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  • 1
    Publication Date: 2013-10-11
    Description: In systemic sclerosis (SSc), a common and aetiologically mysterious form of scleroderma (defined as pathological fibrosis of the skin), previously healthy adults acquire fibrosis of the skin and viscera in association with autoantibodies. Familial recurrence is extremely rare and causal genes have not been identified. Although the onset of fibrosis in SSc typically correlates with the production of autoantibodies, whether they contribute to disease pathogenesis or simply serve as a marker of disease remains controversial and the mechanism for their induction is largely unknown. The study of SSc is hindered by a lack of animal models that recapitulate the aetiology of this complex disease. To gain a foothold in the pathogenesis of pathological skin fibrosis, we studied stiff skin syndrome (SSS), a rare but tractable Mendelian disorder leading to childhood onset of diffuse skin fibrosis with autosomal dominant inheritance and complete penetrance. We showed previously that SSS is caused by heterozygous missense mutations in the gene (FBN1) encoding fibrillin-1, the main constituent of extracellular microfibrils. SSS mutations all localize to the only domain in fibrillin-1 that harbours an Arg-Gly-Asp (RGD) motif needed to mediate cell-matrix interactions by binding to cell-surface integrins. Here we show that mouse lines harbouring analogous amino acid substitutions in fibrillin-1 recapitulate aggressive skin fibrosis that is prevented by integrin-modulating therapies and reversed by antagonism of the pro-fibrotic cytokine transforming growth factor beta (TGF-beta). Mutant mice show skin infiltration of pro-inflammatory immune cells including plasmacytoid dendritic cells, T helper cells and plasma cells, and also autoantibody production; these findings are normalized by integrin-modulating therapies or TGF-beta antagonism. These results show that alterations in cell-matrix interactions are sufficient to initiate and sustain inflammatory and pro-fibrotic programmes and highlight new therapeutic strategies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3992987/" 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/PMC3992987/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gerber, Elizabeth E -- Gallo, Elena M -- Fontana, Stefani C -- Davis, Elaine C -- Wigley, Fredrick M -- Huso, David L -- Dietz, Harry C -- P01 AR049698/AR/NIAMS NIH HHS/ -- P01-AR049698/AR/NIAMS NIH HHS/ -- R01 AR041135/AR/NIAMS NIH HHS/ -- R01-AR41135/AR/NIAMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Nov 7;503(7474):126-30. doi: 10.1038/nature12614. Epub 2013 Oct 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24107997" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs/genetics ; Amino Acid Substitution/genetics ; Animals ; Antibodies, Antinuclear/immunology ; Antibodies, Neutralizing/immunology/pharmacology/therapeutic use ; Autoimmunity/*drug effects/immunology ; Contracture/*drug therapy/immunology/*pathology/prevention & control ; Dendritic Cells/drug effects ; Female ; Fibrosis/drug therapy/pathology/prevention & control ; Integrins/*drug effects/*metabolism ; Male ; Mice ; Microfilament Proteins/chemistry/genetics/metabolism ; Mutation, Missense/genetics ; Plasma Cells/drug effects ; Scleroderma, Systemic/*drug therapy/immunology/*pathology/prevention & control ; Skin Diseases, Genetic/*drug therapy/immunology/*pathology/prevention & control ; T-Lymphocytes, Helper-Inducer/drug effects ; Transforming Growth Factor beta/antagonists & inhibitors/immunology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    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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