{"doi":"10.1002/art.42844","title":"Amplified Type I Interferon Response in Sjögren's Disease via Ectopic Toll‐Like Receptor 7 Expression in Salivary Gland Epithelial Cells Induced by Lysosome‐Associated Membrane Protein 3","abstract":"OBJECTIVE: Lysosome-associated membrane protein 3 (LAMP3) misexpression in salivary gland epithelial cells plays a causal role in the development of salivary gland dysfunction and autoimmunity associated with Sjögren's disease (SjD). This study aimed to clarify how epithelial LAMP3 misexpression is induced in SjD. METHODS: To explore upstream signaling pathways associated with LAMP3 expression, we conducted multiple RNA sequencing analyses of minor salivary glands from patients with SjD, submandibular glands from a mouse model of SjD, and salivary gland epithelial cell lines. A hypothesis generated by the RNA sequencing analyses was further tested by in vitro and in vivo assays with gene manipulation. RESULTS: Transcriptome analysis suggested LAMP3 expression was associated with enhanced type I interferon (IFN) and IFNγ signaling pathways in patients with SjD. In vitro studies showed that type I IFN but not IFNγ stimulation could induce LAMP3 expression in salivary gland epithelial cells. Moreover, we discovered that LAMP3 overexpression could induce ectopic Toll-like receptor 7 (TLR-7) expression and type I IFN production in salivary gland epithelial cells both in vitro and in vivo. TLR-7 knockout mice did not develop any SjD-related symptoms following LAMP3 induction. CONCLUSION: Epithelial LAMP3 misexpression can be induced through enhanced type I IFN response in salivary glands. In addition, LAMP3 can promote type I IFN production via ectopic TLR-7 expression in salivary gland epithelial cells. This positive feedback loop can contribute to maintaining LAMP3 misexpression and amplifying type I IFN production in salivary glands, which plays an essential role in the pathophysiology of SjD.","journal":"Arthritis & Rheumatology","year":2024,"id":432829,"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":0.9423,"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":242303,"name":"Tsutomu Tanaka","orcid":"0000-0001-9729-4006","position":1,"is_corresponding":false},{"id":161553,"name":"Changyu Zheng","orcid":null,"position":2,"is_corresponding":false},{"id":391413,"name":"Sandra Afione","orcid":null,"position":3,"is_corresponding":false},{"id":77995,"name":"Tatsuya Atsumi","orcid":"0000-0001-5657-962X","position":4,"is_corresponding":false},{"id":242302,"name":"Masayuki Noguchi","orcid":"0000-0002-1787-2724","position":5,"is_corresponding":false},{"id":323409,"name":"Fabíola Reis de Oliveira","orcid":"0000-0002-9196-7422","position":6,"is_corresponding":false},{"id":323410,"name":"Ana Carolina Fragoso Motta","orcid":"0000-0002-3887-9239","position":7,"is_corresponding":false},{"id":1237793,"name":"Fernando Chahud","orcid":"0000-0002-8099-9648","position":8,"is_corresponding":false},{"id":323412,"name":"Eduardo Melani Rocha","orcid":"0000-0001-9888-7313","position":9,"is_corresponding":false},{"id":298802,"name":"Blake M. Warner","orcid":"0000-0002-4961-018X","position":10,"is_corresponding":false},{"id":242306,"name":"John A. Chiorini","orcid":"0000-0003-4919-4056","position":11,"is_corresponding":false},{"id":323408,"name":"Hiroyuki Nakamura","orcid":"0000-0003-2149-7573","position":0,"is_corresponding":true}],"reference_count":41,"raw_metadata":null,"created_at":"2026-07-19T01:59:39.937122Z","pmid":"38472139","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":[]}