LAMP3 induces apoptosis and autoantigen release in Sjögren’s syndrome patients

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.

Differentially Expressed Gene Pathways in the Conjunctiva of Sjögren Syndrome Keratoconjunctivitis Sicca

“…Genome-wide studies have shown that DEGs TAP1, TAP2, PSMB9, HLA-DR, HLA-DMA have been associated with SS in more than one study ( 52 , 125 , 126 ). LAMP3 was the third most upregulated DEG in our results, in agreement with previous studies that also reported elevated LAMP3 levels in SS ( 62 , 117 ). MX1 has also been found elevated in other cohorts of SS patients, including conjunctiva ( 13 , 14 ), labial salivary biopsies ( 53 , 62 , 127 , 128 ), and serum ( 129 ).…”

“…LAMP3 is a marker of mature DCs in humans ( 114 ), and we and others have shown that the conjunctiva of SS KCS patients is rich in antigen-presenting cells ( 8 , 33 , 115 , 116 ). LAMP3+ patients have increased levels of autoantibodies in their serum, and in-vitro , overexpression of LAMP3 induces apoptosis of minor salivary gland epithelial cells ( 117 ). Adenovirus transfection with LAMP3 in mice induces an SS-like phenotype accompanied by decreased salivary function ( 118 ).…”

Lysosome-associated membrane protein 3 misexpression in salivary glands induces a Sjögren’s syndrome-like phenotype in mice

“…11 Transfection of LAMP3 expression plasmid into SGEC-driven cell lines increased caspase-dependent apoptosis and promoted the release of intracellular SSA and SSB autoantigens via extracellular vesicles. 11 These in vitro studies suggested LAMP3 expression in SGECs could contribute to the induction of salivary dysfunction and autoantibody production. The lysosome is a membrane-bound organelle that contains hydrolytic enzymes to degrade many kinds of biomolecules, and has various cellular functions, such as energy metabolism, plasma membrane repair and protein secretion, by ingesting and dissolving cell debris, other damaged organelles or foreign substances that have entered the cell.…”

Characterising COVID-19 as a Viral Clotting Fever: A Mixed Methods Scoping Review

“…There is evidence that when senescent neutrophils are not cleared through apoptosis this is associated with the development of autoimmune disease (Kawano et al, 2018). (Tanaka et al, 2020) have demonstrated an association between apoptosis-associated release of autoantigens and SLE. (Yang et al, 2019) note that autoantigens and damage associated molecular patterns (DAMPS) are released after apoptosis, pyroptosis, necroptosis and by NET’s resulting in inflammation and with a potential for autoimmune reactions.…”