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

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Abstract
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 LTα‐deficient and wild‐type C57BL/6 mice were immunized with CII. Male DBA/1 mice were immunized with CII and treated with LTβ receptor immunoglobulin fusion protein (LTβR‐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 LTα‐deficient mice was more severe and prolonged than that which developed in wild‐type mice. Blocking LT signaling with LTβR‐Ig significantly exacerbated the disease. Exacerbation of CIA was associated with an enhanced Th1‐type response, including increased type 1 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.