Progress in spondylarthritis. Immunopathogenesis of spondyloarthritis: which cells drive disease?

Spondyloarthritides, or SpA, form a cluster of chronic inflammatory diseases with the axial skeleton as the most typical disease localisation, although extra-articular manifestations such as intestinal inflammation may frequently occur during the course of the disease. This review summarises recent progress in our understanding of the immunopathogenesis of SpA with special emphasis on the cellular constituents considered to be responsible for the initiation and/or perpetuation of inflammation. There are several arguments favouring a role for haematopoietic cells in the pathophysiology of spondyloarthritis, including HLA-B27-associated dendritic cell disturbances, HLA-B27 misfolding properties and T helper 17 cells. In addition, recent studies have pointed toward a pivotal role for stromal cells. A major challenge, however, remains to determine how recently identified genetic associations such as interleukin-23 receptor polymorphisms may influence cellular targets in spondyloarthritis

Systemic levels of IL-23 are strongly associated with disease activity in rheumatoid arthritis but not spondyloarthritis

Objectives Th17 cells are an effector T-cell population that plays a role in chronic inflammatory conditions and is dependent on IL-23 for their survival and expansion. More recently, a genetic association was discovered between polymorphisms in the gene coding for the IL-23 receptor and spondyloarthritis. This study aimed to evaluate the role of Th17-associated cytokines in spondyloarthritis pathogenesis by measuring their levels in the joints and circulation as well as correlating them with disease activity parameters. Methods Paired synovial fluid (SF), serum and synovial biopsies were obtained from 30 non-PsA (psoriatic arthritis) spondyloarthritis, 22 PsA and 22 rheumatoid arthritis (RA) patients. IL-17, IL-23 and CCL20 were measured by ELISA in the SF and serum of patients and correlated with systemic and local parameters of disease activity. Results Concentrations of CCL20, a major Th17-attracting chemokine, tended to be higher in the joints of RA than in spondyloarthritis patients. Interestingly, levels of CCL20 were markedly higher in SF as opposed to serum. In addition, there was a remarkable association between the expression of the Th17 cytokine system and the presence of intimal lining layer hyperplasia in RA. Also in the serum, there was a tendency for higher IL-23 levels in RA, which correlated strongly with disease activity parameters. Conclusions Th17-related cytokines are expressed in joints of spondyloarthritis as well as RA patients. IL-23 levels, however, correlate with disease activity parameters in RA only. These results point towards a differential regulation of the Th17 cytokine system in spondyloarthritis compared with RA

Differential mucosal expression of Th17-related genes between the inflamed colon and ileum of patients with inflammatory bowel disease

<p>Abstract</p> <p>Background</p> <p>Immunological and genetic findings implicate Th17 effector cytokines in the pathogenesis of inflammatory bowel disease (IBD). Expression of Th17 pathway-associated genes is mainly studied in colonic disease. The present study assessed the mRNA expression levels of Th17 effector cytokines (<it>IL17A</it>, <it>IL17F</it>, <it>IL21</it>, <it>IL22 </it>and <it>IL26</it>) and genes involved in differentiation (<it>IL6</it>, <it>IL1B</it>, <it>TGFB1</it>, <it>IL23A </it>and <it>STAT3</it>) and recruitment of Th17 cells (<it>CCR6 </it>and <it>CCL20</it>) by quantitative real-time PCR analysis of colonic and ileal biopsies from 22 healthy control subjects, 26 patients with Crohn's disease (CD) and 12 patients with ulcerative colitis (UC). Inflammation was quantified by measuring expression of the inflammatory mediators <it>IL8 </it>and <it>TNF</it>.</p> <p>Results</p> <p>Evaluation of mRNA expression levels in colonic and ileal control samples revealed that <it>TNF</it>, <it>TGFB1</it>, <it>STAT3 </it>and <it>CCR6 </it>were expressed at higher levels in the ileum than in the colon. Expression of all the Th17 pathway-associated genes was increased in inflamed colonic samples. The increased expression of these genes was predominantly observed in samples from UC patients and was associated with more intense inflammation. Although increased expression of <it>IL17A</it>, <it>IL17F</it>, <it>IL21 </it>and <it>IL26 </it>was detected in inflamed ileal samples, expression of the indispensable Th17 cell differentiation factors <it>TGFB1 </it>and <it>IL23A</it>, the signaling molecule <it>STAT3 </it>and the Th17 recruitment factors <it>CCR6 </it>and <it>CCL20 </it>were unchanged.</p> <p>Conclusions</p> <p>Our findings suggest that immune regulation is different in colonic and ileal disease, which might have important consequences for therapeutic intervention.</p

Senescence marker killer cell lectin-like receptor G1 (KLRG1) contributes to TNF-α production by interaction with its soluble E-cadherin ligand in chronically inflamed joints

Objectives: Killer cell lectin-like receptor G1 (KLRG1) is an NK cell marker also expressed on T cells showing an immunosenescent phenotype. KLRG1 binding to its ligand E-cadherin inhibits functional responses. It was recently shown that soluble E-cadherin (sE-cadherin) also influences KLRG1 signalling, although its involvement in arthritis is unknown. Our goal was to evaluate the contribution of KLRG1(+) T cells to synovitis. Methods: Paired peripheral blood (PB) and synovial fluid (SF) mononuclear cells from 21 patients with spondyloarthritis (SpA) or rheumatoid arthritis (RA), eight with crystal-induced arthritis and 10 controls were obtained. T cells were characterised for KLRG1 expression directly ex vivo, while TNF-alpha/IFN-gamma production was assessed after polyclonal stimulation. Assays of chemotaxis response towards SF were conducted. Additionally, sE-cadherin levels in our paired samples were determined. Moreover, TNF-alpha/IFN-gamma production by antigen-specific T cells was evaluated in the presence of sE-cadherin. Results: KLRG1(+) T cells were enriched in SF as opposed to PB of SpA and RA patients, which contrasts with results obtained in crystal-induced arthritides. KLRG1(+) T cells were more functionally active as opposed to KLRG1-T cells and migrated preferentially towards SpA and RA SF. sE-cadherin levels were higher in SF versus plasma. The presence of sE-cadherin enhanced the number of KLRG1(+) CD4(+) T cells able to produce TNF-alpha but not IFN-gamma. Conclusions: sE-cadherin contributes to the local proinflammatory environment in the joint by favouring TNF-a production by KLRG1(+) CD4(+) T cells. This pathway seems to be operational in both SpA and RA, but not in crystal-induced arthritis

In Vitro Spontaneous Osteoclastogenesis of Human Peripheral Blood Mononuclear Cells Is Not Crucially Dependent on T Lymphocytes

Objective. In vitro spontaneous osteoclastogenesis from peripheral blood mononuclear cells (PBMCs) is increased in diseases with excessive bone loss. The purpose of this study was to reassess the role of T lymphocytes in this process. Methods. Fresh or cryopreserved PBMCs obtained from healthy subjects and from patients with rheumatoid arthritis, psoriatic arthritis, and non-psoriatic spondyllarthritis were cultured at high density and stained for tartrate-resistant acid phosphatase (TRAP). Resorption of mineralized matrix was assessed by a dentin disc assay. CD14+ monocytes and CD3+ T cells were selected using magnetically labeled antibodies. Results. Numerous multinucleated, TRAP+, dentin-resorbing osteoclasts developed spontaneously from fresh PBMCs from healthy individuals. This process was abrogated by T cell depletion and was restored by exogenous macrophage colony-stimulating factor (M-CSF) and RANKL, indicating the important role of T cells in spontaneous osteoclastogenesis in vitro. Using physiologic freezing and thawing as a model for the activation of PBMCs, spontaneous osteoclastogenesis was significantly increased in cryopreserved versus fresh cells. Under these conditions, spontaneous osteoclastogenesis was not dependent on T lymphocytes, since it was not influenced by T cell depletion and persisted in purified CD14+ cell cultures supplemented with M-CSF and RANKL. In contrast to studies with fresh PBMCs, spontaneous osteoclastogenesis under these conditions did not appear to be clearly different between healthy subjects and patients with arthritis. Conclusion. Spontaneous osteoclastogenesis in vitro is dependent on T lymphocytes or on the direct activation of monocytic cells, depending on the test conditions. This variability warrants better validation of the relevance of this functional test for in vivo osteoclastogenesi