Publication Date:
2013-12-07
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4038033/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4038033/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Joseph, Christine G -- Darrah, Erika -- Shah, Ami A -- Skora, Andrew D -- Casciola-Rosen, Livia A -- Wigley, Fredrick M -- Boin, Francesco -- Fava, Andrea -- Thoburn, Chris -- Kinde, Isaac -- Jiao, Yuchen -- Papadopoulos, Nickolas -- Kinzler, Kenneth W -- Vogelstein, Bert -- Rosen, Antony -- CA 57345/CA/NCI NIH HHS/ -- CA 62924/CA/NCI NIH HHS/ -- CA43460/CA/NCI NIH HHS/ -- K23 AR061439/AR/NIAMS NIH HHS/ -- P30 AR053503/AR/NIAMS NIH HHS/ -- P30-AR053503/AR/NIAMS NIH HHS/ -- P50 CA062924/CA/NCI NIH HHS/ -- R37 CA043460/CA/NCI NIH HHS/ -- R37 CA057345/CA/NCI NIH HHS/ -- T32 GM007309/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2014 Jan 10;343(6167):152-7. doi: 10.1126/science.1246886. Epub 2013 Dec 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Ludwig Center, the Howard Hughes Medical Institutions, and the Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24310608" target="_blank"〉PubMed〈/a〉
Keywords:
Alleles
;
Autoantibodies/blood/immunology
;
Autoantigens/genetics/*immunology
;
Autoimmune Diseases/*complications/genetics
;
Autoimmunity/genetics
;
CD4-Positive T-Lymphocytes/immunology
;
Genetic Loci
;
Humans
;
Mutation, Missense
;
Neoplasms/complications/genetics/*immunology
;
Polymorphism, Single Nucleotide
;
RNA Polymerase III/genetics/*immunology
;
Scleroderma, Systemic/*complications/genetics
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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