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Objective Divergent therapeutic outcomes on different disease domains have been noted with IL-23 and IL-17A-blockade in 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 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.

ObjectivesGut and joint inflammation commonly co-occur in spondyloarthritis (SpA) which strongly restricts therapeutic modalities. The immunobiology underlying differences between gut and joint immune regulation, however, is poorly understood. We therefore assessed the immunoregulatory role of CD4+FOXP3+regulatory T (Treg) cells in a model of Crohn’s-like ileitis and concomitant arthritis.MethodsRNA-sequencing and flow cytometry was performed on inflamed gut and joint samples and tissue-derived Tregs from tumour necrosis factor (TNF)∆AREmice. In situ hybridisation of TNF and its receptors (TNFR) was applied to human SpA gut biopsies. Soluble TNFR (sTNFR) levels were measured in serum of mice and patients with SpA and controls. Treg function was explored by in vitro cocultures and in vivo by conditional Treg depletion.ResultsChronic TNF exposure induced several TNF superfamily (TNFSF) members (4-1BBL, TWEAK and TRAIL) in synovium and ileum in a site-specific manner. Elevated TNFR2 messenger RNA levels were noted in TNF∆ARE/+mice leading to increased sTNFR2 release. Likewise, sTNFR2 levels were higher in patients with SpA with gut inflammation and distinct from inflammatory and healthy controls. Tregs accumulated at both gut and joints of TNF∆AREmice, yet their TNFR2 expression and suppressive function was significantly lower in synovium versus ileum. In line herewith, synovial and intestinal Tregs displayed a distinct transcriptional profile with tissue-restricted TNFSF receptor and p38MAPK gene expression.ConclusionsThese data point to profound differences in immune-regulation between Crohn’s ileitis and peripheral arthritis. Whereas Tregs control ileitis they fail to dampen joint inflammation. Synovial resident Tregs are particularly maladapted to chronic TNF exposure.

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 time-dependent effects of MALT-1 deficiency were assessed in mice with deletion of tamoxifen-inducible T cell-specific 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 mu m in control mice versus 40 +/- 1.1 mu m 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.

Background Rheumatoid 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. Methods To 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. Results We 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. Conclusion Altogether, 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.