Ludwig Center, the Howard Hughes Medical Institutions, and the Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Science. 2014 Jan 10;343(6167):152-7. doi: 10.1126/science.1246886. Epub 2013 Dec 5.
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.
自身免疫性疾病被认为是由与内源性分子发生交叉反应的外来抗原引起的。硬皮病是一种自身免疫性结缔组织疾病，患者会针对包括由 POLR3A 基因编码的 RPC1 在内的有限组自身抗原产生抗体。由于患有硬皮病和针对 RPC1 的抗体的患者患癌症的风险增加，我们假设这种自身免疫性疾病中的“外来”抗原是由患者初发癌症中体细胞突变基因编码的。在对硬皮病患者的癌症进行研究时，我们发现，在 8 名抗 RPC1 抗体患者中的 6 名中存在 POLR3A 基因座的遗传改变，但在 8 名未产生抗 RPC1 抗体的患者中则不存在。对外周血淋巴细胞和血清的分析表明，POLR3A 突变引发了细胞免疫和交叉反应性体液免疫反应。这些结果为硬皮病的发病机制提供了深入了解，并为获得性免疫有助于控制自然发生的癌症的观点提供了支持。
