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The potential for newly synthesized dystrophin to trigger an immune response in DMD patients, however, is not well established. We have evaluated the effect of chronic phosphorodiamidate morpholino oligomer (PMO) treatment on skeletal muscle pathology and asked whether sustained dystrophin expression elicits a dystrophin\u2010specific autoimmune response. Here, two independent cohorts of dystrophic <jats:italic>mdx<\/jats:italic> mice were treated chronically with either 800\u2009mg\/kg\/month PMO for 6\u00a0months (<jats:italic>n<\/jats:italic>\u2009=\u20098) or 100\u2009mg\/kg\/week PMO for 12\u2009weeks (<jats:italic>n<\/jats:italic>\u2009=\u200911). We found that significant muscle inflammation persisted after exon skipping in skeletal muscle. Evaluation of humoral responses showed serum\u2010circulating antibodies directed against <jats:italic>de novo<\/jats:italic> dystrophin in a subset of mice, as assessed both by Western blotting and immunofluorescent staining; however, no dystrophin\u2010specific antibodies were observed in the control saline\u2010treated <jats:italic>mdx<\/jats:italic> cohorts (<jats:italic>n<\/jats:italic>\u2009=\u20098) or in aged (12\u2010month\u2010old) <jats:italic>mdx<\/jats:italic> mice with expanded \u2018revertant\u2019 dystrophin\u2010expressing fibers. Reactive antibodies recognized both full\u2010length and truncated exon\u2010skipped dystrophin isoforms in mouse skeletal muscle. We found more antigen\u2010specific T\u2010cell cytokine responses (e.g. IFN\u2010g, IL\u20102) in dystrophin antibody\u2010positive mice than in dystrophin antibody\u2010negative mice. We also found expression of major histocompatibility complex class I on some of the dystrophin\u2010expressing fibers along with CD8+ and perforin\u2010positive T cells in the vicinity, suggesting an activation of cell\u2010mediated damage had occurred in the muscle. Evaluation of complement membrane attack complex (MAC) deposition on the muscle fibers further revealed lower MAC deposition on muscle fibers of dystrophin antibody\u2010negative mice than on those of dystrophin antibody\u2010positive mice. Our results indicate that <jats:italic>de novo<\/jats:italic> dystrophin expression after exon skipping can trigger both cell\u2010mediated and humoral immune responses in <jats:italic>mdx<\/jats:italic> mice. Our data highlights the need to further investigate the autoimmune response and its long\u2010term consequences after exon\u2010skipping therapy. Copyright \u00a9 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/path.5263","type":"journal-article","created":{"date-parts":[[2019,3,18]],"date-time":"2019-03-18T17:52:35Z","timestamp":1552931555000},"page":"339-351","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Morpholino\u2010induced exon skipping stimulates cell\u2010mediated and humoral responses to dystrophin in <i>mdx<\/i> mice"],"prefix":"10.1002","volume":"248","author":[{"given":"Maria C","family":"Vila","sequence":"first","affiliation":[{"name":"Center for Genetic Medicine Children's National Health System  Washington DC USA"},{"name":"Institute for Biomedical Sciences The George Washington University, School of Medicine and Health Sciences  Washington DC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9989-8724","authenticated-orcid":false,"given":"James 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USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5997-7700","authenticated-orcid":false,"given":"Ning","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences Binghamton University  Binghamton NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa","family":"Morales","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences Binghamton University  Binghamton NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander G","family":"Fritz","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences Binghamton University  Binghamton NY 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