{"doi":"10.4049/jimmunol.2300080","title":"The Eotaxin-1/CCR3 Axis and Matrix Metalloproteinase-9 Are Critical in Anti-NC16A IgE-Induced Bullous Pemphigoid","abstract":"Bullous pemphigoid (BP) is the most common autoimmune bullous skin disease of humans and is characterized by eosinophilic inflammation and circulating and tissue-bound IgG and IgE autoantibodies directed against two hemidesmosomal proteins: BP180 and BP230. The noncollagenous 16A domain (NC16A) of BP180 has been found to contain major epitopes recognized by autoantibodies in BP. We recently established the pathogenicity of anti-NC16A IgE through passive transfer of patient-derived autoantibodies to double-humanized mice that express the human high-affinity IgE receptor, FcεRI, and human NC16A domain (FcεRI/NC16A). In this model, anti-NC16A IgEs recruit eosinophils to mediate tissue injury and clinical disease in FcεRI/NC16A mice. The objective of this study was to characterize the molecular and cellular events that underlie eosinophil recruitment and eosinophil-dependent tissue injury in anti-NC16A IgE-induced BP. We show that anti-NC16A IgEs significantly increase levels of key eosinophil chemoattractants, eotaxin-1 and eotaxin-2, as well as the proteolytic enzyme matrix metalloproteinase-9 (MMP-9) in the lesional skin of FcεRI/NC16A mice. Importantly, neutralization of eotaxin-1, but not eotaxin-2, and blockade of the main eotaxin receptor, CCR3, drastically reduce anti-NC16A IgE-induced disease activity. We further show that anti-NC16A IgE/NC16A immune complexes induce the release of MMP-9 from eosinophils, and that MMP-9-deficient mice are resistant to anti-NC16A IgE-induced BP. Lastly, we find significantly increased levels of eotaxin-1, eotaxin-2, and MMP-9 in blister fluids of BP patients. Taken together, this study establishes the eotaxin-1/CCR3 axis and MMP-9 as key players in anti-NC16A IgE-induced BP and candidate therapeutic targets for future drug development and testing.","journal":"The Journal of Immunology","year":2023,"id":330394,"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":14,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9557,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":527497,"name":"Jinbo Chen","orcid":"0000-0002-9665-8506","position":1,"is_corresponding":false},{"id":528941,"name":"Ning Li","orcid":"0000-0003-0185-983X","position":2,"is_corresponding":false},{"id":783886,"name":"Susan Burette","orcid":"0000-0002-4485-8207","position":3,"is_corresponding":false},{"id":1054092,"name":"Li Wan","orcid":"0000-0003-4434-9426","position":4,"is_corresponding":false},{"id":1054093,"name":"Liuqing Chen","orcid":"0000-0002-8398-4652","position":5,"is_corresponding":false},{"id":411078,"name":"Donna A. Culton","orcid":"0000-0002-7692-6446","position":6,"is_corresponding":false},{"id":881762,"name":"Songmei Geng","orcid":"0000-0001-8731-6267","position":7,"is_corresponding":false},{"id":530459,"name":"Paul B. Googe","orcid":"0000-0002-9185-3548","position":8,"is_corresponding":false},{"id":388155,"name":"Nancy E. Thomas","orcid":"0000-0002-2230-1328","position":9,"is_corresponding":false},{"id":419926,"name":"Luis A. Diaz","orcid":"0000-0002-7308-292X","position":10,"is_corresponding":false},{"id":528942,"name":"Zhi Liu","orcid":"0000-0003-4060-9585","position":11,"is_corresponding":false},{"id":500731,"name":"Tyler J. M. Jordan","orcid":"0000-0002-6833-0167","position":0,"is_corresponding":true}],"reference_count":70,"raw_metadata":null,"created_at":"2026-07-19T01:09:10.120703Z","pmid":"37672029","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":[]}