{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T13:50:46Z","timestamp":1776779446422,"version":"3.51.2"},"reference-count":28,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2023,5,7]],"date-time":"2023-05-07T00:00:00Z","timestamp":1683417600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Cutan Pathol"],"published-print":{"date-parts":[[2023,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Immune checkpoint inhibitor (ICI)\u2010based cancer therapies cause a variety of cutaneous immune\u2010related adverse events (irAEs) including immunobullous skin eruptions like bullous pemphigoid (BP). However, little is known about the underlying immunopathogenic drivers of these reactions, and understanding the unique gene expression profile and immune composition of BP\u2010irAE remains a critical knowledge gap in the field of oncodermatology\/oncodermatopathology.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>BP\u2010irAE (<jats:italic>n<\/jats:italic>\u2009=\u20098) and de novo BP control (<jats:italic>n<\/jats:italic>\u2009=\u20098) biopsy samples were subjected to gene expression profiling using the NanoString\u00ae Technologies nCounter PanCancer Immune Profiling Panel. Multiplex immunofluorescence (mIF) studies using markers for T\u2010cells (CD3 and CD8), T helper 1 (T<jats:sub>H<\/jats:sub>1) cells (Tbet), T<jats:sub>H<\/jats:sub>2 cells (Gata3), T<jats:sub>H<\/jats:sub>17 cells (ROR\u03b3T), and regulatory T\u2010cells (Tregs; FoxP3) were further evaluated using InForm\u00ae image analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Compared with de novo BP controls, BP\u2010irAE samples exhibited upregulation of 30 mRNA transcripts (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.025), including toll\u2010like receptor 4 (TLR4) and genes associated with complement activation, and downregulation of 89 mRNA transcripts (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.025), including genes associated with T<jats:sub>H<\/jats:sub>2, T<jats:sub>H<\/jats:sub>17, and B\u2010cell immune response. BP\u2010irAE demonstrated a greater density of Tbet<jats:sup>+<\/jats:sup> (T<jats:sub>H<\/jats:sub>1) cells in the dermis (<jats:italic>p<\/jats:italic>\u2009=\u20090.004) and fewer Tregs in the blister floor (<jats:italic>p<\/jats:italic>\u2009=\u20090.028) when compared with that of de novo control BP samples.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>BP\u2010irAE exhibited activation of the TLR4\/complement\u2010driven classical innate immune response pathway, with dermal T<jats:sub>H<\/jats:sub>1 immune cell polarization and decreased Tregs in the blister floor. TLR\/complement signaling may underlie the immunopathogenesis of BP\u2010irAE.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cup.14442","type":"journal-article","created":{"date-parts":[[2023,5,8]],"date-time":"2023-05-08T03:10:00Z","timestamp":1683515400000},"page":"661-673","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Gene expression profiling and multiplex immunofluorescence analysis of bullous pemphigoid immune\u2010related adverse event reveal upregulation of toll\u2010like receptor 4\/complement\u2010induced innate immune response and increased density of <scp>T<sub>H<\/sub>1<\/scp> T\u2010cells"],"prefix":"10.1111","volume":"50","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6324-2096","authenticated-orcid":false,"given":"Mario L.","family":"Marques\u2010Piubelli","sequence":"first","affiliation":[{"name":"Department of Translational Molecular Pathology The University of Texas MD Anderson Cancer Center  Houston Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7210-8350","authenticated-orcid":false,"given":"Riyad N. H.","family":"Seervai","sequence":"additional","affiliation":[{"name":"Medical Scientist Training Program Baylor College of Medicine  Houston Texas USA"},{"name":"Department of Molecular &amp; Cellular Biology Baylor College of Medicine  Houston Texas USA"},{"name":"Internal Medicine Residency Program Providence Portland Medical Center  Portland Oregon USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kumaran M.","family":"Mudaliar","sequence":"additional","affiliation":[{"name":"Department of Pathology Loyola University Medical Center  Maywood Illinois USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wencai","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Biostatistics The University of Texas MD Anderson Cancer Center  Houston Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Den\u00e1i R.","family":"Milton","sequence":"additional","affiliation":[{"name":"Department of Biostatistics The 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