Association of the autoimmune disease scleroderma with an immunologic response to cancer.
Association of the autoimmune disease scleroderma with an immunologic response to cancer.
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DOI：
10.1126/science.1246886
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发表时间：
2014-01-10
期刊：
影响因子：
--
通讯作者：
Rosen A
中科院分区：
文献类型：
--
作者：
Joseph CG;Darrah E;Shah AA;Skora AD;Casciola-Rosen LA;Wigley FM;Boin F;Fava A;Thoburn C;Kinde I;Jiao Y;Papadopoulos N;Kinzler KW;Vogelstein B;Rosen A
自身免疫性疾病被认为是由暴露于与内源性分子交叉反应的外源抗原引发的。硬皮病是一种自身免疫性结缔组织疾病，其中患者产生针对有限组自身抗原的抗体，包括由POLR3A基因编码的RPC1。由于患有硬皮病和RPC1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”抗原是由患者早期癌症中的体细胞突变基因编码的。通过研究硬皮病患者的癌症，我们在8名有RPC1抗体的患者中发现了6名POLR3A基因座的遗传改变，但在8名没有RPC1抗体的患者中没有发现。外周血淋巴细胞和血清分析表明，POLR3A突变引发细胞免疫和交叉反应性体液免疫应答。这些结果提供了对硬皮病发病机制的深入了解，并为获得性免疫有助于控制自然发生的癌症的想法提供了支持。
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.
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