{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T20:58:10Z","timestamp":1788209890110,"version":"build-2803163510"},"reference-count":188,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T00:00:00Z","timestamp":1763683200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background\/Objectives: Cutaneous lupus erythematosus (CLE) is a complex autoimmune skin disease driven by genetic predisposition, environmental triggers, and immune dysregulation. Environmental factors such as ultraviolet radiation, smoking, and certain drugs can initiate disease onset by inducing keratinocyte apoptosis. The subsequent release of nucleic acids and danger-associated molecular patterns activates pattern recognition receptors (PRRs) on keratinocytes and immune cells, leading to the production of type I and type III interferons (IFNs) and pro-inflammatory cytokines. The objective of this review is to summarize recent advances in understanding the immunopathogenesis of CLE, with particular attention to emerging cellular players and their therapeutic implications. Methods: A narrative review of the recent literature was performed, including experimental, translational, and clinical studies investigating the cellular and molecular mechanisms underlying CLE and novel targeted treatments derived from these findings. Results: Although plasmacytoid dendritic cells (pDCs) have traditionally been considered the major producers of IFN-I, recent data indicate that pDCs in CLE are functionally impaired and are not the primary source. Other cells, such as keratinocytes have emerged as key producers of IFN-I, contributing to a prelesional, IFN-rich microenvironment. This promotes the recruitment and activation of dendritic cells and other inflammatory myeloid subsets, which are now recognized as central players in amplifying local inflammation. Concurrently, T cells infiltrate the skin, where cytotoxic CD8+ T cells attack keratinocytes and CD4+ T cells further propagate inflammation via cytokine production. B cells and plasma cells produce autoantibodies, forming immune complexes that perpetuate inflammation. Neutrophils release neutrophil extracellular traps (NETs), exposing autoantigens and further stimulating IFN pathways. Macrophages contribute by presenting autoantigens, producing pro-inflammatory mediators, and failing to effectively clear apoptotic cells and immune complexes. Conclusions: The dynamic interplay between the innate and adaptive immune systems sustains the chronic inflammatory state characteristic of CLE. Based on the pathogenetic novelties, new therapeutic agents targeting specific molecules have been developed, which may improve the treatment of this complex disease in the future.<\/jats:p>","DOI":"10.3390\/jcm14238285","type":"journal-article","created":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T15:33:06Z","timestamp":1763739186000},"page":"8285","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["An Overview of the Pathogenesis of Cutaneous Lupus Erythematosus"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1982-888X","authenticated-orcid":false,"given":"Alice","family":"Verdelli","sequence":"first","affiliation":[{"name":"Rare Skin Diseases Unit, P.O. Piero Palagi, Azienda USL Toscana Centro, European Reference Network-Skin Member, University of Florence, 50122 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7493-1498","authenticated-orcid":false,"given":"Emanuela","family":"Barletta","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Biomedical Sciences \u201cMario Serio\u201d, Experimental Pathology and Oncology Section, University of Florence, 50134 Firenze, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0388-1037","authenticated-orcid":false,"given":"Elena Biancamaria","family":"Mariotti","sequence":"additional","affiliation":[{"name":"Rare Skin Diseases Unit, P.O. Piero Palagi, Azienda USL Toscana Centro, European Reference Network-Skin Member, University of Florence, 50122 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5416-4392","authenticated-orcid":false,"given":"Simone","family":"Landini","sequence":"additional","affiliation":[{"name":"Dermatology, Department of Health Sciences, University of Florence, 50125 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1701-8772","authenticated-orcid":false,"given":"Alessandro","family":"Magnatta","sequence":"additional","affiliation":[{"name":"Dermatology, Department of Health Sciences, University of Florence, 50125 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0307-6636","authenticated-orcid":false,"given":"Valentina","family":"Ruffo di Calabria","sequence":"additional","affiliation":[{"name":"Dermatology, Department of Health Sciences, University of Florence, 50125 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0903-4998","authenticated-orcid":false,"given":"Alberto","family":"Corr\u00e0","sequence":"additional","affiliation":[{"name":"U.O.C. Dermatologia, Ospedale San Bortolo, Azienda ULSS 8 Berica, 36100 Vicenza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lavinia","family":"Quintarelli","sequence":"additional","affiliation":[{"name":"Dermatology, Department of Health Sciences, University of Florence, 50125 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Bonanni","sequence":"additional","affiliation":[{"name":"Rare Skin Diseases Unit, P.O. Piero Palagi, Azienda USL Toscana Centro, European Reference Network-Skin Member, University of Florence, 50122 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0630-3501","authenticated-orcid":false,"given":"Luca","family":"Sanna","sequence":"additional","affiliation":[{"name":"Dermatology, Department of Health Sciences, University of Florence, 50125 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-3637-9845","authenticated-orcid":false,"given":"Virginia","family":"Corti","sequence":"additional","affiliation":[{"name":"Dermatology, Department of Health Sciences, University of Florence, 50125 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7471-3471","authenticated-orcid":false,"given":"Marzia","family":"Caproni","sequence":"additional","affiliation":[{"name":"Rare Skin Diseases Unit, P.O. Piero Palagi, Azienda USL Toscana Centro, European Reference Network-Skin Member, University of Florence, 50122 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1007\/s40257-023-00774-8","article-title":"Cutaneous Lupus Erythematosus: An Update on Pathogenesis and Future Therapeutic Directions","volume":"24","author":"Niebel","year":"2023","journal-title":"Am. J. Clin. Dermatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/S0190-9622(81)80261-7","article-title":"Distinctive cutaneous subsets in the spectrum of lupus erythe-matosus","volume":"4","author":"Gilliam","year":"1981","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Kuhn, A., Lehmann, P., and Ruzicka, T. (2005). Classification of cutaneous lupus erythematosus. 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