Journal Article

Association of the Autoimmune Disease Scleroderma with an Immunologic Response to Cancer

Rosen, Antony, Casciola-Rosen, Livia A., Boin, Francesco, Jiao, Yuchen, Vogelstein, Bert, Skora, Andrew D., Kinzler, Kenneth W., Thoburn, Chris, Papadopoulos, Nickolas, Kinde, Isaac, Fava, Andrea, Shah, Ami A., Darrah, Erika, Joseph, Christine G., Wigley, Fredrick M.

2014

Overview

Autoimmune diseases are thought to be initiated by exposures to foreign antigens that cross-react with endogenous molecules. Scleroderma is an autoimmune connective tissue disease in which patients make antibodies to a limited group of autoantigens, including RPC1, encoded by the POLR3A gene. As patients with scleroderma and antibodies against RPC1 are at increased risk for cancer, we hypothesized that the \"foreign\" antigens in this autoimmune disease are encoded by somatically mutated genes in the patients' incipient cancers. Studying cancers from scleroderma patients, we found genetic alterations of the POLR3A locus in six of eight patients with antibodies to RPC1 but not in eight patients without antibodies to RPC1. Analyses of peripheral blood lymphocytes and serum suggested that POLR3A mutations triggered cellular immunity and cross-reactive humoral immune responses. These results offer insight into the pathogenesis of scleroderma and provide support for the idea that acquired immunity helps to control naturally occurring cancers.

• Publisher: American Association for the Advancement of Science,The American Association for the Advancement of Science
• Subject: Alleles / Antibodies / Antigens / Autoantibodies / Autoantibodies - blood / Autoantibodies - immunology / Autoantigens - genetics / Autoantigens - immunology / Autoimmune diseases / Autoimmune Diseases - complications / Autoimmune Diseases - genetics / Autoimmunity - genetics / Breast cancer / Cancer / CD4-Positive T-Lymphocytes - immunology / cell culture / DNA-directed RNA polymerase / genes / Genetic Loci / Genetic mutation / Humans / humoral immunity / immune response / Immunology / Loss of heterozygosity / Lymphocytes / Mutation / Mutation, Missense / neoplasm cells / neoplasms / Neoplasms - complications / Neoplasms - genetics / Neoplasms - immunology / Patients / Polymorphism, Single Nucleotide / RESEARCH ARTICLE / risk / RNA Polymerase III - genetics / RNA Polymerase III - immunology / scleroderma (skin disease) / Scleroderma, Systemic - complications / Scleroderma, Systemic - genetics / sequence analysis / Studies / T cell antigen receptors / T lymphocytes