Although the mechanisms of the autoimmune rheumatic diseases remain incompletely understood, there is a striking association of autoimmune responses against specific antigens with distinct clinical phenotypes. In some instances, specific immune responses are associated with an increased prevalence of cancer, with the diagnosis of both processes frequently occurring within a short time. For example, scleroderma patients with antibodies against the large subunit of RNA polymerase-3 (POLR3A, RPC1) have an increased prevalence of cancer, which is frequently coincident with the onset of severe, diffuse scleroderma.
In cancers from scleroderma patients, we have found genetic alterations of the POLR3A locus in six of eight patients with antibodies to RPC1 but not in eight patients without these antibodies. 3 RPC1 antibody-positive patients had somatic mutations in POLR3A; 5 RPC1 patients had loss of heterozygosity at the POLR3A locus. Analyses of peripheral blood lymphocytes and serum suggested that POLR3A mutations sparked cellular immunity and cross-reactive humoral immune responses. These results offer insight into the pathogenesis of scleroderma, and potentially other autoimmune syndromes. They also provide support for the idea that acquired immunity helps to control naturally occurring cancers in patients with autoimmune rheumatic diseases; it is possible that this immune response may sometimes be fully effective, preventing the emergence of cancer.
Disclosure of Interest None declared