Antitumor Immune Responses Trigger Autoimmune Disease

The chronic autoimmune disease scleroderma is characterized by systemic tissue fibrosis in the skin, vasculature, and internal organs in response to autoantibodies against proteins including the DNA-directed RNA polymerase III subunit RPC1. Intriguingly, patients with RPC1 autoantibodies exhibit an increased risk of developing cancer, which is often temporally correlated with the diagnosis of scleroderma, suggesting a potential mechanistic link between these two diseases. Joseph and colleagues hypothesized that an immune response directed against tumor antigens might trigger the development of scleroderma in this particular subset of patients. Consistent with this idea, somatic missense mutations in the gene encoding RPC1, POLR3A, were identified in 3 of 8 patients with antibodies against RPC1, all of whom developed cancer prior to or shortly after the onset of scleroderma, but not in patients with autoantibodies against other proteins. In addition, LOH of the region containing POLR3A was specifically detected in 5 patients with RPC1 autoantibodies, including 3 patients lacking POLR3A mutations, suggestive of selective pressure against these mutations during tumor growth. Tumor-associated POLR3A mutations stimulated activation of distinct mutant RPC1–reactive CD4⁺ T-cell clones in the peripheral blood of 2 of 3 patients, suggesting that this tumor antigen initiates a cellular immune response. In addition, RPC1 antibodies from patients with POLR3A mutations were not specific to mutant RPC1 but instead recognized both the wild-type and mutant RPC1 proteins equivalently, indicative of a cross-reactive humoral immune response that can injure normal tissues and induce scleroderma. These findings suggest that cancer-associated mutations initiate an antitumor immune response that contributes to the development of autoimmune disease in this subset of patients. Moreover, these results support the notion that active immune responses such as immunoediting are required to protect against tumor formation.

Joseph CG, Darrah E, Shah AA, Skora AD, Casciola-Rosen LA, Wigley FM, et al. Association of the autoimmune disease scleroderma with an immunologic response to cancer. Science 2014;343:152–7.

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