[show abstract][hide abstract] ABSTRACT: To investigate the role of inducible costimulator (ICOS) in the pathogenesis of SLE, we assessed its expression on peripheral blood CD4 and CD8 T cells and functional roles in patients with systemic lupus erythematosus (SLE).
Expression of ICOS on peripheral blood CD4 and CD8 T cells and ICOS ligand (ICOSL) on peripheral blood CD19 B cells from patients with SLE, patients with rheumatoid arthritis (RA) and healthy volunteers were determined by two-colour flow cytometry. The functional costimulatory effects of ICOS on peripheral blood mononuclear cells (PBMC) were assessed by T-cell proliferative responses, cytokines, anti-double-stranded DNA (anti-dsDNA) antibody and total IgG production.
Peripheral blood CD4 and CD8 T cells expressing ICOS were significantly increased in patients with SLE compared with patients with RA and healthy subjects. Peripheral blood CD19 B cells expressing ICOSL in SLE were markedly reduced compared with RA. Proliferative responses of anti-CD3/ICOS costimulation were significantly higher than those of anti-CD3/hamster IgG (HIgG) in healthy subjects, but not in patients with SLE. Anti-CD3/ICOS-stimulated SLE PBMC secreted similar levels of IL-10 and IFN-gamma but a significantly lower level of IL-2 than healthy PBMC. Anti-CD3/ICOS-mediated costimulation significantly enhanced the production of anti-dsDNA antibodies and total IgG in patients with SLE.
Hyperexpression of ICOS on peripheral blood CD4 and CD8 T cells from patients with SLE contributed to the dysregulated T-cell proliferation, T-cell activation and pathogenic autoantibody production, which showed that the abnormality of ICOS costimulation may play an immunopathological role(s) in the pathogenesis of SLE.
[show abstract][hide abstract] ABSTRACT: Experimental autoimmune myocarditis (EAM) has been used as a model for human myocarditis in relation to the autoimmune mechanism and proved as a T cell-mediated autoimmune disease. Interaction of T cell receptors (TCR) with its ligand peptide-MHC complex on APCs is critical for antigen-specific T cell activation under physiological and pathological conditions. CIITA is a transcriptional coactivator that functions as a key regulatory factor for MHC-II expression. To achieve effective inhibition of interaction of TCR and peptide-MHC-II complex, adenovirus vectors containing antisense CIITA were constructed and their effects in preventing EAM were examined. Ad-CIITA was injected intravenously into mice on days 0-2 or 14-16 after myosin immunization to study the preventive effects on EAM in the T cell activation phase or inflammatory phase. Disease severity was determined by the microscopic grade of heart check, concentration of plasma cTnI, and cellular and humoral immune responses on day 21. Results show that onset of EAM after Ad-CIITA treatment on days 0-2 was almost completely inhibited and antigen-specific lymphocyte proliferation was significantly reduced in adenovirus treatment group, which demonstrate that this adenovirus vector inhibit auto-responsive T cells activation and proliferation. Moreover, compared with EAM mice, even administered on days 14-16, the Ad-CIITA treated mice achieved significant reduction in disease severity. It indicates the therapeutic potential of blocking T cells activation by gene-transfer in myocarditis.
Journal of Molecular and Cellular Cardiology 05/2005; 38(4):593-605. · 5.15 Impact Factor