Blockade of lymphotoxin pathway exacerbates autoimmune arthritis by enhancing the Th1 response

Objective. To study the role of the lymphotoxin (LT) signaling pathway in the development and pathogenesis of collagen-induced arthritis (CIA), and to understand the mechanisms by which blockade of the LT pathway influences the arthritogenic response to type II collagen (CII). Methods. LT alpha-deficient and wild-type C57BL/6 mice were immunized with CII. Male DBA/1 mice were immunized with CH and treated with LT beta receptor immunoglobulin fusion protein (LT beta R-Ig) or control Ig. Mice were monitored for the development and severity of arthritis. The effects of LT blockade on immune responses were evaluated by cytokine production and antigen-specific proliferation in vitro, the delayed-type hypersensitivity (DTH) response, and serum levels of CII-specific antibodies. Results. CIA that developed in LT alpha-deficient mice was more severe and prolonged than that which developed in wild-type mice. Blocking LT signaling with LT beta R-Ig significantly exacerbated the disease. Exacerbation of CIA was associated with an enhanced Th1-type response, including increased type I cytokine production, an enhanced DTH response, and elevated production of CII-specific IgG2a antibodies. Conclusion. Blockade of the LT signaling pathway exacerbates the development and progression of CIA, probably by skewing the Th1/Th2 balance that determines the outcome of autoimmune responses.