Abstract
Collagen-induced arthritis (CIA), an approved animal model for rheumatoid arthritis, is thought to be a T cell-dependent disease. There is evidence that CD8+ T cells are a major subset controlling the pathogenesis of CIA. They probably contribute to certain features of disease, namely tissue destruction and synovial hyperplasia. In this study we examined the role of perforin (pfp), a key molecule of the cytotoxic death pathway that is expressed mainly in CD8+ T cells, for the pathogenesis of CIA. We generated DBA/1J mice suffering from mutations of the pfp molecule, DBA/1J-pfp-/-, and studied their susceptibility to arthritis. As a result, pfp-deficient mice showed a reduced incidence (DBA/1J-pfp+/+, 64%; DBA/1J-pfp-/-, 54%), a slightly delayed onset (onset of disease: DBA/1J-pfp+/+, 53 ± 3.6; DBA/1J-pfp-/-, 59 ± 4.9 (mean ± SEM), and milder form of the disease (maximum disease score: DBA/1J-pfp+/+, 7.3 ± 1.1; DBA/1J-pfp-/-, 3.4 ± 1.4 (mean ± SEM); P < 0.05). Concomitantly, peripheral T cell proliferation in response to the specific antigen bovine collagen II was increased in pfp-/- mice compared with pfp+/+ mice, arguing for an impaired killing of autoreactive T cells caused by pfp deficiency. Thus, pfp-mediated cytotoxicity is involved in the initiation of tissue damage in arthritis, but pfp-independent cytotoxic death pathways might also contribute to CIA.
Highlights
Collagen-induced arthritis (CIA) is an experimental model of arthritis inducible in susceptible strains of mice, for example DBA1/J, by immunization with bovine collagen type II (CII) in complete Freund's adjuvant (CFA) [1,2,3,4]
The development of CIA is known to depend on T cells, and disease susceptibility is linked to the major histocompatibility complex (MHC) region [5]
Some of the main features of disease are synovial hyperplasia and mononuclear cell infiltration. Factors contributing to this phenomenon are unknown; an imbalance between rates of cell proliferation and cell death has been suggested by recent studies of rheumatoid synovium demonstrating that apoptosis of synovial cells and infiltrating lymphocytes was common in situ [10,11]
Summary
Collagen-induced arthritis (CIA) is an experimental model of arthritis inducible in susceptible strains of mice, for example DBA1/J, by immunization with bovine collagen type II (CII) in complete Freund's adjuvant (CFA) [1,2,3,4]. Some of the main features of disease are synovial hyperplasia and mononuclear cell infiltration. Apoptosis is involved in development and in the negative selection of lymphocytes. It is crucial in downregulating immune responses to foreign antigens. Cytotoxic T lymphocytes and other killer cells can eliminate their targets by the induction of cell death All of these functions are primarily mediated through the receptors Fas/ APO-1, tumor necrosis factor receptor 1 (TNFR1; p55 TNFR) and the perforin (pfp)/granzyme pathway [12,13]
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