Mature dendritic cells readily break tolerance in normal mice but do not lead to disease expression.

OBJECTIVE: To examine the ability of mature dendritic cells (DCs) or macrophages intentionally exposed to lipopolysaccharide or apoptotic or necrotic cells to break tolerance in normal mice. METHODS: We adoptively transferred into C57BL/6 mice a variety of syngeneic myeloid antigen-presenting cell populations exposed to different activation stimuli as well as to meals of necrotic and apoptotic cells. We studied expression of autoimmunity in the immunized mice by serologic evaluation of autoantibody production, subclass analysis of Ig production, clinical evidence of kidney disease, glomerular immune complex deposition, and renal pathology. RESULTS: Injection of mice with DCs incubated with apoptotic or necrotic cells, as well as, surprisingly, with DCs cultured in media alone, induced high levels of IgG autoantibodies, including anti-double-stranded DNA (anti-dsDNA) antibodies. In striking contrast, transfer of equivalent-treated macrophages failed to generate IgG autoantibodies. IgG was deposited in the kidneys of mice vaccinated with DCs, but despite high levels of anti-dsDNA antibodies, these mice did not develop overt nephritis. Serologic evaluation of the antibody response revealed that the mice primarily developed elevated levels of IgG1 antibodies, including high levels of IgG1 anti-dsDNA. CONCLUSION: The data suggest that mature myeloid DCs are able to break tolerance and induce lupus autoantibodies in normal hosts, but that other susceptibility factors must be in place to induce long-lasting autoimmunity and clinical expression of disease.

Impaired T cell death and lupus-like autoimmunity in T cell-specific adapter protein-deficient mice.

T cell-specific adaptor protein (TSAd) is a T lineage-restricted signaling adaptor molecule that is thought to participate in the assembly of intracellular signaling complexes in T cells. Previous studies of TSAd-deficient mice have revealed a role for TSAd in the induction of T cell interleukin 2 secretion and proliferation. We now show that TSAd-deficient mice are susceptible to lupus-like autoimmune disease. On the nonautoimmune-prone C57BL/6 genetic background, TSAd deficiency results in hypergammaglobulinemia that affects all immunoglobulin (Ig)G subclasses. Older C57BL/6 TSAd-deficient mice (1 yr of age) accumulate large numbers of activated T and B cells in spleen, produce autoantibodies against a variety of self-targets including single stranded (ss) and double stranded (ds) DNA, and, in addition, develop glomerulonephritis. We further show that immunization of younger C57BL/6 TSAd-deficient mice (at age 2 mo) with pristane, a recognized nonspecific inflammatory trigger of lupus, results in more severe glomerulonephritis compared with C57BL/6 controls and the production of high titer ss and ds DNA antibodies of the IgG subclass that are not normally produced by C57BL/6 mice in this model. The development of autoimmunity in TSAd-deficient mice is associated with defective T cell death in vivo. These findings illustrate the role of TSAd as a critical regulator of T cell death whose absence promotes systemic autoimmunity.