Intracellular Sensing of DNA in Autoinflammation and Autoimmunity
Evidence has shown that DNA is a pathogen‐associated molecular pattern, posing a unique challenge in the discrimination between endogenous and foreign DNA. This challenge is highlighted by certain autoinflammatory diseases that arise from monogenic mutations and result in periodic flares of inflamma...
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Veröffentlicht in: | Arthritis & rheumatology (Hoboken, N.J.) N.J.), 2022-10, Vol.74 (10), p.1615-1624 |
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description | Evidence has shown that DNA is a pathogen‐associated molecular pattern, posing a unique challenge in the discrimination between endogenous and foreign DNA. This challenge is highlighted by certain autoinflammatory diseases that arise from monogenic mutations and result in periodic flares of inflammation, typically in the absence of autoantibodies or antigen‐specific T lymphocytes. Several autoinflammatory diseases arise due to mutations in genes that normally prevent the accrual of endogenous DNA or are due to mutations that cause activation of intracellular DNA–sensing pathway components. Evidence from genetically modified murine models further support an ability of endogenous DNA and DNA sensing to drive disease pathogenesis, prompting the question of whether endogenous DNA can also induce inflammation in human autoimmune diseases. In this review, we discuss the current understanding of intracellular DNA sensing and downstream signaling pathways as they pertain to autoinflammatory disease, including the development of monogenic disorders such as Stimulator of interferon genes–associated vasculopathy with onset in infancy and Aicardi‐Goutières syndrome. In addition, we discuss systemic rheumatic diseases, including certain forms of systemic lupus erythematosus, familial chilblain lupus, and other diseases with established links to intracellular DNA–sensing pathways, and highlight the lessons learned from these examples as they apply to the development of therapies targeting these pathways. |
doi_str_mv | 10.1002/art.42256 |
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This challenge is highlighted by certain autoinflammatory diseases that arise from monogenic mutations and result in periodic flares of inflammation, typically in the absence of autoantibodies or antigen‐specific T lymphocytes. Several autoinflammatory diseases arise due to mutations in genes that normally prevent the accrual of endogenous DNA or are due to mutations that cause activation of intracellular DNA–sensing pathway components. Evidence from genetically modified murine models further support an ability of endogenous DNA and DNA sensing to drive disease pathogenesis, prompting the question of whether endogenous DNA can also induce inflammation in human autoimmune diseases. In this review, we discuss the current understanding of intracellular DNA sensing and downstream signaling pathways as they pertain to autoinflammatory disease, including the development of monogenic disorders such as Stimulator of interferon genes–associated vasculopathy with onset in infancy and Aicardi‐Goutières syndrome. In addition, we discuss systemic rheumatic diseases, including certain forms of systemic lupus erythematosus, familial chilblain lupus, and other diseases with established links to intracellular DNA–sensing pathways, and highlight the lessons learned from these examples as they apply to the development of therapies targeting these pathways.</description><identifier>ISSN: 2326-5191</identifier><identifier>ISSN: 2326-5205</identifier><identifier>EISSN: 2326-5205</identifier><identifier>DOI: 10.1002/art.42256</identifier><identifier>PMID: 35656967</identifier><language>eng</language><publisher>Boston, USA: Wiley Periodicals, Inc</publisher><subject>Animal models ; Animals ; Antigens ; Autoantibodies ; Autoimmune diseases ; Autoimmune Diseases - genetics ; Autoimmunity ; Chronic conditions ; Deoxyribonucleic acid ; DNA ; Genes ; Genetic modification ; Hereditary Autoinflammatory Diseases ; Humans ; Inflammation ; Inflammation - metabolism ; Inflammatory diseases ; Interferon ; Interferons ; Intracellular ; Intracellular signalling ; Lupus ; Lymphocytes ; Lymphocytes T ; Mice ; Mutation ; Pathogen-Associated Molecular Pattern Molecules ; Pathogenesis ; Rheumatic diseases ; Stimulators ; Systemic lupus erythematosus ; Vascular diseases</subject><ispartof>Arthritis & rheumatology (Hoboken, N.J.), 2022-10, Vol.74 (10), p.1615-1624</ispartof><rights>2022 American College of Rheumatology</rights><rights>2022 American College of Rheumatology.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4196-6bfd234ee9840d7a9298f382eda01b60873420cb694e8246cb2b1fcd1b00dd993</citedby><cites>FETCH-LOGICAL-c4196-6bfd234ee9840d7a9298f382eda01b60873420cb694e8246cb2b1fcd1b00dd993</cites><orcidid>0000-0001-9689-0826 ; 0000-0002-0981-0996 ; 0000-0003-3175-609X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fart.42256$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fart.42256$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35656967$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>MacLauchlan, Susan</creatorcontrib><creatorcontrib>Fitzgerald, Katherine A.</creatorcontrib><creatorcontrib>Gravallese, Ellen M.</creatorcontrib><title>Intracellular Sensing of DNA in Autoinflammation and Autoimmunity</title><title>Arthritis & rheumatology (Hoboken, N.J.)</title><addtitle>Arthritis Rheumatol</addtitle><description>Evidence has shown that DNA is a pathogen‐associated molecular pattern, posing a unique challenge in the discrimination between endogenous and foreign DNA. This challenge is highlighted by certain autoinflammatory diseases that arise from monogenic mutations and result in periodic flares of inflammation, typically in the absence of autoantibodies or antigen‐specific T lymphocytes. Several autoinflammatory diseases arise due to mutations in genes that normally prevent the accrual of endogenous DNA or are due to mutations that cause activation of intracellular DNA–sensing pathway components. Evidence from genetically modified murine models further support an ability of endogenous DNA and DNA sensing to drive disease pathogenesis, prompting the question of whether endogenous DNA can also induce inflammation in human autoimmune diseases. In this review, we discuss the current understanding of intracellular DNA sensing and downstream signaling pathways as they pertain to autoinflammatory disease, including the development of monogenic disorders such as Stimulator of interferon genes–associated vasculopathy with onset in infancy and Aicardi‐Goutières syndrome. In addition, we discuss systemic rheumatic diseases, including certain forms of systemic lupus erythematosus, familial chilblain lupus, and other diseases with established links to intracellular DNA–sensing pathways, and highlight the lessons learned from these examples as they apply to the development of therapies targeting these pathways.</description><subject>Animal models</subject><subject>Animals</subject><subject>Antigens</subject><subject>Autoantibodies</subject><subject>Autoimmune diseases</subject><subject>Autoimmune Diseases - genetics</subject><subject>Autoimmunity</subject><subject>Chronic conditions</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>Genes</subject><subject>Genetic modification</subject><subject>Hereditary Autoinflammatory Diseases</subject><subject>Humans</subject><subject>Inflammation</subject><subject>Inflammation - metabolism</subject><subject>Inflammatory diseases</subject><subject>Interferon</subject><subject>Interferons</subject><subject>Intracellular</subject><subject>Intracellular signalling</subject><subject>Lupus</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Mice</subject><subject>Mutation</subject><subject>Pathogen-Associated Molecular Pattern Molecules</subject><subject>Pathogenesis</subject><subject>Rheumatic diseases</subject><subject>Stimulators</subject><subject>Systemic lupus erythematosus</subject><subject>Vascular diseases</subject><issn>2326-5191</issn><issn>2326-5205</issn><issn>2326-5205</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kF1LwzAUhoMobsxd-Aek4I1edDtJ07S5LPNrMBR0Xoe0SSWjTWfSIvv3dnbzQvDcnMPh4eXlQegSwwwDkLl07YwSErMTNCYRYWFMID493pjjEZp6v4F-eAIM4nM0imIWM86SMcqWtnWy0FXVVdIFb9p6Yz-CpgzunrPA2CDr2sbYspJ1LVvT2EBaNTzrurOm3V2gs1JWXk8Pe4LeH-7Xi6dw9fK4XGSrsKCYs5DlpSIR1ZqnFFQiOeFpGaVEKwk4Z5AmESVQ5IxTnRLKipzkuCwUzgGU4jyaoJshd-uaz077VtTG74tLq5vOC8KSKIoTCnv0-g-6aTpn-3aCJJhTRgiGnrodqMI13jtdiq0ztXQ7gUHs1YperfhR27NXh8Qur7X6JY8ie2A-AF-m0rv_k0T2uh4ivwFgmYC3</recordid><startdate>202210</startdate><enddate>202210</enddate><creator>MacLauchlan, Susan</creator><creator>Fitzgerald, Katherine A.</creator><creator>Gravallese, Ellen M.</creator><general>Wiley Periodicals, Inc</general><general>Wiley Subscription Services, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QL</scope><scope>7QP</scope><scope>7T5</scope><scope>7TM</scope><scope>7U7</scope><scope>C1K</scope><scope>H94</scope><scope>K9.</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-9689-0826</orcidid><orcidid>https://orcid.org/0000-0002-0981-0996</orcidid><orcidid>https://orcid.org/0000-0003-3175-609X</orcidid></search><sort><creationdate>202210</creationdate><title>Intracellular Sensing of DNA in Autoinflammation and Autoimmunity</title><author>MacLauchlan, Susan ; Fitzgerald, Katherine A. ; Gravallese, Ellen M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4196-6bfd234ee9840d7a9298f382eda01b60873420cb694e8246cb2b1fcd1b00dd993</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Animal models</topic><topic>Animals</topic><topic>Antigens</topic><topic>Autoantibodies</topic><topic>Autoimmune diseases</topic><topic>Autoimmune Diseases - genetics</topic><topic>Autoimmunity</topic><topic>Chronic conditions</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>Genes</topic><topic>Genetic modification</topic><topic>Hereditary Autoinflammatory Diseases</topic><topic>Humans</topic><topic>Inflammation</topic><topic>Inflammation - metabolism</topic><topic>Inflammatory diseases</topic><topic>Interferon</topic><topic>Interferons</topic><topic>Intracellular</topic><topic>Intracellular signalling</topic><topic>Lupus</topic><topic>Lymphocytes</topic><topic>Lymphocytes T</topic><topic>Mice</topic><topic>Mutation</topic><topic>Pathogen-Associated Molecular Pattern Molecules</topic><topic>Pathogenesis</topic><topic>Rheumatic diseases</topic><topic>Stimulators</topic><topic>Systemic lupus erythematosus</topic><topic>Vascular diseases</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>MacLauchlan, Susan</creatorcontrib><creatorcontrib>Fitzgerald, Katherine A.</creatorcontrib><creatorcontrib>Gravallese, Ellen M.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><jtitle>Arthritis & rheumatology (Hoboken, N.J.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>MacLauchlan, Susan</au><au>Fitzgerald, Katherine A.</au><au>Gravallese, Ellen M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Intracellular Sensing of DNA in Autoinflammation and Autoimmunity</atitle><jtitle>Arthritis & rheumatology (Hoboken, N.J.)</jtitle><addtitle>Arthritis Rheumatol</addtitle><date>2022-10</date><risdate>2022</risdate><volume>74</volume><issue>10</issue><spage>1615</spage><epage>1624</epage><pages>1615-1624</pages><issn>2326-5191</issn><issn>2326-5205</issn><eissn>2326-5205</eissn><abstract>Evidence has shown that DNA is a pathogen‐associated molecular pattern, posing a unique challenge in the discrimination between endogenous and foreign DNA. This challenge is highlighted by certain autoinflammatory diseases that arise from monogenic mutations and result in periodic flares of inflammation, typically in the absence of autoantibodies or antigen‐specific T lymphocytes. Several autoinflammatory diseases arise due to mutations in genes that normally prevent the accrual of endogenous DNA or are due to mutations that cause activation of intracellular DNA–sensing pathway components. Evidence from genetically modified murine models further support an ability of endogenous DNA and DNA sensing to drive disease pathogenesis, prompting the question of whether endogenous DNA can also induce inflammation in human autoimmune diseases. In this review, we discuss the current understanding of intracellular DNA sensing and downstream signaling pathways as they pertain to autoinflammatory disease, including the development of monogenic disorders such as Stimulator of interferon genes–associated vasculopathy with onset in infancy and Aicardi‐Goutières syndrome. In addition, we discuss systemic rheumatic diseases, including certain forms of systemic lupus erythematosus, familial chilblain lupus, and other diseases with established links to intracellular DNA–sensing pathways, and highlight the lessons learned from these examples as they apply to the development of therapies targeting these pathways.</abstract><cop>Boston, USA</cop><pub>Wiley Periodicals, Inc</pub><pmid>35656967</pmid><doi>10.1002/art.42256</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0001-9689-0826</orcidid><orcidid>https://orcid.org/0000-0002-0981-0996</orcidid><orcidid>https://orcid.org/0000-0003-3175-609X</orcidid></addata></record> |
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subjects | Animal models Animals Antigens Autoantibodies Autoimmune diseases Autoimmune Diseases - genetics Autoimmunity Chronic conditions Deoxyribonucleic acid DNA Genes Genetic modification Hereditary Autoinflammatory Diseases Humans Inflammation Inflammation - metabolism Inflammatory diseases Interferon Interferons Intracellular Intracellular signalling Lupus Lymphocytes Lymphocytes T Mice Mutation Pathogen-Associated Molecular Pattern Molecules Pathogenesis Rheumatic diseases Stimulators Systemic lupus erythematosus Vascular diseases |
title | Intracellular Sensing of DNA in Autoinflammation and Autoimmunity |
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