CD5 Plays an Inhibitory Role in the Suppressive Function of Murine CD4\u3csup\u3e+\u3c/sup\u3e CD25\u3csup\u3e+\u3c/sup\u3e T\u3csub\u3ereg\u3c/sub\u3e Cells

A subset of CD4+ T cells, the CD4+ CD25+ regulatory T (Treg) cells in the lymphoid organs and peripheral blood are known to possess suppressive function. Previous in vitro and in vivo studies have indicated that T cell receptor (TCR) signal is required for development of such ‘natural regulatory (Treg) cells’ and for activation of the effector function of CD4+ CD25+ regulatory T cells. CD5 is a cell surface molecule present on all T cells and a subtype of B lymphocytes, the B-1 cells, primarily localized to coelomic cavities, Peyer\u27s patches, tonsils and spleen. CD5 acts as a negative regulator of T cell and B cell signaling via recruitment of SHP-1. Here, we demonstrate that Treg cells obtained from CD5−/− mice are more potent than those from wild type mice in suppressing the in vitro cell proliferation of anti-CD3 stimulated CD4+ CD25− responder T cells. This phenomenon was cell contact and GITR dependent. Lack of CD5 expression on Treg cells (from spleen, lymph node and thymus) did not affect the intracellular levels of Foxp3. However, CD5−/− Tregthymocytes were able to elicit a higher Ca2+ response to TCR + co-stimulatory signals than the wild type cells. CD5−/− mice expressed more Foxp3 mRNA in the colon than wild type mice, and additionally, the severity of the dextran sulfate sodium (DSS)-induced colitis in CD5−/− mice was less than the wild type strain. We suggest that manipulation of CD5 expression or the downstream signaling components of CD4+ CD25+ Treg cells as a potential strategy for therapeutic intervention in cases of auto-immune disorders

Multifactorial Patterns of Gene Expression in Colonic Epithelial Cells Predict Disease Phenotypes in Experimental Colitis

Background— The pathogenesis of inflammatory bowel disease (IBD) is complex and the need to identify molecular biomarkers is critical. Epithelial cells play a central role in maintaining intestinal homeostasis. We previously identified five “signature” biomarkers in colonic epithelial cells (CEC) that are predictive of disease phenotype in Crohn\u27s disease. Here we investigate the ability of CEC biomarkers to define the mechanism and severity of intestinal inflammation. Methods— We analyzed the expression of RelA, A20, pIgR, tumor necrosis factor (TNF), and macrophage inflammatory protein (MIP)-2 in CEC of mice with dextran sodium sulfate (DSS) acute colitis or T-cell-mediated chronic colitis. Factor analysis was used to combine the five biomarkers into two multifactorial principal components (PCs). PC scores for individual mice were correlated with disease severity. Results— For both colitis models, PC1 was strongly weighted toward RelA, A20, and pIgR, and PC2 was strongly weighted toward TNF and MIP-2, while the contributions of other biomarkers varied depending on the etiology of inflammation. Disease severity was correlated with elevated PC2 scores in DSS colitis and reduced PC1 scores in T-cell transfer colitis. Downregulation of pIgR was a common feature observed in both colitis models and was associated with altered cellular localization of pIgR and failure to transport IgA. Conclusions— A multifactorial analysis of epithelial gene expression may be more informative than examining single gene responses in IBD. These results provide insight into the homeostatic and proinflammatory functions of CEC in IBD pathogenesis and suggest that biomarker analysis could be useful for evaluating therapeutic options for IBD patients

Original Article Prevalence of metabolic syndrome in women with rheumatoid arthritis and effective factors

Abstract: Purpose: Metabolic syndrome (MS), which is framed by cardiovascular risk factors such as hypertension, obesity, glucose intolerance and dyslipidemia, is thought to be associated with the rheumatic diseases

Bone Marrow Dendritic Cell-Mediated Regulation of TLR and B Cell Receptor Signaling in B Cells

Dendritic cells (DCs) play an essential role in regulation of immune responses. In the periphery, Ag presentation by DCs is critical for adaptive responses; for this reason, DCs are often targets of adjuvants that enhance vaccine responses. Activated mature DCs enhance B cell activation and differentiation by providing cytokines like BAFF and a proliferation-inducing ligand. However, the role of immature DCs in B cell tolerance is not well studied. Recently, mouse immature bone marrow-derived DCs (iBMDCs) have been shown to suppress anti-IgM–induced B cell activation. In this study, we tested the ability of mouse DCs to modulate B cell functions during TLR activation. We found that iBMDCs potently suppressed proliferation and differentiation of various B cell subsets on TLR stimulation. However, iBMDCs did not affect CD40-mediated B cell activation. Optimal suppression of B cell activation by iBMDCs required cell contact via the CD22 receptor on B cells. The B cell suppression was a property of iBMDCs or DCs resident in the bone marrow (BM), but not mature BM-derived DCs or DCs resident in the spleen. Presence of iBMDCs also enhanced the Ag-induced apoptotic response of BM B cells, suggesting that the suppressive effects of iBMDCs may have a role in B cell tolerance

Regulation of the Mucosal Phenotype in Dendritic Cells by PPARγ: Role of Tissue Microenvironment

Mucosal DCs play a critical role in tissue homeostasis. Several stimuli can induce a mucosal phenotype; however, molecular pathways that regulate development of mucosal DC function are relatively unknown. This study sought to determine whether PPARγ contributes to the development of the “mucosal” phenotype in mouse DCs. Experiments demonstrated that PPARγ activation in BMDCs induced an immunosuppressive phenotype in which BMDCs had reduced expression of MHC class II and costimulatory molecules, increased IL‐10 secretion, and reduced the ability to induce CD4 T cell proliferation. Activation of PPARγ enhanced the ability of BMDC to polarize CD4 T cells toward iTregs and to induce T cell expression of the mucosal homing receptor, CCR9. Activation of PPARγ increased the ability of BMDCs to induce T cell‐independent IgA production in B cells. BMDCs from PPARγΔDC mice displayed enhanced expression of costimulatory molecules, enhanced proinflammatory cytokine production, and decreased IL‐10 synthesis. Contrary to the inflammatory BMDC phenotype in vitro, PPARγΔDC mice showed no change in the frequency or phenotype of mDC in the colon. In contrast, mDCs in the lungs were increased significantly in PPARγΔDC mice. A modest increase in colitis severity was observed in DSS‐treated PPARγΔDC mice compared with control. These results indicate that PPARγ activation induces a mucosal phenotype in mDCs and that loss of PPARγ promotes an inflammatory phenotype. However, the intestinal microenvironment in vivo can maintain the mucosal DC phenotype of via PPARγ‐independent mechanisms