Cellular-based immune modulation in arthritis

Abstract

While the symptoms associated with rheumatoid arthritis (RA) are well described, the factors that are crucially involved in induction and/or progression of RA are poorly defined. Nonetheless, it is generally accepted that cells belonging to the adaptive immune system (i.e. B cells and T cells) are intimately engaged in the processes responsible for RA induction and/or progression. As these cells require triggering of their antigen receptors before they can exert their functions, it is likely that antigen recognition is important in the pathological processes driving RA. Unfortunately, no antigens casually related to the induction/perpetuation of RA are known. Nonetheless, studies addressing the question of how immunity against autoantigens is regulated, combined with studies aiming at defining the molecular identity of antigens involved in disease, will be important to gain a better understanding of the pathways involved in the induction/progression of RA. Recently, we have found that CD4+CD25+regulatory T cells play a pivotal role in the control of arthritis in mice. More importantly, treatment of established arthritis by adoptive transfer of these cells stopped further progression of disease. These data indicate the feasibility to inhibit ongoing disease by specific manipulation of the immune system. The data described also indicate that the class of immune response against autoantigens could profoundly influence the susceptibility for, and/or outcome of, autoimmune responses. However, until now, there has been only limited evidence for autoantigen-specific regulatory responses in humans. Here we analyzed the natural immune response against Human Cartilage gp39 (HC-Gp39), a candidate autoantigen in RA. Peripheral blood mononuclear cells from healthy individuals reacted against HC Gp39 with the production of IL-10, but not interferon gamma. Ex vivo assays indicated that the natural occurring HC Gp39-directed immune response in bulk is capable of suppressing cytotoxic T-cell and recall responses, indicating that, rather than being unresponsive, the HC Gp39-directed immune response in healthy individuals is biased towards a regulatory phenotype. Moreover, CD4+ T-cell lines directed against HC Gp39 expressed CD25, GITR, CTLA-4 and Foxp3 molecules and were capable of suppressing other immune responses. Cell–cell contact was required for this suppression. In contrast, the quality of the HC Gp39-directed immune response in patients with RA exhibits polarization toward a proinflammatory Th1 phenotype. Together these findings indicate that the presence of HC Gp39-specific immune responses in healthy individuals may have a profound inhibitory effect on inflammatory responses in areas were HC Gp39 is present, and imply that the balance of autoreactive proinflammatory and antiinflammatory HC Gp39-directed immune responsiveness is disrupted in RA patients.