The role of the immune system in arthritis

by Sustackova, Helena

The role of the immune system in arthritis Doctor of Philosophy thesis 1997 by Helena Sustackova Clinical Biochemistry, University of Toronto Rheumatoid arVlritis (RA), which is the most prevalent inflammatory joint disease, is characterized by synovitis, infiltration of inflammatory cells into the joints and degradation of articular cartilage. AIthough RA has been tradiionally considered an autoimmune disease, there is increasing evidence supporting the role of non-antigen driven processes in the disease. Overproduction of cytokines and proteolytic enzymes leading to the destruction of cartilage extracellular matrix, is mostly due to activated synovial &Is and infiltrating macrophages and neutrophils. The main focus of this research was to determine whether antigen driven lymphocyte activation is required for the induction and progression of inflammatory joint disease in animal models, and if so, whether it plays a major role in the disease process. First, we assessed whether lymphocyte stimldation with Mycoplasma afhrifiicrrs superantigen (MAS) by itself or in combination with degenerative joint damage induced by collagenase enzyme, would lead to the development of joint inflammation in BALBIc mice. MAS ii administered intraahcuIarIy did not induce inflammatory joint disease. When administered intraperitoneally in naive mice or mice with collagenase induced arthritis, MAS led to the stimulation of peripheral lymphocytes in BALBIc mice but it did not significantly contribute to joint inflammation. Second, we compared inflammatory joint disease induced by intraarticular zymosan injections in severe combined immunodeficiency (SCID) mice which lack B and T cells with that induced in the parent strain, CB17. We determined that some aspects of inflammatory joint disease, such as synovial hyperplasia, agiogenesis and loss of proteoglycans, can develop in the absence of B and T dls. Third, using SCID mice reconstituted with labelled human peripheral blood leukocytes (hu-SCID), we demonstrated that human cells are able to infiltrate into joints with zymosan induced infiammatory joint disease within 24 hours. This finding indicates that local events in the joint alone are important in triggering cell infiltration in absence of an antigen-driven process. This research supports the importance of non-antigen driven processes in the development of joint inflamm-on in animal models. Given findings from human RA, such as presence of mutations in synovial lining and indentifidion of macrophages as a major source of cytokines in the joints, it is likely that similar processes are prominent in human disease.