Epigenetic dysregulation of ACE2 and interferon-regulated genes might suggest increased COVID-19 susceptibility and severity in lupus patients
Identifieur interne : 000838 ( Pmc/Corpus ); précédent : 000837; suivant : 000839Epigenetic dysregulation of ACE2 and interferon-regulated genes might suggest increased COVID-19 susceptibility and severity in lupus patients
Auteurs : Amr H. Sawalha ; Ming Zhao ; Patrick Coit ; Qianjin LuSource :
- Clinical Immunology (Orlando, Fla.) [ 1521-6616 ] ; 2020.
Abstract
Infection caused by SARS-CoV-2 can result in severe respiratory complications and death. Patients with a compromised immune system are expected to be more susceptible to a severe disease course. In this report we suggest that patients with systemic lupus erythematous might be especially prone to severe COVID-19 independent of their immunosuppressed state from lupus treatment. Specifically, we provide evidence in lupus to suggest hypomethylation and overexpression of
Url:
DOI: 10.1016/j.clim.2020.108410
PubMed: 32276140
PubMed Central: 7139239
Links to Exploration step
PMC:7139239Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Epigenetic dysregulation of <italic>ACE2</italic> and interferon-regulated genes might suggest increased COVID-19 susceptibility and severity in lupus patients</title><author><name sortKey="Sawalha, Amr H" sort="Sawalha, Amr H" uniqKey="Sawalha A" first="Amr H." last="Sawalha">Amr H. Sawalha</name><affiliation><nlm:aff id="af0005">Division of Rheumatology, Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USA</nlm:aff></affiliation><affiliation><nlm:aff id="af0010">Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA</nlm:aff></affiliation><affiliation><nlm:aff id="af0015">Lupus Center of Excellence, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA</nlm:aff></affiliation></author><author><name sortKey="Zhao, Ming" sort="Zhao, Ming" uniqKey="Zhao M" first="Ming" last="Zhao">Ming Zhao</name><affiliation><nlm:aff id="af0020">Department of Dermatology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China</nlm:aff></affiliation><affiliation><nlm:aff id="af0025">Hunan Key Laboratory of Medical Epigenomics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China</nlm:aff></affiliation></author><author><name sortKey="Coit, Patrick" sort="Coit, Patrick" uniqKey="Coit P" first="Patrick" last="Coit">Patrick Coit</name><affiliation><nlm:aff id="af0005">Division of Rheumatology, Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USA</nlm:aff></affiliation><affiliation><nlm:aff id="af0030">Graduate Immunology Program, University of Michigan School of Medicine, Ann Arbor, MI, USA</nlm:aff></affiliation></author><author><name sortKey="Lu, Qianjin" sort="Lu, Qianjin" uniqKey="Lu Q" first="Qianjin" last="Lu">Qianjin Lu</name><affiliation><nlm:aff id="af0020">Department of Dermatology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China</nlm:aff></affiliation><affiliation><nlm:aff id="af0025">Hunan Key Laboratory of Medical Epigenomics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">32276140</idno><idno type="pmc">7139239</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139239</idno><idno type="RBID">PMC:7139239</idno><idno type="doi">10.1016/j.clim.2020.108410</idno><date when="2020">2020</date><idno type="wicri:Area/Pmc/Corpus">000838</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000838</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Epigenetic dysregulation of <italic>ACE2</italic> and interferon-regulated genes might suggest increased COVID-19 susceptibility and severity in lupus patients</title><author><name sortKey="Sawalha, Amr H" sort="Sawalha, Amr H" uniqKey="Sawalha A" first="Amr H." last="Sawalha">Amr H. Sawalha</name><affiliation><nlm:aff id="af0005">Division of Rheumatology, Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USA</nlm:aff></affiliation><affiliation><nlm:aff id="af0010">Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA</nlm:aff></affiliation><affiliation><nlm:aff id="af0015">Lupus Center of Excellence, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA</nlm:aff></affiliation></author><author><name sortKey="Zhao, Ming" sort="Zhao, Ming" uniqKey="Zhao M" first="Ming" last="Zhao">Ming Zhao</name><affiliation><nlm:aff id="af0020">Department of Dermatology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China</nlm:aff></affiliation><affiliation><nlm:aff id="af0025">Hunan Key Laboratory of Medical Epigenomics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China</nlm:aff></affiliation></author><author><name sortKey="Coit, Patrick" sort="Coit, Patrick" uniqKey="Coit P" first="Patrick" last="Coit">Patrick Coit</name><affiliation><nlm:aff id="af0005">Division of Rheumatology, Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USA</nlm:aff></affiliation><affiliation><nlm:aff id="af0030">Graduate Immunology Program, University of Michigan School of Medicine, Ann Arbor, MI, USA</nlm:aff></affiliation></author><author><name sortKey="Lu, Qianjin" sort="Lu, Qianjin" uniqKey="Lu Q" first="Qianjin" last="Lu">Qianjin Lu</name><affiliation><nlm:aff id="af0020">Department of Dermatology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China</nlm:aff></affiliation><affiliation><nlm:aff id="af0025">Hunan Key Laboratory of Medical Epigenomics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China</nlm:aff></affiliation></author></analytic><series><title level="j">Clinical Immunology (Orlando, Fla.)</title><idno type="ISSN">1521-6616</idno><idno type="eISSN">1521-7035</idno><imprint><date when="2020">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Infection caused by SARS-CoV-2 can result in severe respiratory complications and death. Patients with a compromised immune system are expected to be more susceptible to a severe disease course. In this report we suggest that patients with systemic lupus erythematous might be especially prone to severe COVID-19 independent of their immunosuppressed state from lupus treatment. Specifically, we provide evidence in lupus to suggest hypomethylation and overexpression of <italic>ACE2</italic>, which is located on the X chromosome and encodes a functional receptor for the SARS-CoV-2 spike glycoprotein. Oxidative stress induced by viral infections exacerbates the DNA methylation defect in lupus, possibly resulting in further <italic>ACE2</italic> hypomethylation and enhanced viremia. In addition, demethylation of interferon-regulated genes, NFκB, and key cytokine genes in lupus patients might exacerbate the immune response to SARS-CoV-2 and increase the likelihood of cytokine storm. These arguments suggest that inherent epigenetic dysregulation in lupus might facilitate viral entry, viremia, and an excessive immune response to SARS-CoV-2. Further, maintaining disease remission in lupus patients is critical to prevent a vicious cycle of demethylation and increased oxidative stress, which will exacerbate susceptibility to SARS-CoV-2 infection during the current pandemic. Epigenetic control of the <italic>ACE2</italic> gene might be a target for prevention and therapy in COVID-19.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Huang, C" uniqKey="Huang C">C. Huang</name></author><author><name sortKey="Wang, Y" uniqKey="Wang Y">Y. Wang</name></author><author><name sortKey="Li, X" uniqKey="Li X">X. Li</name></author><author><name sortKey="Ren, L" uniqKey="Ren L">L. Ren</name></author><author><name sortKey="Zhao, J" uniqKey="Zhao J">J. Zhao</name></author><author><name sortKey="Hu, Y" uniqKey="Hu Y">Y. Hu</name></author><author><name sortKey="Zhang, L" uniqKey="Zhang L">L. Zhang</name></author><author><name sortKey="Fan, G" uniqKey="Fan G">G. Fan</name></author><author><name sortKey="Xu, J" uniqKey="Xu J">J. Xu</name></author><author><name sortKey="Gu, X" uniqKey="Gu X">X. Gu</name></author><author><name sortKey="Cheng, Z" uniqKey="Cheng Z">Z. Cheng</name></author><author><name sortKey="Yu, T" uniqKey="Yu T">T. Yu</name></author><author><name sortKey="Xia, J" uniqKey="Xia J">J. Xia</name></author><author><name sortKey="Wei, Y" uniqKey="Wei Y">Y. Wei</name></author><author><name sortKey="Wu, W" uniqKey="Wu W">W. Wu</name></author><author><name sortKey="Xie, X" uniqKey="Xie X">X. Xie</name></author><author><name sortKey="Yin, W" uniqKey="Yin W">W. Yin</name></author><author><name sortKey="Li, H" uniqKey="Li H">H. Li</name></author><author><name sortKey="Liu, M" uniqKey="Liu M">M. Liu</name></author><author><name sortKey="Xiao, Y" uniqKey="Xiao Y">Y. Xiao</name></author><author><name sortKey="Gao, H" uniqKey="Gao H">H. Gao</name></author><author><name sortKey="Guo, L" uniqKey="Guo L">L. Guo</name></author><author><name sortKey="Xie, J" uniqKey="Xie J">J. Xie</name></author><author><name sortKey="Wang, G" uniqKey="Wang G">G. Wang</name></author><author><name sortKey="Jiang, R" uniqKey="Jiang R">R. Jiang</name></author><author><name sortKey="Gao, Z" uniqKey="Gao Z">Z. Gao</name></author><author><name sortKey="Jin, Q" uniqKey="Jin Q">Q. Jin</name></author><author><name sortKey="Wang, J" uniqKey="Wang J">J. Wang</name></author><author><name sortKey="Cao, B" uniqKey="Cao B">B. Cao</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhou, F" uniqKey="Zhou F">F. Zhou</name></author><author><name sortKey="Yu, T" uniqKey="Yu T">T. Yu</name></author><author><name sortKey="Du, R" uniqKey="Du R">R. Du</name></author><author><name sortKey="Fan, G" uniqKey="Fan G">G. Fan</name></author><author><name sortKey="Liu, Y" uniqKey="Liu Y">Y. Liu</name></author><author><name sortKey="Liu, Z" uniqKey="Liu Z">Z. Liu</name></author><author><name sortKey="Xiang, J" uniqKey="Xiang J">J. Xiang</name></author><author><name sortKey="Wang, Y" uniqKey="Wang Y">Y. Wang</name></author><author><name sortKey="Song, B" uniqKey="Song B">B. Song</name></author><author><name sortKey="Gu, X" uniqKey="Gu X">X. Gu</name></author><author><name sortKey="Guan, L" uniqKey="Guan L">L. Guan</name></author><author><name sortKey="Wei, Y" uniqKey="Wei Y">Y. Wei</name></author><author><name sortKey="Li, H" uniqKey="Li H">H. Li</name></author><author><name sortKey="Wu, X" uniqKey="Wu X">X. Wu</name></author><author><name sortKey="Xu, J" uniqKey="Xu J">J. Xu</name></author><author><name sortKey="Tu, S" uniqKey="Tu S">S. Tu</name></author><author><name sortKey="Zhang, Y" uniqKey="Zhang Y">Y. Zhang</name></author><author><name sortKey="Chen, H" uniqKey="Chen H">H. Chen</name></author><author><name sortKey="Cao, B" uniqKey="Cao B">B. Cao</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Teruel, M" uniqKey="Teruel M">M. Teruel</name></author><author><name sortKey="Sawalha, A H" uniqKey="Sawalha A">A.H. Sawalha</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Coit, P" uniqKey="Coit P">P. Coit</name></author><author><name sortKey="Jeffries, M" uniqKey="Jeffries M">M. Jeffries</name></author><author><name sortKey="Altorok, N" uniqKey="Altorok N">N. Altorok</name></author><author><name sortKey="Dozmorov, M G" uniqKey="Dozmorov M">M.G. Dozmorov</name></author><author><name sortKey="Koelsch, K A" uniqKey="Koelsch K">K.A. Koelsch</name></author><author><name sortKey="Wren, J D" uniqKey="Wren J">J.D. Wren</name></author><author><name sortKey="Merrill, J T" uniqKey="Merrill J">J.T. Merrill</name></author><author><name sortKey="Mccune, W J" uniqKey="Mccune W">W.J. McCune</name></author><author><name sortKey="Sawalha, A H" uniqKey="Sawalha A">A.H. Sawalha</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Coit, P" uniqKey="Coit P">P. Coit</name></author><author><name sortKey="Yalavarthi, S" uniqKey="Yalavarthi S">S. Yalavarthi</name></author><author><name sortKey="Ognenovski, M" uniqKey="Ognenovski M">M. Ognenovski</name></author><author><name sortKey="Zhao, W" uniqKey="Zhao W">W. Zhao</name></author><author><name sortKey="Hasni, S" uniqKey="Hasni S">S. Hasni</name></author><author><name sortKey="Wren, J D" uniqKey="Wren J">J.D. Wren</name></author><author><name sortKey="Kaplan, M J" uniqKey="Kaplan M">M.J. Kaplan</name></author><author><name sortKey="Sawalha, A H" uniqKey="Sawalha A">A.H. Sawalha</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Imgenberg Kreuz, J" uniqKey="Imgenberg Kreuz J">J. Imgenberg-Kreuz</name></author><author><name sortKey="Carlsson Almlof, J" uniqKey="Carlsson Almlof J">J. Carlsson Almlof</name></author><author><name sortKey="Leonard, D" uniqKey="Leonard D">D. Leonard</name></author><author><name sortKey="Alexsson, A" uniqKey="Alexsson A">A. Alexsson</name></author><author><name sortKey="Nordmark, G" uniqKey="Nordmark G">G. Nordmark</name></author><author><name sortKey="Eloranta, M L" uniqKey="Eloranta M">M.L. Eloranta</name></author><author><name sortKey="Rantapaa Dahlqvist, S" uniqKey="Rantapaa Dahlqvist S">S. Rantapaa-Dahlqvist</name></author><author><name sortKey="Bengtsson, A A" uniqKey="Bengtsson A">A.A. Bengtsson</name></author><author><name sortKey="Jonsen, A" uniqKey="Jonsen A">A. Jonsen</name></author><author><name sortKey="Padyukov, L" uniqKey="Padyukov L">L. Padyukov</name></author><author><name sortKey="Gunnarsson, I" uniqKey="Gunnarsson I">I. Gunnarsson</name></author><author><name sortKey="Svenungsson, E" uniqKey="Svenungsson E">E. Svenungsson</name></author><author><name sortKey="Sjowall, C" uniqKey="Sjowall C">C. Sjowall</name></author><author><name sortKey="Ronnblom, L" uniqKey="Ronnblom L">L. Ronnblom</name></author><author><name sortKey="Syvanen, A C" uniqKey="Syvanen A">A.C. Syvanen</name></author><author><name sortKey="Sandling, J K" uniqKey="Sandling J">J.K. Sandling</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lu, Q" uniqKey="Lu Q">Q. Lu</name></author><author><name sortKey="Wu, A" uniqKey="Wu A">A. Wu</name></author><author><name sortKey="Tesmer, L" uniqKey="Tesmer L">L. Tesmer</name></author><author><name sortKey="Ray, D" uniqKey="Ray D">D. Ray</name></author><author><name sortKey="Yousif, N" uniqKey="Yousif N">N. Yousif</name></author><author><name sortKey="Richardson, B" uniqKey="Richardson B">B. Richardson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sawalha, A H" uniqKey="Sawalha A">A.H. Sawalha</name></author><author><name sortKey="Harley, J B" uniqKey="Harley J">J.B. Harley</name></author><author><name sortKey="Scofield, R H" uniqKey="Scofield R">R.H. Scofield</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hoffmann, M" uniqKey="Hoffmann M">M. Hoffmann</name></author><author><name sortKey="Kleine Weber, H" uniqKey="Kleine Weber H">H. Kleine-Weber</name></author><author><name sortKey="Schroeder, S" uniqKey="Schroeder S">S. Schroeder</name></author><author><name sortKey="Kruger, N" uniqKey="Kruger N">N. Kruger</name></author><author><name sortKey="Herrler, T" uniqKey="Herrler T">T. Herrler</name></author><author><name sortKey="Erichsen, S" uniqKey="Erichsen S">S. Erichsen</name></author><author><name sortKey="Schiergens, T S" uniqKey="Schiergens T">T.S. Schiergens</name></author><author><name sortKey="Herrler, G" uniqKey="Herrler G">G. Herrler</name></author><author><name sortKey="Wu, N H" uniqKey="Wu N">N.H. Wu</name></author><author><name sortKey="Nitsche, A" uniqKey="Nitsche A">A. Nitsche</name></author><author><name sortKey="Muller, M A" uniqKey="Muller M">M.A. Muller</name></author><author><name sortKey="Drosten, C" uniqKey="Drosten C">C. Drosten</name></author><author><name sortKey="Pohlmann, S" uniqKey="Pohlmann S">S. Pohlmann</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Strickland, F M" uniqKey="Strickland F">F.M. Strickland</name></author><author><name sortKey="Patel, D" uniqKey="Patel D">D. Patel</name></author><author><name sortKey="Khanna, D" uniqKey="Khanna D">D. Khanna</name></author><author><name sortKey="Somers, E" uniqKey="Somers E">E. Somers</name></author><author><name sortKey="Robida, A M" uniqKey="Robida A">A.M. Robida</name></author><author><name sortKey="Pihalja, M" uniqKey="Pihalja M">M. Pihalja</name></author><author><name sortKey="Swartz, R" uniqKey="Swartz R">R. Swartz</name></author><author><name sortKey="Marder, W" uniqKey="Marder W">W. Marder</name></author><author><name sortKey="Richardson, B" uniqKey="Richardson B">B. Richardson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gensterblum, E" uniqKey="Gensterblum E">E. Gensterblum</name></author><author><name sortKey="Renauer, P" uniqKey="Renauer P">P. Renauer</name></author><author><name sortKey="Coit, P" uniqKey="Coit P">P. Coit</name></author><author><name sortKey="Strickland, F M" uniqKey="Strickland F">F.M. Strickland</name></author><author><name sortKey="Kilian, N C" uniqKey="Kilian N">N.C. Kilian</name></author><author><name sortKey="Miller, S" uniqKey="Miller S">S. Miller</name></author><author><name sortKey="Ognenovski, M" uniqKey="Ognenovski M">M. Ognenovski</name></author><author><name sortKey="Wren, J D" uniqKey="Wren J">J.D. Wren</name></author><author><name sortKey="Tsou, P S" uniqKey="Tsou P">P.S. Tsou</name></author><author><name sortKey="Lewis, E E" uniqKey="Lewis E">E.E. Lewis</name></author><author><name sortKey="Maksimowicz Mckinnon, K" uniqKey="Maksimowicz Mckinnon K">K. Maksimowicz-McKinnon</name></author><author><name sortKey="Mccune, W J" uniqKey="Mccune W">W.J. McCune</name></author><author><name sortKey="Richardson, B C" uniqKey="Richardson B">B.C. Richardson</name></author><author><name sortKey="Sawalha, A H" uniqKey="Sawalha A">A.H. Sawalha</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhao, M" uniqKey="Zhao M">M. Zhao</name></author><author><name sortKey="Liu, S" uniqKey="Liu S">S. Liu</name></author><author><name sortKey="Luo, S" uniqKey="Luo S">S. Luo</name></author><author><name sortKey="Wu, H" uniqKey="Wu H">H. Wu</name></author><author><name sortKey="Tang, M" uniqKey="Tang M">M. Tang</name></author><author><name sortKey="Cheng, W" uniqKey="Cheng W">W. Cheng</name></author><author><name sortKey="Zhang, Q" uniqKey="Zhang Q">Q. Zhang</name></author><author><name sortKey="Zhang, P" uniqKey="Zhang P">P. Zhang</name></author><author><name sortKey="Yu, X" uniqKey="Yu X">X. Yu</name></author><author><name sortKey="Xia, Y" uniqKey="Xia Y">Y. Xia</name></author><author><name sortKey="Yi, N" uniqKey="Yi N">N. Yi</name></author><author><name sortKey="Gao, F" uniqKey="Gao F">F. Gao</name></author><author><name sortKey="Wang, L" uniqKey="Wang L">L. Wang</name></author><author><name sortKey="Yung, S" uniqKey="Yung S">S. Yung</name></author><author><name sortKey="Chan, T M" uniqKey="Chan T">T.M. Chan</name></author><author><name sortKey="Sawalha, A H" uniqKey="Sawalha A">A.H. Sawalha</name></author><author><name sortKey="Richardson, B" uniqKey="Richardson B">B. Richardson</name></author><author><name sortKey="Gershwin, M E" uniqKey="Gershwin M">M.E. Gershwin</name></author><author><name sortKey="Li, N" uniqKey="Li N">N. Li</name></author><author><name sortKey="Lu, Q" uniqKey="Lu Q">Q. Lu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Crispin, J C" uniqKey="Crispin J">J.C. Crispin</name></author><author><name sortKey="Oukka, M" uniqKey="Oukka M">M. Oukka</name></author><author><name sortKey="Bayliss, G" uniqKey="Bayliss G">G. Bayliss</name></author><author><name sortKey="Cohen, R A" uniqKey="Cohen R">R.A. Cohen</name></author><author><name sortKey="Van Beek, C A" uniqKey="Van Beek C">C.A. Van Beek</name></author><author><name sortKey="Stillman, I E" uniqKey="Stillman I">I.E. Stillman</name></author><author><name sortKey="Kyttaris, V C" uniqKey="Kyttaris V">V.C. Kyttaris</name></author><author><name sortKey="Juang, Y T" uniqKey="Juang Y">Y.T. Juang</name></author><author><name sortKey="Tsokos, G C" uniqKey="Tsokos G">G.C. Tsokos</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Renauer, P A" uniqKey="Renauer P">P.A. Renauer</name></author><author><name sortKey="Coit, P" uniqKey="Coit P">P. Coit</name></author><author><name sortKey="Sawalha, A H" uniqKey="Sawalha A">A.H. Sawalha</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gu, J" uniqKey="Gu J">J. Gu</name></author><author><name sortKey="Gong, E" uniqKey="Gong E">E. Gong</name></author><author><name sortKey="Zhang, B" uniqKey="Zhang B">B. Zhang</name></author><author><name sortKey="Zheng, J" uniqKey="Zheng J">J. Zheng</name></author><author><name sortKey="Gao, Z" uniqKey="Gao Z">Z. Gao</name></author><author><name sortKey="Zhong, Y" uniqKey="Zhong Y">Y. Zhong</name></author><author><name sortKey="Zou, W" uniqKey="Zou W">W. Zou</name></author><author><name sortKey="Zhan, J" uniqKey="Zhan J">J. Zhan</name></author><author><name sortKey="Wang, S" uniqKey="Wang S">S. Wang</name></author><author><name sortKey="Xie, Z" uniqKey="Xie Z">Z. Xie</name></author><author><name sortKey="Zhuang, H" uniqKey="Zhuang H">H. Zhuang</name></author><author><name sortKey="Wu, B" uniqKey="Wu B">B. Wu</name></author><author><name sortKey="Zhong, H" uniqKey="Zhong H">H. Zhong</name></author><author><name sortKey="Shao, H" uniqKey="Shao H">H. Shao</name></author><author><name sortKey="Fang, W" uniqKey="Fang W">W. Fang</name></author><author><name sortKey="Gao, D" uniqKey="Gao D">D. Gao</name></author><author><name sortKey="Pei, F" uniqKey="Pei F">F. Pei</name></author><author><name sortKey="Li, X" uniqKey="Li X">X. Li</name></author><author><name sortKey="He, Z" uniqKey="He Z">Z. He</name></author><author><name sortKey="Xu, D" uniqKey="Xu D">D. Xu</name></author><author><name sortKey="Shi, X" uniqKey="Shi X">X. Shi</name></author><author><name sortKey="Anderson, V M" uniqKey="Anderson V">V.M. Anderson</name></author><author><name sortKey="Leong, A S" uniqKey="Leong A">A.S. Leong</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gu, J" uniqKey="Gu J">J. Gu</name></author><author><name sortKey="Korteweg, C" uniqKey="Korteweg C">C. Korteweg</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Li, Y" uniqKey="Li Y">Y. Li</name></author><author><name sortKey="Gorelik, G" uniqKey="Gorelik G">G. Gorelik</name></author><author><name sortKey="Strickland, F M" uniqKey="Strickland F">F.M. Strickland</name></author><author><name sortKey="Richardson, B C" uniqKey="Richardson B">B.C. Richardson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gorelik, G" uniqKey="Gorelik G">G. Gorelik</name></author><author><name sortKey="Fang, J Y" uniqKey="Fang J">J.Y. Fang</name></author><author><name sortKey="Wu, A" uniqKey="Wu A">A. Wu</name></author><author><name sortKey="Sawalha, A H" uniqKey="Sawalha A">A.H. Sawalha</name></author><author><name sortKey="Richardson, B" uniqKey="Richardson B">B. Richardson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Perl, A" uniqKey="Perl A">A. Perl</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Weeding, E" uniqKey="Weeding E">E. Weeding</name></author><author><name sortKey="Sawalha, A H" uniqKey="Sawalha A">A.H. Sawalha</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Coit, P" uniqKey="Coit P">P. Coit</name></author><author><name sortKey="Dozmorov, M G" uniqKey="Dozmorov M">M.G. Dozmorov</name></author><author><name sortKey="Merrill, J T" uniqKey="Merrill J">J.T. Merrill</name></author><author><name sortKey="Mccune, W J" uniqKey="Mccune W">W.J. McCune</name></author><author><name sortKey="Maksimowicz Mckinnon, K" uniqKey="Maksimowicz Mckinnon K">K. Maksimowicz-McKinnon</name></author><author><name sortKey="Wren, J D" uniqKey="Wren J">J.D. Wren</name></author><author><name sortKey="Sawalha, A H" uniqKey="Sawalha A">A.H. Sawalha</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Katsuyama, E" uniqKey="Katsuyama E">E. Katsuyama</name></author><author><name sortKey="Suarez Fueyo, A" uniqKey="Suarez Fueyo A">A. Suarez-Fueyo</name></author><author><name sortKey="Bradley, S J" uniqKey="Bradley S">S.J. Bradley</name></author><author><name sortKey="Mizui, M" uniqKey="Mizui M">M. Mizui</name></author><author><name sortKey="Marin, A V" uniqKey="Marin A">A.V. Marin</name></author><author><name sortKey="Mulki, L" uniqKey="Mulki L">L. Mulki</name></author><author><name sortKey="Krishfield, S" uniqKey="Krishfield S">S. Krishfield</name></author><author><name sortKey="Malavasi, F" uniqKey="Malavasi F">F. Malavasi</name></author><author><name sortKey="Yoon, J" uniqKey="Yoon J">J. Yoon</name></author><author><name sortKey="Sui, S J H" uniqKey="Sui S">S.J.H. Sui</name></author><author><name sortKey="Kyttaris, V C" uniqKey="Kyttaris V">V.C. Kyttaris</name></author><author><name sortKey="Tsokos, G C" uniqKey="Tsokos G">G.C. Tsokos</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="brief-report"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Clin Immunol</journal-id><journal-id journal-id-type="iso-abbrev">Clin. Immunol</journal-id><journal-title-group><journal-title>Clinical Immunology (Orlando, Fla.)</journal-title></journal-title-group><issn pub-type="ppub">1521-6616</issn><issn pub-type="epub">1521-7035</issn><publisher><publisher-name>Elsevier Inc.</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">32276140</article-id><article-id pub-id-type="pmc">7139239</article-id><article-id pub-id-type="publisher-id">S1521-6616(20)30239-4</article-id><article-id pub-id-type="doi">10.1016/j.clim.2020.108410</article-id><article-id pub-id-type="publisher-id">108410</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Epigenetic dysregulation of <italic>ACE2</italic> and interferon-regulated genes might suggest increased COVID-19 susceptibility and severity in lupus patients</article-title></title-group><contrib-group><contrib contrib-type="author" id="au0005"><name><surname>Sawalha</surname><given-names>Amr H.</given-names></name><email>asawalha@pitt.edu</email><xref rid="af0005" ref-type="aff">a</xref><xref rid="af0010" ref-type="aff">b</xref><xref rid="af0015" ref-type="aff">c</xref><xref rid="cr0005" ref-type="corresp">⁎</xref></contrib><contrib contrib-type="author" id="au0010"><name><surname>Zhao</surname><given-names>Ming</given-names></name><xref rid="af0020" ref-type="aff">d</xref><xref rid="af0025" ref-type="aff">e</xref></contrib><contrib contrib-type="author" id="au0015"><name><surname>Coit</surname><given-names>Patrick</given-names></name><xref rid="af0005" ref-type="aff">a</xref><xref rid="af0030" ref-type="aff">f</xref></contrib><contrib contrib-type="author" id="au0020"><name><surname>Lu</surname><given-names>Qianjin</given-names></name><xref rid="af0020" ref-type="aff">d</xref><xref rid="af0025" ref-type="aff">e</xref></contrib></contrib-group><aff id="af0005"><label>a</label>Division of Rheumatology, Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USA</aff><aff id="af0010"><label>b</label>Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA</aff><aff id="af0015"><label>c</label>Lupus Center of Excellence, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA</aff><aff id="af0020"><label>d</label>Department of Dermatology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China</aff><aff id="af0025"><label>e</label>Hunan Key Laboratory of Medical Epigenomics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China</aff><aff id="af0030"><label>f</label>Graduate Immunology Program, University of Michigan School of Medicine, Ann Arbor, MI, USA</aff><author-notes><corresp id="cr0005"><label>⁎</label>Corresponding author at: 7123 Rangos Research Center, 4401 Penn Avenue, Pittsburgh, PA 15224, USA. <email>asawalha@pitt.edu</email></corresp></author-notes><pub-date pub-type="pmc-release"><day>8</day><month>4</month><year>2020</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on .</pmc-comment>
<pub-date pub-type="ppub"><month>6</month><year>2020</year></pub-date><pub-date pub-type="epub"><day>8</day><month>4</month><year>2020</year></pub-date><volume>215</volume><fpage>108410</fpage><lpage>108410</lpage><history><date date-type="received"><day>1</day><month>4</month><year>2020</year></date><date date-type="rev-recd"><day>4</day><month>4</month><year>2020</year></date><date date-type="accepted"><day>4</day><month>4</month><year>2020</year></date></history><permissions><copyright-statement>© 2020 Elsevier Inc. All rights reserved.</copyright-statement><copyright-year>2020</copyright-year><copyright-holder>Elsevier Inc.</copyright-holder><license><license-p>Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.</license-p></license></permissions><abstract id="ab0005"><p>Infection caused by SARS-CoV-2 can result in severe respiratory complications and death. Patients with a compromised immune system are expected to be more susceptible to a severe disease course. In this report we suggest that patients with systemic lupus erythematous might be especially prone to severe COVID-19 independent of their immunosuppressed state from lupus treatment. Specifically, we provide evidence in lupus to suggest hypomethylation and overexpression of <italic>ACE2</italic>, which is located on the X chromosome and encodes a functional receptor for the SARS-CoV-2 spike glycoprotein. Oxidative stress induced by viral infections exacerbates the DNA methylation defect in lupus, possibly resulting in further <italic>ACE2</italic> hypomethylation and enhanced viremia. In addition, demethylation of interferon-regulated genes, NFκB, and key cytokine genes in lupus patients might exacerbate the immune response to SARS-CoV-2 and increase the likelihood of cytokine storm. These arguments suggest that inherent epigenetic dysregulation in lupus might facilitate viral entry, viremia, and an excessive immune response to SARS-CoV-2. Further, maintaining disease remission in lupus patients is critical to prevent a vicious cycle of demethylation and increased oxidative stress, which will exacerbate susceptibility to SARS-CoV-2 infection during the current pandemic. Epigenetic control of the <italic>ACE2</italic> gene might be a target for prevention and therapy in COVID-19.</p></abstract><abstract abstract-type="author-highlights" id="ab0010"><title>Highlights</title><p><list list-type="simple" id="l0005"><list-item id="li0005"><label>•</label><p id="p0005"><italic>ACE2</italic> encodes a key viral entry receptor for SARS-CoV-2 and is methylation sensitive</p></list-item><list-item id="li0010"><label>•</label><p id="p0010"><italic>ACE2</italic> is hypomethylated and overexpressed in lupus T cells suggesting an increased possibility of disseminated disease during SARS-CoV-2 infection</p></list-item><list-item id="li0015"><label>•</label><p id="p0015"><italic>ACE2</italic> demethylation might be exacerbated after SARS-CoV-2 infection due to increased oxidative stress</p></list-item><list-item id="li0020"><label>•</label><p id="p0020">Demethylation in interferon-regulated and key cytokine genes might predispose lupus patients to cytokine storm in COVID-19</p></list-item><list-item id="li0025"><label>•</label><p id="p0025">Maintaining remission in lupus is critical to prevent further demethylation and overexpression of <italic>ACE2</italic></p></list-item></list></p></abstract><kwd-group id="ks0005"><title>Keywords</title><kwd>SARS-CoV-2</kwd><kwd>Lupus</kwd><kwd>COVID-19</kwd><kwd>Epigenetics</kwd><kwd>ACE2</kwd><kwd>Methylation</kwd><kwd>Interferon</kwd></kwd-group></article-meta></front><body><p id="p0030">Coronavirus Disease-2019 (COVID-19) is a respiratory disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which is a novel single-stranded RNA virus of the <italic>Coronaviridae</italic> family. The disease can be associated with severe lower respiratory manifestations leading to acute respiratory distress syndrome, cytokine storm, and death [<xref rid="bb0005" ref-type="bibr">1</xref>]. Older individuals and patients with pre-existing chronic medical illnesses appear to be at increased risk of severe COVID-19 [<xref rid="bb0010" ref-type="bibr">2</xref>].</p><p id="p0035">Lupus is a chronic autoimmune disease of incompletely understood etiology. We propose that lupus patients might be at an increased risk for infection by SARS-CoV-2 and for developing a more severe form of COVID-19, independent of the possible effect of immunosuppressive medications.</p><p id="p0040">Epigenetic dysregulation plays an important role in the pathogenesis of lupus [<xref rid="bb0015" ref-type="bibr">3</xref>]. While most epigenetic studies in lupus have been performed in T cells, there is evidence to suggest reduced DNA methylation levels in multiple cell types in this disease. For example, a robust demethylation signature in interferon-regulated genes in lupus is wide-spread and characteristic of the disease [<xref rid="bb0020" ref-type="bibr">[4]</xref>, <xref rid="bb0025" ref-type="bibr">[5]</xref>, <xref rid="bb0030" ref-type="bibr">[6]</xref>].</p><p id="p0045">DNA methylation plays an important role in the inactivation of the X chromosome. X chromosome inactivation, whereby gene expression from one copy of X chromosome genes is silenced by DNA methylation, is essential to maintain normal and comparable expression levels between male and female cells. In women with lupus, reduced DNA methylation has been shown to result in defective X chromosome inactivation [<xref rid="bb0035" ref-type="bibr">7</xref>]. Hypomethylation of the normally inactivate X chromosome leads to an abnormal increase in the expression levels of affected genes. This abnormal X chromosome inactivation has been demonstrated to mediate increased expression of CD40LG in CD4<sup>+</sup> T cells in women with lupus, contributing to T cell autoreactivity in this disease [<xref rid="bb0035" ref-type="bibr">7</xref>]. CD40LG expression in CD4<sup>+</sup> T cells isolated from healthy women was similarly increased after treatment with the DNA methylation inhibitor 5-azacytidine. This gene-dose effect of the X chromosome has been proposed to explain, at least in part, sex bias in lupus. Of interest, men with two X chromosomes, Klinefelter syndrome (47, XXY), have a significantly higher risk to develop lupus compared to normal men (46, XY) and a similar risk to women [<xref rid="bb0040" ref-type="bibr">8</xref>].</p><p id="p0050">SARS-CoV-2 binds to target host cells through angiotensin-converting enzyme 2 (ACE2). ACE2 is a functional receptor for the viral spike glycoprotein that allows the entry of SARS-CoV-2 into cells [<xref rid="bb0045" ref-type="bibr">9</xref>]. <italic>ACE2</italic> gene is located on the X chromosome, similar to <italic>CD40LG.</italic> Recent findings suggest the expansion of a demethylated T cell subset in lupus patients characterized by the expression of several genes known to be demethylated in lupus, including <italic>CD40LG</italic>, <italic>CD70</italic>, <italic>ITGAL</italic> (<italic>CD11A</italic>), and the KIR gene cluster (defined using flow cytometry as KIR<sup>+</sup>CD11a<sup>hi</sup> CD4<sup>+</sup>CD28<sup>+</sup> T cell subset) [<xref rid="bb0050" ref-type="bibr">10</xref>,<xref rid="bb0055" ref-type="bibr">11</xref>]. Indeed, we can induce this T cell subset in normal healthy individuals using the DNA methylation inhibitor 5-azacytidine [<xref rid="bb0055" ref-type="bibr">11</xref>]. Examining whole-genome DNA methylation data generated using an array-based approach, we observe significant hypomethylation in the <italic>ACE2</italic> gene in this T cell subset compared to KIR<sup>−</sup>CD11a<sup>low</sup> T cells isolated from the same lupus patients (<xref rid="f0005" ref-type="fig">Fig. 1</xref>A). This hypomethylation involves several CpG sites located in the <italic>ACE2</italic> promoter region proximal to the transcription start site, the 5′-untranslated region, and the 3′-untranslated region, suggesting functional regulatory effect of the methylation changes. Furthermore, we can induce hypomethylation in some of these same CpG sites in CD4<sup>+</sup> T cells isolated from normal healthy women treated with the DNA methylation inhibitor 5-azacytidine [<xref rid="bb0055" ref-type="bibr">11</xref>]. Importantly, in a subset of female lupus patients characterized by skin, joint, and kidney involvement <italic>ACE2</italic> promoter region was significantly hypomethylated in CD4<sup>+</sup> T cells compared to age and sex matched normal healthy controls [<xref rid="bb0060" ref-type="bibr">12</xref>]. Gene expression profiles extracted from a publicly available dataset (GEO accession: <ext-link ext-link-type="uri" xlink:href="ncbi-geo:GSE4588" id="ir0010">GSE4588</ext-link>) showed a significant overexpression of ACE2 mRNA in lupus CD4<sup>+</sup> T cells compared to normal healthy controls (<xref rid="f0005" ref-type="fig">Fig. 1</xref>B). We further confirm hypomethylation in <italic>ACE2</italic> in an independent set of female lupus patients characterized by kidney involvement (<xref rid="f0005" ref-type="fig">Fig. 1</xref>C). Gene expression profiles in the same set of patients showed ~1.5–2-fold ACE2 overexpression compared to healthy controls, although his did not reach statistical significance (<xref rid="f0005" ref-type="fig">Fig. 1</xref>D).<fig id="f0005"><label>Fig. 1</label><caption><p>A) DNA hypomethylation of <italic>ACE2</italic> in a subset of CD4<sup>+</sup> T cells characterized by expression of KIR genes and high levels of CD11a (KIR<sup>+</sup>CD11a<sup>hi</sup>) compared to autologous KIR<sup>−</sup>CD11a<sup>low</sup> CD4<sup>+</sup> T cells in lupus patients. The KIR<sup>+</sup>CD11a<sup>hi</sup> T cell subset has been previously shown to overexpress other methylation sensitive genes in lupus patients including <italic>CD40LG</italic>, also located on the X chromosome. (*, <italic>P</italic> < .01, corrected for multiple testing and derived using GenomeStudio (Illumina)). B) Normalized mRNA expression values of ACE2 in CD4<sup>+</sup> T cells isolated from lupus patients compared to healthy controls. These data were extracted from Gene Expression Omnibus (GEO accession: <ext-link ext-link-type="uri" xlink:href="ncbi-geo:GSE4588" id="ir0005">GSE4588</ext-link>) (<italic>P</italic> = .01; Mann-Whitney test). C) Demethylation of a CpG site in the 3′-untranslated region of <italic>ACE2</italic> (cg23232263) in CD4<sup>+</sup> T cells from lupus patients with a history of kidney involvement compared to age, sex, and ethnicity matched healthy controls. DNA methylation beta values were extracted from genome-wide methylation data generated using the HumanMethylation450 array (<italic>P</italic> = .03; Mann-Whitney test) D) Normalized mRNA expression values of ACE2 in the same CD4+ T cell samples from lupus patients and controls shown in panel C. Values were extracted from Affymetrix U133 plus 2.0 array data (<italic>P</italic> = .18; Mann-Whitney test).</p></caption><alt-text id="al0005">Fig. 1</alt-text><graphic xlink:href="gr1_lrg"></graphic></fig></p><p id="p0055">Lupus patients are also characterized by expansion of a pro-inflammatory double negative T cell subset (CD4<sup>−</sup>CD8<sup>−</sup>) [<xref rid="bb0065" ref-type="bibr">13</xref>]. We have previously demonstrated that double negative T cells heavily demethylate cytokine genes including IL-18 and IFNγ, among others [<xref rid="bb0070" ref-type="bibr">14</xref>]. Interestingly, we also observe significant hypomethylation in the <italic>ACE2</italic> gene in double negative T cells compared to autologous CD4<sup>+</sup> and CD8<sup>+</sup> T cells isolated from normal healthy women [<xref rid="bb0070" ref-type="bibr">14</xref>].</p><p id="p0060">Together, these data support that ACE2 expression is regulated by DNA methylation and that a methylation defect in lupus extends to regulatory sequences in the <italic>ACE2</italic> gene, which could result in ACE2 overexpression in lupus patients.</p><p id="p0065">It is important to note that a major limitation to these arguments is the absence of data from alveolar epithelial cells in lupus patients. However, it is worth highlighting that overexpression of ACE2 in other cell types might facilitate viremia and organ damage in COVID-19. Indeed, in SARS, SARS-CoV viral particles (which also utilize ACE2 for cell entry) have been shown to infect immune cells in large numbers, including peripheral blood T cells, which can result in viral dissemination [<xref rid="bb0075" ref-type="bibr">15</xref>]. Direct tissue damage from viral infection of target tissues, such as the kidneys, intestine, and brain has been reported [<xref rid="bb0080" ref-type="bibr">16</xref>].</p><p id="p0070">Overall, the DNA methylation defect in lupus patients is more evident in patients with increased disease activity, and is exacerbated by increased oxidative stress, such as in the case of viral infections [<xref rid="bb0085" ref-type="bibr">17</xref>]. Oxidative stress has been shown to inhibit DNA methylation in lupus T cells by blocking PKC-δ activation, resulting in attenuated MEK/ERK signaling and reduced expression of the main DNA methyltransferase DNMT1 [<xref rid="bb0085" ref-type="bibr">17</xref>,<xref rid="bb0090" ref-type="bibr">18</xref>]. In addition, oxidative stress depletes NADPH and glutathione levels leading to mTOR activation which also exacerbates the DNA methylation defect by inhibiting DNMT1 [<xref rid="bb0095" ref-type="bibr">19</xref>]. Therefore, it is reasonable to suggest the possibility that the DNA methylation defect in lupus patients, exacerbated by oxidative stress generated from SARS-CoV-2 infection, will further enhance viral entry in lupus patients through epigenetic de-repression of <italic>ACE2</italic> and increased ACE2 expression.</p><p id="p0075">Lupus patients are characterized by robust demethylation of interferon-regulated genes, which is persistent and present across multiple cell types and disease subsets [<xref rid="bb0100" ref-type="bibr">20</xref>]. We have previously suggested that this epigenetic activation poises interferon-regulated genes for transcription in lupus patients, and likely explains the exaggerated expression response of interferon-regulated genes in the presence of type-I interferons [<xref rid="bb0020" ref-type="bibr">4</xref>]. Therefore, it is possible that interferon production induced by viral infections, including SARS-CoV-2, will be complicated by an exaggerated immune-response in lupus patients. This might contribute to a cytokine storm and tissue damage during COVID-19 infections in lupus patients. Indeed, we have also demonstrated in CD4<sup>+</sup> T cells progressive demethylation of the gene that encodes the master cytokine regulator NFκB and a number of pro-inflammatory cytokine genes and their key transcription factors with increasing disease activity in lupus patients [<xref rid="bb0105" ref-type="bibr">21</xref>]. Response to SARS-CoV-2 resulting in tissue damage and oxidative stress might further exacerbate the pro-inflammatory epigenetic changes observed in lupus patients resulting in a vicious circle of cytokine response (<xref rid="f0010" ref-type="fig">Fig. 2</xref>).<fig id="f0010"><label>Fig. 2</label><caption><p>Schematic presentation suggesting mechanisms that might increase susceptibility to and severity of COVID-19 in lupus patients. Lupus is characterized by a DNA methylation defect which has been demonstrated in multiple cell types. SARS-CoV-2 utilizes ACE2 as a receptor for entry into cells. <italic>ACE2</italic> is a methylation-sensitive gene located on the X chromosome. Lupus patients show evidence of <italic>ACE2</italic> hypomethylation possibly mediating ACE2 overexpression which will increase the likelihood of SARS-CoV-2 infection. Viral infections are associated with increased oxidative stress, which is known to induce lupus flares and induce further DNA demethylation. Hypomethylation and overexpression of <italic>ACE2</italic> in T cells (and possibly other cell types) will facilitate T cell viral infections and viral dissemination resulting in a more severe COVID-19. Interferon-regulated genes and other inflammatory cytokine genes are hypomethylated in lupus patients and thereby epigenetically primed for transcription upon interferon exposure resulting from viral immune response. This epigenetic priming might increase the possibility of cytokine storm in lupus patients.</p></caption><alt-text id="al0010">Fig. 2</alt-text><graphic xlink:href="gr2_lrg"></graphic></fig></p><p id="p0080">Taken together, these observations suggest that epigenetic dysregulation might increase the risk and severity of SARS-CoV-2 infections in lupus patients. The likelihood of disseminated SARS-CoV-2 infection in lupus patients might be increased due to ACE2 overexpression in peripheral blood mononuclear cells. This is independent of any potential effects of immunosuppressive medications. Based on this model, we also expect that lupus flares will increase the likelihood of infection with SARS-CoV-2 due to increased oxidative stress and DNA demethylation of <italic>ACE2</italic>. Therefore, maintaining remission in lupus patients is of critical importance during this pandemic. Drugs that target epigenetic mechanisms should be considered for further investigation in COVID-19.</p><p id="p0085">In conclusion, our data suggest that lupus patients are more prone to SARS-CoV-2 infections and complicated disease course of COVID-19. This is consistent with recent evidence demonstrating that lupus patients are inherently more susceptible to viral infections [<xref rid="bb0110" ref-type="bibr">22</xref>].</p><sec id="s0005"><title>Funding information</title><p id="p0090">This work was supported by the <funding-source id="gts0005">Lupus Research Alliance</funding-source> and the <funding-source id="gts0010">National Institute of Allergy and Infectious Diseases</funding-source> of the <funding-source id="gts0015">National Institutes of Health</funding-source> grants number U19AI110502 and R01AI097134 to Dr. Sawalha; and the <funding-source id="gts0020">National Natural Science Foundation of China</funding-source> (No. 81830097), the <funding-source id="gts0025">Innovation project of Chinese Academy of Medical Sciences</funding-source> (Research Unit, No. 2019-I2M-5–033) and an urgent grant of <funding-source id="gts0030">Hunan Province for fighting against coronavirus disease- 2019 epidemic</funding-source> (2020SK3005) to Dr. Lu.</p></sec><sec sec-type="COI-statement"><title>Declaration of Competing Interest</title><p id="p0095">None of the authors has any financial conflict of interest to disclose.</p></sec></body><back><ref-list id="bi0005"><title>References</title><ref id="bb0005"><label>1</label><element-citation publication-type="journal" id="rf0005"><person-group person-group-type="author"><name><surname>Huang</surname><given-names>C.</given-names></name><name><surname>Wang</surname><given-names>Y.</given-names></name><name><surname>Li</surname><given-names>X.</given-names></name><name><surname>Ren</surname><given-names>L.</given-names></name><name><surname>Zhao</surname><given-names>J.</given-names></name><name><surname>Hu</surname><given-names>Y.</given-names></name><name><surname>Zhang</surname><given-names>L.</given-names></name><name><surname>Fan</surname><given-names>G.</given-names></name><name><surname>Xu</surname><given-names>J.</given-names></name><name><surname>Gu</surname><given-names>X.</given-names></name><name><surname>Cheng</surname><given-names>Z.</given-names></name><name><surname>Yu</surname><given-names>T.</given-names></name><name><surname>Xia</surname><given-names>J.</given-names></name><name><surname>Wei</surname><given-names>Y.</given-names></name><name><surname>Wu</surname><given-names>W.</given-names></name><name><surname>Xie</surname><given-names>X.</given-names></name><name><surname>Yin</surname><given-names>W.</given-names></name><name><surname>Li</surname><given-names>H.</given-names></name><name><surname>Liu</surname><given-names>M.</given-names></name><name><surname>Xiao</surname><given-names>Y.</given-names></name><name><surname>Gao</surname><given-names>H.</given-names></name><name><surname>Guo</surname><given-names>L.</given-names></name><name><surname>Xie</surname><given-names>J.</given-names></name><name><surname>Wang</surname><given-names>G.</given-names></name><name><surname>Jiang</surname><given-names>R.</given-names></name><name><surname>Gao</surname><given-names>Z.</given-names></name><name><surname>Jin</surname><given-names>Q.</given-names></name><name><surname>Wang</surname><given-names>J.</given-names></name><name><surname>Cao</surname><given-names>B.</given-names></name></person-group><article-title>Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China</article-title><source>Lancet</source><volume>395</volume><year>2020</year><fpage>497</fpage><lpage>506</lpage><pub-id pub-id-type="pmid">31986264</pub-id></element-citation></ref><ref id="bb0010"><label>2</label><element-citation publication-type="journal" id="rf0010"><person-group person-group-type="author"><name><surname>Zhou</surname><given-names>F.</given-names></name><name><surname>Yu</surname><given-names>T.</given-names></name><name><surname>Du</surname><given-names>R.</given-names></name><name><surname>Fan</surname><given-names>G.</given-names></name><name><surname>Liu</surname><given-names>Y.</given-names></name><name><surname>Liu</surname><given-names>Z.</given-names></name><name><surname>Xiang</surname><given-names>J.</given-names></name><name><surname>Wang</surname><given-names>Y.</given-names></name><name><surname>Song</surname><given-names>B.</given-names></name><name><surname>Gu</surname><given-names>X.</given-names></name><name><surname>Guan</surname><given-names>L.</given-names></name><name><surname>Wei</surname><given-names>Y.</given-names></name><name><surname>Li</surname><given-names>H.</given-names></name><name><surname>Wu</surname><given-names>X.</given-names></name><name><surname>Xu</surname><given-names>J.</given-names></name><name><surname>Tu</surname><given-names>S.</given-names></name><name><surname>Zhang</surname><given-names>Y.</given-names></name><name><surname>Chen</surname><given-names>H.</given-names></name><name><surname>Cao</surname><given-names>B.</given-names></name></person-group><article-title>Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study</article-title><source>Lancet</source><volume>395</volume><issue>10229</issue><year>2020</year><fpage>1054</fpage><lpage>1062</lpage><pub-id pub-id-type="pmid">32171076</pub-id></element-citation></ref><ref id="bb0015"><label>3</label><element-citation publication-type="journal" id="rf0015"><person-group person-group-type="author"><name><surname>Teruel</surname><given-names>M.</given-names></name><name><surname>Sawalha</surname><given-names>A.H.</given-names></name></person-group><article-title>Epigenetic variability in systemic lupus erythematosus: what we learned from genome-wide DNA methylation studies</article-title><source>Curr. Rheumatol. Rep.</source><volume>19</volume><year>2017</year><fpage>32</fpage><pub-id pub-id-type="pmid">28470479</pub-id></element-citation></ref><ref id="bb0020"><label>4</label><element-citation publication-type="journal" id="rf0020"><person-group person-group-type="author"><name><surname>Coit</surname><given-names>P.</given-names></name><name><surname>Jeffries</surname><given-names>M.</given-names></name><name><surname>Altorok</surname><given-names>N.</given-names></name><name><surname>Dozmorov</surname><given-names>M.G.</given-names></name><name><surname>Koelsch</surname><given-names>K.A.</given-names></name><name><surname>Wren</surname><given-names>J.D.</given-names></name><name><surname>Merrill</surname><given-names>J.T.</given-names></name><name><surname>McCune</surname><given-names>W.J.</given-names></name><name><surname>Sawalha</surname><given-names>A.H.</given-names></name></person-group><article-title>Genome-wide DNA methylation study suggests epigenetic accessibility and transcriptional poising of interferon-regulated genes in naive CD4+ T cells from lupus patients</article-title><source>J. Autoimmun.</source><volume>43</volume><year>2013</year><fpage>78</fpage><lpage>84</lpage><pub-id pub-id-type="pmid">23623029</pub-id></element-citation></ref><ref id="bb0025"><label>5</label><element-citation publication-type="journal" id="rf0025"><person-group person-group-type="author"><name><surname>Coit</surname><given-names>P.</given-names></name><name><surname>Yalavarthi</surname><given-names>S.</given-names></name><name><surname>Ognenovski</surname><given-names>M.</given-names></name><name><surname>Zhao</surname><given-names>W.</given-names></name><name><surname>Hasni</surname><given-names>S.</given-names></name><name><surname>Wren</surname><given-names>J.D.</given-names></name><name><surname>Kaplan</surname><given-names>M.J.</given-names></name><name><surname>Sawalha</surname><given-names>A.H.</given-names></name></person-group><article-title>Epigenome profiling reveals significant DNA demethylation of interferon signature genes in lupus neutrophils</article-title><source>J. Autoimmun.</source><volume>58</volume><year>2015</year><fpage>59</fpage><lpage>66</lpage><pub-id pub-id-type="pmid">25638528</pub-id></element-citation></ref><ref id="bb0030"><label>6</label><element-citation publication-type="journal" id="rf0030"><person-group person-group-type="author"><name><surname>Imgenberg-Kreuz</surname><given-names>J.</given-names></name><name><surname>Carlsson Almlof</surname><given-names>J.</given-names></name><name><surname>Leonard</surname><given-names>D.</given-names></name><name><surname>Alexsson</surname><given-names>A.</given-names></name><name><surname>Nordmark</surname><given-names>G.</given-names></name><name><surname>Eloranta</surname><given-names>M.L.</given-names></name><name><surname>Rantapaa-Dahlqvist</surname><given-names>S.</given-names></name><name><surname>Bengtsson</surname><given-names>A.A.</given-names></name><name><surname>Jonsen</surname><given-names>A.</given-names></name><name><surname>Padyukov</surname><given-names>L.</given-names></name><name><surname>Gunnarsson</surname><given-names>I.</given-names></name><name><surname>Svenungsson</surname><given-names>E.</given-names></name><name><surname>Sjowall</surname><given-names>C.</given-names></name><name><surname>Ronnblom</surname><given-names>L.</given-names></name><name><surname>Syvanen</surname><given-names>A.C.</given-names></name><name><surname>Sandling</surname><given-names>J.K.</given-names></name></person-group><article-title>DNA methylation mapping identifies gene regulatory effects in patients with systemic lupus erythematosus</article-title><source>Ann. Rheum. Dis.</source><volume>77</volume><year>2018</year><fpage>736</fpage><lpage>743</lpage><pub-id pub-id-type="pmid">29437559</pub-id></element-citation></ref><ref id="bb0035"><label>7</label><element-citation publication-type="journal" id="rf0035"><person-group person-group-type="author"><name><surname>Lu</surname><given-names>Q.</given-names></name><name><surname>Wu</surname><given-names>A.</given-names></name><name><surname>Tesmer</surname><given-names>L.</given-names></name><name><surname>Ray</surname><given-names>D.</given-names></name><name><surname>Yousif</surname><given-names>N.</given-names></name><name><surname>Richardson</surname><given-names>B.</given-names></name></person-group><article-title>Demethylation of CD40LG on the inactive X in T cells from women with lupus</article-title><source>J. Immunol.</source><volume>179</volume><year>2007</year><fpage>6352</fpage><lpage>6358</lpage><pub-id pub-id-type="pmid">17947713</pub-id></element-citation></ref><ref id="bb0040"><label>8</label><element-citation publication-type="journal" id="rf0040"><person-group person-group-type="author"><name><surname>Sawalha</surname><given-names>A.H.</given-names></name><name><surname>Harley</surname><given-names>J.B.</given-names></name><name><surname>Scofield</surname><given-names>R.H.</given-names></name></person-group><article-title>Autoimmunity and Klinefelter’s syndrome: when men have two X chromosomes</article-title><source>J. Autoimmun.</source><volume>33</volume><year>2009</year><fpage>31</fpage><lpage>34</lpage><pub-id pub-id-type="pmid">19464849</pub-id></element-citation></ref><ref id="bb0045"><label>9</label><element-citation publication-type="journal" id="rf0045"><person-group person-group-type="author"><name><surname>Hoffmann</surname><given-names>M.</given-names></name><name><surname>Kleine-Weber</surname><given-names>H.</given-names></name><name><surname>Schroeder</surname><given-names>S.</given-names></name><name><surname>Kruger</surname><given-names>N.</given-names></name><name><surname>Herrler</surname><given-names>T.</given-names></name><name><surname>Erichsen</surname><given-names>S.</given-names></name><name><surname>Schiergens</surname><given-names>T.S.</given-names></name><name><surname>Herrler</surname><given-names>G.</given-names></name><name><surname>Wu</surname><given-names>N.H.</given-names></name><name><surname>Nitsche</surname><given-names>A.</given-names></name><name><surname>Muller</surname><given-names>M.A.</given-names></name><name><surname>Drosten</surname><given-names>C.</given-names></name><name><surname>Pohlmann</surname><given-names>S.</given-names></name></person-group><article-title>SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor</article-title><source>Cell</source><year>2020</year></element-citation></ref><ref id="bb0050"><label>10</label><element-citation publication-type="journal" id="rf0050"><person-group person-group-type="author"><name><surname>Strickland</surname><given-names>F.M.</given-names></name><name><surname>Patel</surname><given-names>D.</given-names></name><name><surname>Khanna</surname><given-names>D.</given-names></name><name><surname>Somers</surname><given-names>E.</given-names></name><name><surname>Robida</surname><given-names>A.M.</given-names></name><name><surname>Pihalja</surname><given-names>M.</given-names></name><name><surname>Swartz</surname><given-names>R.</given-names></name><name><surname>Marder</surname><given-names>W.</given-names></name><name><surname>Richardson</surname><given-names>B.</given-names></name></person-group><article-title>Characterisation of an epigenetically altered CD4(+) CD28(+) Kir(+) T cell subset in autoimmune rheumatic diseases by multiparameter flow cytometry</article-title><source>Lupus Sci. Med.</source><volume>3</volume><year>2016</year><object-id pub-id-type="publisher-id">e000147</object-id></element-citation></ref><ref id="bb0055"><label>11</label><element-citation publication-type="journal" id="rf0055"><person-group person-group-type="author"><name><surname>Gensterblum</surname><given-names>E.</given-names></name><name><surname>Renauer</surname><given-names>P.</given-names></name><name><surname>Coit</surname><given-names>P.</given-names></name><name><surname>Strickland</surname><given-names>F.M.</given-names></name><name><surname>Kilian</surname><given-names>N.C.</given-names></name><name><surname>Miller</surname><given-names>S.</given-names></name><name><surname>Ognenovski</surname><given-names>M.</given-names></name><name><surname>Wren</surname><given-names>J.D.</given-names></name><name><surname>Tsou</surname><given-names>P.S.</given-names></name><name><surname>Lewis</surname><given-names>E.E.</given-names></name><name><surname>Maksimowicz-McKinnon</surname><given-names>K.</given-names></name><name><surname>McCune</surname><given-names>W.J.</given-names></name><name><surname>Richardson</surname><given-names>B.C.</given-names></name><name><surname>Sawalha</surname><given-names>A.H.</given-names></name></person-group><article-title>CD4+CD28+KIR+CD11a(hi) T cells correlate with disease activity and are characterized by a pro-inflammatory epigenetic and transcriptional profile in lupus patients</article-title><source>J. Autoimmun.</source><volume>86</volume><year>2018</year><fpage>19</fpage><lpage>28</lpage><pub-id pub-id-type="pmid">29066026</pub-id></element-citation></ref><ref id="bb0060"><label>12</label><element-citation publication-type="journal" id="rf0060"><person-group person-group-type="author"><name><surname>Zhao</surname><given-names>M.</given-names></name><name><surname>Liu</surname><given-names>S.</given-names></name><name><surname>Luo</surname><given-names>S.</given-names></name><name><surname>Wu</surname><given-names>H.</given-names></name><name><surname>Tang</surname><given-names>M.</given-names></name><name><surname>Cheng</surname><given-names>W.</given-names></name><name><surname>Zhang</surname><given-names>Q.</given-names></name><name><surname>Zhang</surname><given-names>P.</given-names></name><name><surname>Yu</surname><given-names>X.</given-names></name><name><surname>Xia</surname><given-names>Y.</given-names></name><name><surname>Yi</surname><given-names>N.</given-names></name><name><surname>Gao</surname><given-names>F.</given-names></name><name><surname>Wang</surname><given-names>L.</given-names></name><name><surname>Yung</surname><given-names>S.</given-names></name><name><surname>Chan</surname><given-names>T.M.</given-names></name><name><surname>Sawalha</surname><given-names>A.H.</given-names></name><name><surname>Richardson</surname><given-names>B.</given-names></name><name><surname>Gershwin</surname><given-names>M.E.</given-names></name><name><surname>Li</surname><given-names>N.</given-names></name><name><surname>Lu</surname><given-names>Q.</given-names></name></person-group><article-title>DNA methylation and mRNA and microRNA expression of SLE CD4+ T cells correlate with disease phenotype</article-title><source>J. Autoimmun.</source><volume>54</volume><year>2014</year><fpage>127</fpage><lpage>136</lpage><pub-id pub-id-type="pmid">25091625</pub-id></element-citation></ref><ref id="bb0065"><label>13</label><element-citation publication-type="journal" id="rf0065"><person-group person-group-type="author"><name><surname>Crispin</surname><given-names>J.C.</given-names></name><name><surname>Oukka</surname><given-names>M.</given-names></name><name><surname>Bayliss</surname><given-names>G.</given-names></name><name><surname>Cohen</surname><given-names>R.A.</given-names></name><name><surname>Van Beek</surname><given-names>C.A.</given-names></name><name><surname>Stillman</surname><given-names>I.E.</given-names></name><name><surname>Kyttaris</surname><given-names>V.C.</given-names></name><name><surname>Juang</surname><given-names>Y.T.</given-names></name><name><surname>Tsokos</surname><given-names>G.C.</given-names></name></person-group><article-title>Expanded double negative T cells in patients with systemic lupus erythematosus produce IL-17 and infiltrate the kidneys</article-title><source>J. Immunol.</source><volume>181</volume><year>2008</year><fpage>8761</fpage><lpage>8766</lpage><pub-id pub-id-type="pmid">19050297</pub-id></element-citation></ref><ref id="bb0070"><label>14</label><element-citation publication-type="journal" id="rf0070"><person-group person-group-type="author"><name><surname>Renauer</surname><given-names>P.A.</given-names></name><name><surname>Coit</surname><given-names>P.</given-names></name><name><surname>Sawalha</surname><given-names>A.H.</given-names></name></person-group><article-title>The DNA methylation signature of human TCRalphabeta+CD4-CD8- double negative T cells reveals CG demethylation and a unique epigenetic architecture permissive to a broad stimulatory immune response</article-title><source>Clin. Immunol.</source><volume>156</volume><year>2015</year><fpage>19</fpage><lpage>27</lpage><pub-id pub-id-type="pmid">25451162</pub-id></element-citation></ref><ref id="bb0075"><label>15</label><element-citation publication-type="journal" id="rf0075"><person-group person-group-type="author"><name><surname>Gu</surname><given-names>J.</given-names></name><name><surname>Gong</surname><given-names>E.</given-names></name><name><surname>Zhang</surname><given-names>B.</given-names></name><name><surname>Zheng</surname><given-names>J.</given-names></name><name><surname>Gao</surname><given-names>Z.</given-names></name><name><surname>Zhong</surname><given-names>Y.</given-names></name><name><surname>Zou</surname><given-names>W.</given-names></name><name><surname>Zhan</surname><given-names>J.</given-names></name><name><surname>Wang</surname><given-names>S.</given-names></name><name><surname>Xie</surname><given-names>Z.</given-names></name><name><surname>Zhuang</surname><given-names>H.</given-names></name><name><surname>Wu</surname><given-names>B.</given-names></name><name><surname>Zhong</surname><given-names>H.</given-names></name><name><surname>Shao</surname><given-names>H.</given-names></name><name><surname>Fang</surname><given-names>W.</given-names></name><name><surname>Gao</surname><given-names>D.</given-names></name><name><surname>Pei</surname><given-names>F.</given-names></name><name><surname>Li</surname><given-names>X.</given-names></name><name><surname>He</surname><given-names>Z.</given-names></name><name><surname>Xu</surname><given-names>D.</given-names></name><name><surname>Shi</surname><given-names>X.</given-names></name><name><surname>Anderson</surname><given-names>V.M.</given-names></name><name><surname>Leong</surname><given-names>A.S.</given-names></name></person-group><article-title>Multiple organ infection and the pathogenesis of SARS</article-title><source>J. Exp. Med.</source><volume>202</volume><year>2005</year><fpage>415</fpage><lpage>424</lpage><pub-id pub-id-type="pmid">16043521</pub-id></element-citation></ref><ref id="bb0080"><label>16</label><element-citation publication-type="journal" id="rf0080"><person-group person-group-type="author"><name><surname>Gu</surname><given-names>J.</given-names></name><name><surname>Korteweg</surname><given-names>C.</given-names></name></person-group><article-title>Pathology and pathogenesis of severe acute respiratory syndrome</article-title><source>Am. J. Pathol.</source><volume>170</volume><year>2007</year><fpage>1136</fpage><lpage>1147</lpage><pub-id pub-id-type="pmid">17392154</pub-id></element-citation></ref><ref id="bb0085"><label>17</label><element-citation publication-type="journal" id="rf0085"><person-group person-group-type="author"><name><surname>Li</surname><given-names>Y.</given-names></name><name><surname>Gorelik</surname><given-names>G.</given-names></name><name><surname>Strickland</surname><given-names>F.M.</given-names></name><name><surname>Richardson</surname><given-names>B.C.</given-names></name></person-group><article-title>Oxidative stress, T cell DNA methylation, and lupus</article-title><source>Arthritis Rheum.</source><volume>66</volume><year>2014</year><fpage>1574</fpage><lpage>1582</lpage></element-citation></ref><ref id="bb0090"><label>18</label><element-citation publication-type="journal" id="rf0090"><person-group person-group-type="author"><name><surname>Gorelik</surname><given-names>G.</given-names></name><name><surname>Fang</surname><given-names>J.Y.</given-names></name><name><surname>Wu</surname><given-names>A.</given-names></name><name><surname>Sawalha</surname><given-names>A.H.</given-names></name><name><surname>Richardson</surname><given-names>B.</given-names></name></person-group><article-title>Impaired T cell protein kinase C delta activation decreases ERK pathway signaling in idiopathic and hydralazine-induced lupus</article-title><source>J. Immunol.</source><volume>179</volume><year>2007</year><fpage>5553</fpage><lpage>5563</lpage><pub-id pub-id-type="pmid">17911642</pub-id></element-citation></ref><ref id="bb0095"><label>19</label><element-citation publication-type="journal" id="rf0095"><person-group person-group-type="author"><name><surname>Perl</surname><given-names>A.</given-names></name></person-group><article-title>Oxidative stress in the pathology and treatment of systemic lupus erythematosus</article-title><source>Nat. Rev. Rheumatol.</source><volume>9</volume><year>2013</year><fpage>674</fpage><lpage>686</lpage><pub-id pub-id-type="pmid">24100461</pub-id></element-citation></ref><ref id="bb0100"><label>20</label><element-citation publication-type="journal" id="rf0100"><person-group person-group-type="author"><name><surname>Weeding</surname><given-names>E.</given-names></name><name><surname>Sawalha</surname><given-names>A.H.</given-names></name></person-group><article-title>Deoxyribonucleic acid methylation in systemic lupus erythematosus: implications for future clinical practice</article-title><source>Front. Immunol.</source><volume>9</volume><year>2018</year><fpage>875</fpage><pub-id pub-id-type="pmid">29740453</pub-id></element-citation></ref><ref id="bb0105"><label>21</label><element-citation publication-type="journal" id="rf0105"><person-group person-group-type="author"><name><surname>Coit</surname><given-names>P.</given-names></name><name><surname>Dozmorov</surname><given-names>M.G.</given-names></name><name><surname>Merrill</surname><given-names>J.T.</given-names></name><name><surname>McCune</surname><given-names>W.J.</given-names></name><name><surname>Maksimowicz-McKinnon</surname><given-names>K.</given-names></name><name><surname>Wren</surname><given-names>J.D.</given-names></name><name><surname>Sawalha</surname><given-names>A.H.</given-names></name></person-group><article-title>Epigenetic reprogramming in naive CD4+ T cells favoring T cell activation and non-Th1 effector T cell immune response as an early event in lupus flares</article-title><source>Arthritis Rheum.</source><volume>68</volume><year>2016</year><fpage>2200</fpage><lpage>2209</lpage></element-citation></ref><ref id="bb0110"><label>22</label><element-citation publication-type="journal" id="rf0110"><person-group person-group-type="author"><name><surname>Katsuyama</surname><given-names>E.</given-names></name><name><surname>Suarez-Fueyo</surname><given-names>A.</given-names></name><name><surname>Bradley</surname><given-names>S.J.</given-names></name><name><surname>Mizui</surname><given-names>M.</given-names></name><name><surname>Marin</surname><given-names>A.V.</given-names></name><name><surname>Mulki</surname><given-names>L.</given-names></name><name><surname>Krishfield</surname><given-names>S.</given-names></name><name><surname>Malavasi</surname><given-names>F.</given-names></name><name><surname>Yoon</surname><given-names>J.</given-names></name><name><surname>Sui</surname><given-names>S.J.H.</given-names></name><name><surname>Kyttaris</surname><given-names>V.C.</given-names></name><name><surname>Tsokos</surname><given-names>G.C.</given-names></name></person-group><article-title>The CD38/NAD/SIRTUIN1/EZH2 Axis mitigates cytotoxic CD8 T cell function and identifies patients with SLE prone to infections</article-title><source>Cell Rep.</source><volume>30</volume><year>2020</year><fpage>112</fpage><lpage>123</lpage><comment>(e114)</comment><pub-id pub-id-type="pmid">31914379</pub-id></element-citation></ref></ref-list></back></pmc></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Sante/explor/SrasV1/Data/Pmc/Corpus
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000838 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Pmc/Corpus/biblio.hfd -nk 000838 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Sante
|area= SrasV1
|flux= Pmc
|étape= Corpus
|type= RBID
|clé= PMC:7139239
|texte= Epigenetic dysregulation of ACE2 and interferon-regulated genes might suggest increased COVID-19 susceptibility and severity in lupus patients
}}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Pmc/Corpus/RBID.i -Sk "pubmed:32276140" \
| HfdSelect -Kh $EXPLOR_AREA/Data/Pmc/Corpus/biblio.hfd \
| NlmPubMed2Wicri -a SrasV1
| This area was generated with Dilib version V0.6.33. |  |