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LAMP3 induces apoptosis and autoantigen release in Sjögren's syndrome patients
Tsutomu Tanaka1, Blake M Warner1, Toshio Odani1
1National Institute of Dental and Craniofacial Research, National Institutes of Health, NIH 10 Center Dr., Bethesda, MD, 20892, USA.
Abstract:
Primary Sjögren'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 Sjögren's syndrome patients identified increased expression of lysosome-associated membrane protein 3 (LAMP3/CD208/DC-LAMP) in a subset of Sjögren'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 α-fodrin protein, common autoantigens in Sjögren'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.
Insights
Lysosome-associated membrane protein 3 (LAMP3) is elevated in Sjögren's syndrome, driving epithelial cell apoptosis and autoantigen release. This discovery offers new insights into Sjögren's syndrome pathogenesis and potential therapeutic targets.
Area of Science:
- Immunology
- Cell Biology
- Autoimmune Diseases
Background:
- Primary Sjögren's syndrome (pSS) is an autoimmune disorder affecting secretory glands, with complex mechanisms and limited treatment options.
- Diverse clinical presentations in pSS hinder understanding of its underlying pathology.
Purpose of the Study:
- To investigate the role of lysosome-associated membrane protein 3 (LAMP3) in primary Sjögren's syndrome.
- To explore the association between LAMP3 expression and clinical features, including autoantibody profiles.
Main Methods:
- Transcriptome profiling of minor salivary gland biopsies from pSS patients and controls.
- In vitro studies to assess the functional impact of LAMP3 expression on epithelial cells.
- Analysis of autoantigen release via extracellular vesicles.
Main Results:
- Increased LAMP3 expression was identified in a subset of pSS patients, correlating with specific autoantibodies (anti-Ro/SSA, anti-La/SSB, anti-nuclear).
- LAMP3 induced epithelial cell dysfunction and apoptosis in vitro.
- LAMP3 promoted the release of autoantigens (TRIM21, La, α-fodrin) via extracellular vesicles, independent of apoptosis.
Conclusions:
- LAMP3 plays a dual role in pSS: initiating apoptosis and facilitating autoantigen release, contributing to autoantibody formation.
- This study elucidates novel mechanisms in pSS pathogenesis involving LAMP3 and extracellular vesicle-mediated autoantigen presentation.
