combined skin, joint and gut inflammation in vivo, using a PsA model. Methods We tested the efficacy of a RORγt antagonist in B10.RIII mice challenged with systemic overexpression of IL-23 by hydrodynamic injection of IL-23 enhanced episomal vector (IL-23 EEV). Clinical outcomes were evaluated by histopathology. Bone density and surface erosions were examined using micro-computed tomography. Cytokine production was measured in serum and by intracellular flow cytometry. Gene expression in PsA-related tissues was analysed by qPCR. Results RORγt-blockade significantly ameliorated psoriasis, peripheral arthritis and colitis development in IL-23 EEV mice (improvement of clinical scores and weight loss respectively by 91.8%, 58.2% and 7.0%, p< 0.001), in line with profound suppression of an enhanced type IL-17 immune signature in PsA-affected tissues. Moreover, inflammation-induced bone loss and bone erosions were reduced (p< 0.05 in calcaneus, p< 0.01 in tibia). Sustained IL-23 overexpression resulted in only mild signs of sacroiliitis. Gamma-delta (γδ)-T cells, the dominant source of T cell-derived IL-17A and IL-22, were expanded during IL-23 overexpression, and together with Th17 cells, clearly countered by RORγt inhibition (p< 0.001). Conclusion RORγt-blockade shows therapeutic efficacy in a preclinical PsA model with protection towards extra-musculoskeletal manifestations, reflected by a clear attenuation of type 17 cytokine responses by γδ-T cells and Th17 cells.
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
BackgroundRheumatoid arthritis (RA) is characterised by the activation of auto-reactive T-cells and the development of auto-antibodies. Importantly, 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 arthritis.The paracaspase MALT1 is a key player in the activation of lymphoid, myeloid and mast cells, indicating MALT1’s crucial role in innate and adaptive signalling. Therefore, MALT1 is regarded a promising target for the treatment of autoimmune diseases and defining its role in the pathogenesis of RA is a critical first step.MethodsTo unravel MALT1’s role in RA, we initially assessed MALT1-activation in mice challenged with collagen-induced arthritis (CIA), the prototype model for RA. We then sought to address MALT1’s role in the pathogenesis of RA by subjecting MALT1-deficient mice to distinct models of arthritis (CIA and CAIA). To determine the importance of MALT1 in T-cells, CIA was additionally induced in CD4-specific MALT1-deficient mice. Finally, the effect of MALT1-deletion on bone homeostasis was assessed by measuring bone density by µCT-analysis of the tibiae and by a three-point bending test of the femurs.ResultsWe provide evidence that MALT1 is activated in RA and plays a crucial role in its pathogenesis since MALT1-deficent mice were completely protected against CIA. This 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. CAIA on the other hand, which is a T-cell independent model of RA, did not depend on MALT1 since both MALT1+/+ and MALT1-/- mice showed comparable arthritis symptoms. Paradoxically to the protective effect of MALT1-deletion on inflammation, we show that MALT1-deficiency negatively influences bone density at steady state. More specifically, both the tibiae and femurs of MALT1-/- mice had a significantly reduced bone density and strength compared to MALT1+/+ mice.ConclusionAltogether, our data provide evidence for a dual role of MALT1 in arthritis, showing a protective effect of its deletion on the inflammatory aspect and a negative effect on bone homeostasis.
BackgroundForce induced microdamage to joint tissue is hypothesized to trigger inflammatory events in the joint leading to arthritis. Patients with inflammatory arthritis, such as rheumatoid arthritis (RA) and spondyloarthritis (SpA), are found to have inflammation in “mechanical hotspots” and mechanical loading in mouse models of these diseases is pro-arthritogenic1,2. To date, the molecular mechanism involved in converting force to a biological signal that promotes arthritis is not known.ObjectivesThis study aims to identify stretch induced genes in synovial fibroblasts, and the effect of these “mechano-sensitive” genes on arthritis.MethodsHuman synovial fibroblasts were stretched in vitro for 4hrs using the FlexCell system and analysed by microarray. Top stretch induced genes were measured in RA, SpA and healthy synovial tissue by qPCR. Patient synovium was further analysed by immunohistochemistry. Bhlhe40 deficient mice were subjected to collagen induced arthritis (CIA) and KBxN serum transfer arthritis (STA). FACS was performed on ankle synovium. uCT was performed on whole ankles, with morphological changes scored by blinded readers, and calcaneus erosions by customs scripts in FIJI.Results600 genes were found to be differentially expressed in stretched synovial fibroblasts (fold change > +/-1.5, adjusted p<0.05). 25% of these genes were found to be transcription factors, which included BHLHE40. BHLHE40 mRNA was elevated in the synovial tissue of RA/SpA vs healthy subjects (1.56 fold change), and BHLHE40 protein was widely detectable in synovial fibroblasts and macrophages (Figure 1). Bhlhe40 deficient mice were completely protected against CIA (incidence: 0% vs 40%, n=30 per group), but Bhlhe40 did not block the generation of anti-collagen antibodies. Bhlhe40 deficient mice were partially protected against STA (peak clinical score at day 7; 5.2 vs 6.8, n=15 per group), with reduced synovial macrophage (CD11b+Ly6G-F4/80+) and neutrophil (CD11b+Ly6G+) frequency observed in the arthritic Bhlhe40 deficient mice compared to wildtype controls. Bhlhe40 had no impact on bone erosions with STA.Figure 1.BHLHE40 is widely expressed in human synovium. Synovium obtained from total knee replacement. FFPE samples were stained for synovial macrophages (HLADR+) and fibroblasts (FAP+). Images acquired with the Zeiss LSM 780.ConclusionBHLHE40 was identified as a force-induced gene in synovial fibroblasts and was found to be upregulated in patients with inflammatory arthritis. Importantly, Bhlhe40 strongly promotes joint inflammation in murine models of arthritis and uncouples systemic autoimmunity from joint tissue inflammation. Thus, we have identified BHLHE40 as a novel regulator of mechanical loading-associated inflammation.References[1]Cambré, I. et al. Mechanical strain determines the site-specific localization of inflammation and tissue damage in arthritis. Nat. Commun.9, 4613 (2018).[2]Jacques, P. et al. Proof of concept: enthesitis and new bone formation in spondyloarthritis are driven by mechanical strain and stromal cells. Ann. Rheum. Dis.73, 437–445 (2014).Disclosure of InterestsNone declared
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