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Immunol."],"abstract":"<jats:p>Psoriasis is a chronic skin disease evolving to psoriatic arthritis (PsA) in 30% of cases. LL37 is a psoriasis T-cell autoantigen and, in complex with self-DNA\/RNA, a trigger of type I interferon (IFN-I) and pro-inflammatory factors in dendritic cells. LL37 can undergo irreversible post-translational modifications (PTMs), namely, citrullination and carbamylation, which are linked to a neutrophil-dominated inflammation. Notably, in PsA, carbamylated and citrullinated LL37 (carb-LL37 and cit-LL37) become antibody targets. Here, we analyze the presence of, and the T-cell and antibody reactivity to, cit-LL37 and carb-LL37, to address the occurrence and significance of these PTMs in psoriasis. The presence of modified LL37 in skin biopsies was assessed by laser scanner confocal microscopy (LSCM); T-cell responses to modified LL37 were assessed by Ki67 assay and intracellular cytokine staining using flow cytometry; serum autoantibodies to the same antigens were tested by enzyme-linked immunosorbent assay (ELISA). The results show that native and modified LL37 (both carb-LL37 and cit-LL37) are detectable in psoriatic skin, but not in healthy donors\u2019 (HD) skin, where they colocalize with neutrophil infiltrates and neutrophil extracellular trap formation (NETosis). Psoriatic T cells and antibodies recognize native LL37, cit-LL37, and carb-LL37, but only CD4-T-cell responses to native LL37 and carb-LL37 correlate with psoriasis area severity index (PASI), whereas CD8-T-cell responses to the same peptides correlate with PASI in the HLA-Cw6*02-positive subgroup. CD4-T cells specific for modified LL37 express heterogeneous T-helper (Th) phenotypes: native\/carb-LL37-specific T cells mainly manifest a Th1\/Th17-like phenotype, whereas cit-LL37-specific T cells resemble Th-follicular (Thf)-like cells. <jats:italic>In vitro<\/jats:italic> T-cell polarization experiments suggest that distinct pro-inflammatory effects of LL37 and modified LL37, in complex with self-nucleic acids, may concur to these phenomena. This is the first evidence in psoriasis that PTMs of an autoantigen with innate immune cell stimulatory ability dictate autoreactive Th-cell polarization. These data, obtained using LL37 as a model autoantigen, indicate that citrullination and carbamylation pathways may play a role in the psoriasis course, generating epitopes to which immunological tolerance does not exist and potentially concur to PsA development.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1546422","type":"journal-article","created":{"date-parts":[[2025,4,9]],"date-time":"2025-04-09T05:21:19Z","timestamp":1744176079000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["The nature of the post-translational modifications of the autoantigen LL37 influences the autoreactive T-helper cell phenotype in psoriasis"],"prefix":"10.3389","volume":"16","author":[{"given":"Roberto","family":"Lande","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Mennella","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raffaella","family":"Palazzo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Favaro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Facheris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flavia","family":"Mancini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Ocone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabetta","family":"Botti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Falchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Immacolata","family":"Pietraforte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Curdin","family":"Conrad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Bianchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Costanzo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Loredana","family":"Frasca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,4,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1111\/1346-8138.13186","article-title":"Psoriasis: 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