The genetic and immunopathological processes underlying collagen-induced arthritis

Abstract

Animal models of rheumatoid arthritis (RA) have provided substantial insights into basic pathogenic mechanisms of chronic inflammatory arthritis and autoimmune disease in general. Of the variety of models reported, collagen-induced arthritis (CIA) has been the most characterized in terms of both its pathogenesis and its underlying immunological basis. Collagen-induced arthritis has also been the model of choice in terms of testing potential new therapeutic agents for the treatment of human RA. Nevertheless, the complex nature of the balance between T-cell cytokines and the chronic inflammatory processes is only recently becoming clear. This review focuses on these developments, highlighting their implications for our understanding of RA and for the use of CIA as a suitable animal model.

Figure 1

The temporal relationship between cytokine production and disease in CIA in the DBA/1 mouse. Studies of cytokine production and assays for the presence of mRNA have indicated that the initial response following CII/CFA challenge is dominated by a Th1 response, with IFN-γ being readily detectable in the lymph nodes, and basal levels of endogenous IL-4 and IL-10 being markedly reduced. Around the time of clinical disease onset, the IFN-γ response begins to decline, concomitant with an increase in the levels of IL-4 and IL-10., The production of IL-10 increases to above prechallenge levels and is maintained. The Th1 response in the lymph nodes is matched by the presence of high level IL-12 production by cells in the spleen and peritoneal cavity. Analysis of cytokine production in the joints has revealed that IFN-γ is only present for a limited period around the time of disease onset, while IL-2, IL-4 and IL-5 are undetectable. In contrast, the prolonged presence of the cytokines, IL-1, IL-10, TNFα, TGFβ and IL-6 are detected in the joints.,

Figure 2

A model for the establishment of CIA in H-2^q mice. Under the influence of components of mycobacteria in the CFA, the T-cell response to injected CII develops in the lymph nodes draining the site of challenge. This influence leads to the differentiation of naïve T cells into Th1 cells which then produce IFN-γ; in turn, this acts as an isotype switch factor favouring the production of IgG2a by activated CII-specific B cells. IgG2a antibodies enter the joint and upon binding to CII activate complement which triggers the activation of blood vessel endothelium, facilitating the early entry of activated T cells, monocytes (mφ) and neutrophils (nφ). The activation of macrophages by Th1 cell cytokine production causes the release of TNF-α, further fuelling migration from the blood into the joint space. Inside the joint, the production of IL-1 acts as the primary factor to trigger tissue destruction by infiltrating cells and resident synoviocytes, fibroblasts and chondrocytes. Consequent release of joint antigens and inflammatory mediators triggers a positive feedback circuit which continues to drive the disease process even after the numbers of T cells decline.