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.71 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-10.71,79 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.80 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.89 In contrast, the prolonged presence of the cytokines, IL-1, IL-10, TNFα, TGFβ and IL-6 are detected in the joints.88,89

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.