LAMP3 induces apoptosis and autoantigen release in Sjogren's syndrome patients

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Tanaka, Tsutomu ; Warner, Blake M. ; Odani, Toshio ; Ji, Youngmi ; Mo, Ying-Qian ; Nakamura, Hiroyuki ; Jang, Shyh-Ing ; Yin, Hongen ; Michael, Drew G. ; Hirata, Noriyuki ; Suizu, Futoshi ; Ishigaki, Satoko ; Oliveira, Fabiola Reis ; Motta, Ana Carolina F. ; Ribeiro-Silva, Alfredo ; Rocha, Eduardo M. ; Atsumi, Tatsuya ; Noguchi, Masayuki ; Chiorini, John A.

• Document type: Journal article
• Source: SCIENTIFIC REPORTS; v. 10, n. 1, p. 17-pg., 2020-09-16.

Abstract

Primary Sjogren's syndrome (pSS) is a complex autoimmune disease characterized by dysfunction of secretory epithelia with only palliative therapy. Patients present with a constellation of symptoms, and the diversity of symptomatic presentation has made it difficult to understand the underlying disease mechanisms. In this study, aggregation of unbiased transcriptome profiling data sets of minor salivary gland biopsies from controls and Sjogren's syndrome patients identified increased expression of lysosome-associated membrane protein 3 (LAMP3/CD208/DC-LAMP) in a subset of Sjogren's syndrome cases. Stratification of patients based on their clinical characteristics suggested an association between increased LAMP3 expression and the presence of serum autoantibodies including anti-Ro/SSA, anti-La/SSB, anti-nuclear antibodies. In vitro studies demonstrated that LAMP3 expression induces epithelial cell dysfunction leading to apoptosis. Interestingly, LAMP3 expression resulted in the accumulation and release of intracellular TRIM21 (one component of SSA), La (SSB), and alpha -fodrin protein, common autoantigens in Sjogren's syndrome, via extracellular vesicles in an apoptosis-independent mechanism. This study defines a clear role for LAMP3 in the initiation of apoptosis and an independent pathway for the extracellular release of known autoantigens leading to the formation of autoantibodies associated with this disease.ClinicalTrials.gov Identifier: NCT00001196, NCT00001390, NCT02327884. (AU)

• FAPESP's process: 14/22451-7 - Sustained drug delivery systems targeting the epithelial tissue
• Grantee: Renata Fonseca Vianna Lopez
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 14/23211-0 - The natural history of lacrimal and salivary gland dysfunction in Sjögren's syndrome
• Grantee: Eduardo Melani Rocha
• Support Opportunities: Regular Research Grants