{"doi":"10.1016/j.jid.2024.05.013","title":"Neonatal Fc Receptor Inhibition Reduces Bullous Pemphigoid Anti–Basement Membrane Zone IgG Deposition and Blistering in 3-Dimensional Human Skin Equivalents","abstract":"Bullous pemphigoid (BP) is an autoimmune blistering disease whereby patients develop autoantibodies against the basement membrane zone (BMZ) antigens BP180 and/or BP230. These autoantibodies exert numerous pathogenic Fc receptor (FcR)-dependent and FcR-independent effects (Cole et al., 2022Cole C. Vinay K. Borradori L. Amber K.T. Insights Into the Pathogenesis of Bullous Pemphigoid: The Role of Complement-Independent Mechanisms.Front Immunol. 2022; 13912876Crossref Scopus (15) Google Scholar), and can be readily visualized for diagnosis by direct immunofluorescence (DIF) and indirect immunofluorescence. The neonatal Fc receptor (FcRn) mediates recycling of IgG, extending the half-life of IgG. FcRn is expressed on numerous cell types, including keratinocytes (Cauza et al., 2005Cauza K. Hinterhuber G. Dingelmaier-Hovorka R. Brugger K. Klosner G. Horvat R. et al.Expression of FcRn, the MHC class I-related receptor for IgG, in human keratinocytes.J Invest Dermatol. 2005; 124: 132-139Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). FcRn inhibition has been shown to be efficacious using in vivo models of pemphigoid by reducing circulating antibodies (Pigors et al., 2023Pigors M. Patzelt S. Reichhelm N. Dworschak J. Khil'chenko S. Emtenani S. et al.Bullous pemphigoid induced by IgG targeting type XVII collagen non-NC16A/NC15A extracellular domains is driven by Fc gamma receptor- and complement-mediated effector mechanisms and is ameliorated by neonatal Fc receptor blockade.J Pathol. 2023; PubMed Google Scholar) as well as in vivo or using in vitro models of keratinocytes in pemphigus (Chen et al., 2015Chen Y. Chernyavsky A. Webber R.J. Grando S.A. Wang P.H. Critical Role of the Neonatal Fc Receptor (FcRn) in the Pathogenic Action of Antimitochondrial Autoantibodies Synergizing with Anti-desmoglein Autoantibodies in Pemphigus Vulgaris.J Biol Chem. 2015; 290: 23826-23837Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, Li et al., 2005Li N. Zhao M. Hilario-Vargas J. Prisayanh P. Warren S. Diaz L.A. et al.Complete FcRn dependence for intravenous Ig therapy in autoimmune skin blistering diseases.J Clin Invest. 2005; 115: 3440-3450Crossref PubMed Scopus (222) Google Scholar, Zakrzewicz et al., 2022Zakrzewicz A. Würth C. Beckert B. Feldhoff S. Vanderheyden K. Foss S. et al.Stabilization of Keratinocyte Monolayer Integrity in the Presence of Anti-Desmoglein-3 Antibodies through FcRn Blockade with Efgartigimod: Novel Treatment Paradigm for Pemphigus?.Cells. 2022; 11Crossref Scopus (11) Google Scholar). The contribution of keratinocyte FcRn to BP pathogenesis is unclear. As the persistence of autoantibodies along the BMZ would presumably sustain inflammation, we questioned whether therapeutic FcRn inhibition could exert a potentially acute therapeutic benefit, accelerating local depletion of deposited anti-BMZ antibodies. To test this, we affinity purified IgG from patients with BP or healthy controls. All donors provided written, informed consent. Enrollment criteria and additional methods are described in the Supplementary Methods. We generated 3D human skin equivalents (HSE), pretreating them with efgartigimod, a recombinant Fc mutant with high affinity for FcRn (Ulrichts et al., 2018Ulrichts P. Guglietta A. Dreier T. van Bragt T. Hanssens V. Hofman E. et al.Neonatal Fc receptor antagonist efgartigimod safely and sustainably reduces IgGs in humans.J Clin Invest. 2018; 128: 4372-4386Crossref PubMed Scopus (171) Google Scholar), or wild type recombinant Fc (FcWT). 3D HSE were then subsequently treated with BP-IgG, and IgG deposition and blistering measured by DIF and H&E respectively. Pretreatment with efgartigimod resulted in a significant decrease in histologic blistering (Fig 1a, b). Notably, the efgartigimod treated group demonstrated re-attachment by day 7. In contrast, FcWT treated 3D HSE demonstrated stabilization in blistering by day 3 without significant re-attachment. Efgartigimod treated 3D HSE d","journal":"Journal of Investigative Dermatology","year":2024,"id":454625,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9515,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":720897,"name":"Bethany E. Perez White","orcid":"0000-0002-5594-0599","position":1,"is_corresponding":false},{"id":1278113,"name":"R Chang","orcid":"0000-0003-4963-6926","position":2,"is_corresponding":false},{"id":1071517,"name":"Jing Li","orcid":"0009-0007-4228-0003","position":3,"is_corresponding":false},{"id":1278114,"name":"Katrien Vanderheyden","orcid":"0009-0002-2139-3678","position":4,"is_corresponding":false},{"id":1278115,"name":"Peter Verheesen","orcid":"0000-0001-8760-9158","position":5,"is_corresponding":false},{"id":1278116,"name":"Magdalena Sips","orcid":"0000-0002-6480-9672","position":6,"is_corresponding":false},{"id":1278117,"name":"Maximilian Brinkhaus","orcid":"0000-0002-7426-9980","position":7,"is_corresponding":false},{"id":844639,"name":"Kyle T. Amber","orcid":"0000-0002-2906-2454","position":8,"is_corresponding":false},{"id":1278112,"name":"Lei Bao","orcid":"0000-0002-7834-4327","position":0,"is_corresponding":true}],"reference_count":15,"raw_metadata":null,"created_at":"2026-07-19T02:03:12.720997Z","pmid":"38885876","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}