Rheumatoid Arthritis (RA) is a devastating and common chronic inflammatory disease that affects approximately 1% of individuals worldwide. In this thesis, we employed two mouse models of arthritis to further understand inflammatory mechanisms that contribute to disease during early and late responses in RA. In one model, Collagen-Induced Arthritis (CIA), mice were administered intradermal immunizations of type II collagen with Complete Freund’s adjuvant (CFA) which generates potent anti-collagen B-cell and T-cell responses making this model autoimmune in nature. In the second model, a transgenic mouse line for human TNF-α (Tg197) was utilized to study the downstream events that occur after the initiation of arthritis. Tg197 mice develop severe spontaneous arthritis due to the systemic overexpression of the proinflammatory cytokine TNF-α, which is independent of B-cell and T-cell responses. Use of these mouse models allows examination of: (i) factors that influence immunopathologic B-cell and T-cell responses to collagen and cross-reactivity to collagen-rich joints; and (ii) mechanism(s) downstream of adaptive immune responses that control disease progression and histopathology that are dependent on TNF-α.
Previous work has suggested a novel mediator, Angiopoietin-like 4 (Angptl4), as having a regulatory role on collagen-specific adaptive immune responses in the CIA model. The present studies were designed to investigate our main hypothesis that Angptl4 plays a protective role in arthritis. Specifically, the role of Angptl4 was investigated during the acute phase of disease (CIA), and during downstream events that occur during the latent phase (Tg197 Cytokine-Driven Model).
Upon the induction of CIA, Angptl4-deficient female mice exhibited increased disease incidence and severity of arthritis. However, this phenomenon was not observed in wildtype females or in Angptl4-deficient or wildtype male mice. Microscopic arthritis was also increased in female Angptl4-deficient mice that parallel macroscopic disease observations. Since CIA is an adaptive immune response driven model of arthritis, we hypothesized that Angptl4 is influencing autoreactive T-cell and B-cell responses. In CIA, female Angptl4-deficient mice present increased anti-CII antibody levels, specifically IgG2a, as compared to female wildtype mice. Additionally, female Angptl4-deficient mice exhibited increased spleen cell responses, including splenocyte proliferation and IFN-γ production to CII during the early initiation of arthritis. In a cytokine-driven model of arthritis, Angptl4-deficient male mice exhibited a significant increase in macroscopic disease over wildtype mice. However, upon histological examination, arthritic disease is comparable between Angptl4-deficient and wildtype mice. Additionally, MMP expression along with endothelial staining for angiogenesis was similar between Angptl4-deficient and wildtype mice.
In summary, the data acquired in this thesis suggests that Angptl4 plays a protective role in arthritis, particularly in models that are dependent on adaptive immunity. Our data indicate that a genetic-induced deficiency of Angptl4 renders female mice more susceptible to CIA and causes a more severe disease phenotype, greater disease frequency, and increased histopathology as compared to their wildtype counterparts. These results suggest that Angptl4 is involved in autoimmune components of the pathogenesis of disease and may be a major factor in the female preponderance of autoimmune arthritis, including RA.