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Lysosome-associated membrane protein 3 misexpression in salivary glands induces a Sjögren's syndrome-like phenotype in mice.
Nakamura, Hiroyuki; Tanaka, Tsutomu; Pranzatelli, Thomas; Ji, Youngmi; Yin, Hongen; Perez, Paola; Afione, Sandra A; Jang, Shyh-Ing; Goldsmith, Corrine; Zheng, Chang Yu; Swaim, William D; Warner, Blake M; Hirata, Noriyuki; Noguchi, Masayuki; Atsumi, Tatsuya; Chiorini, John A.
Affiliation
  • Nakamura H; AAV Biology Section, National Institute of Dental and Craniofacial Research, Bethesda, Maryland, USA.
  • Tanaka T; AAV Biology Section, National Institute of Dental and Craniofacial Research, Bethesda, Maryland, USA.
  • Pranzatelli T; AAV Biology Section, National Institute of Dental and Craniofacial Research, Bethesda, Maryland, USA.
  • Ji Y; AAV Biology Section, National Institute of Dental and Craniofacial Research, Bethesda, Maryland, USA.
  • Yin H; AAV Biology Section, National Institute of Dental and Craniofacial Research, Bethesda, Maryland, USA.
  • Perez P; Salivary Disorders Unit, National Institute of Dental and Craniofacial Research, Bethesda, Maryland, USA.
  • Afione SA; AAV Biology Section, National Institute of Dental and Craniofacial Research, Bethesda, Maryland, USA.
  • Jang SI; Salivary Disorders Unit, National Institute of Dental and Craniofacial Research, Bethesda, Maryland, USA.
  • Goldsmith C; AAV Biology Section, National Institute of Dental and Craniofacial Research, Bethesda, Maryland, USA.
  • Zheng CY; AAV Biology Section, National Institute of Dental and Craniofacial Research, Bethesda, Maryland, USA.
  • Swaim WD; AAV Biology Section, National Institute of Dental and Craniofacial Research, Bethesda, Maryland, USA.
  • Warner BM; Salivary Disorders Unit, National Institute of Dental and Craniofacial Research, Bethesda, Maryland, USA.
  • Hirata N; Division of Cancer Biology, Hokkaido University, Sapporo, Japan.
  • Noguchi M; Division of Cancer Biology, Hokkaido University, Sapporo, Japan.
  • Atsumi T; Department of Rheumatology, Endocrinology and Nephrology, Hokkaido University, Sapporo, Japan.
  • Chiorini JA; AAV Biology Section, National Institute of Dental and Craniofacial Research, Bethesda, Maryland, USA jchiorini@dir.nidcr.nih.gov.
Ann Rheum Dis ; 80(8): 1031-1039, 2021 08.
Article in En | MEDLINE | ID: mdl-33658234
OBJECTIVES: Sjögren's syndrome (SS) is an autoimmune sialadenitis with unknown aetiology. Although extensive research implicated an abnormal immune response associated with lymphocytes, an initiating event mediated by salivary gland epithelial cell (SGEC) abnormalities causing activation is poorly characterised. Transcriptome studies have suggested alternations in lysosomal function are associated with SS, but a cause and effect linkage has not been established. In this study, we demonstrated that altered lysosome activity in SGECs by expression of lysosome-associated membrane protein 3 (LAMP3) can initiate an autoimmune response with autoantibody production and salivary dysfunction similar to SS. METHODS: Retroductal cannulation of the submandibular salivary glands with an adeno-associated virus serotype 2 vector encoding LAMP3 was used to establish a model system. Pilocarpine-stimulated salivary flow and the presence of autoantibodies were assessed at several time points post-cannulation. Salivary glands from the mice were evaluated using RNAseq and histologically. RESULTS: Following LAMP3 expression, saliva flow was significantly decreased and serum anti-Ro/SSA and La/SSB antibodies could be detected in the treated mice. Mechanistically, LAMP3 expression increased apoptosis in SGECs and decreased protein expression related to saliva secretion. Analysis of RNAseq data suggested altered lysosomal function in the transduced SGECs, and that the cellular changes can chemoattract immune cells into the salivary glands. Immune cells were activated via toll-like receptors by damage-associated molecular patterns released from LAMP3-expressing SGECs. CONCLUSIONS: These results show a critical role for lysosomal trafficking in the development of SS and establish a causal relationship between LAMP3 misexpression and the development of SS.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Sialadenitis / Sjogren's Syndrome Type of study: Risk_factors_studies Limits: Animals / Humans Language: En Journal: Ann Rheum Dis Year: 2021 Document type: Article Affiliation country: Country of publication:

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Sialadenitis / Sjogren's Syndrome Type of study: Risk_factors_studies Limits: Animals / Humans Language: En Journal: Ann Rheum Dis Year: 2021 Document type: Article Affiliation country: Country of publication: