Abstract
ObjectiveThe objective of this study was to determine the effect of epithelial barrier disruption, caused by deficiency of the membrane-anchored serine protease, matriptase, on salivary gland function and the induction of autoimmunity in an animal model.MethodsEmbryonic and acute ablation of matriptase expression in the salivary glands of mice was induced, leading to decreased epithelial barrier function. Mice were characterized for secretory epithelial function and the induction of autoimmunity including salivary and lacrimal gland dysfunction, lymphocytic infiltration, serum anti-Ro/SSA, anti-La/SSB and antinuclear antibodies. Salivary glands immune activation/regulation, barrier function as well as tight junction proteins expression also were determined. Expression of matriptase in minor salivary gland biopsies was compared among pSS patients and healthy volunteers.ResultsEmbryonic ablation of matriptase expression in mice resulted in the loss of secretory epithelial cell function and the induction of autoimmunity similar to that observed in primary Sjögren’s syndrome. Phenotypic changes included exocrine gland dysfunction, lymphocytic infiltrates, production of Sjögren’s syndrome-specific autoantibodies, and overall activation of the immune system. Acute ablation of matriptase expression resulted in significant salivary gland dysfunction in the absence of overt immune activation. Analysis of the salivary glands indicates a loss of electrical potential across the epithelial layer as well as altered distribution of a tight junction protein. Moreover, a significant decrease in matriptase gene expression was detected in the minor salivary glands of pSS patients compared with healthy volunteers.ConclusionsOur findings demonstrate that local impairment of epithelial barrier function can lead to loss of exocrine gland dysfunction in the absence of inflammation while systemic deletion can induce a primary Sjögren’s syndrome like phenotype with autoimmunity and loss of gland function.
Highlights
Primary Sjogren’s syndrome is a chronic autoimmune disease that primarily affects lacrimal and salivary glands, leading to dry eyes and mouth, but it can affect lungs, kidneys, skin, and thyroid
We recently reported that mice with salivary gland deletion of the protease matriptase, which is important for maintaining epithelial barrier function, display a significant decrease in pilocarpine-stimulated saliva production [18]
We have previously shown that embryonic deletion of salivary gland matriptase in mice leads to a near-complete loss of saliva production [18]
Summary
Primary Sjogren’s syndrome (pSS) is a chronic autoimmune disease that primarily affects lacrimal and salivary glands, leading to dry eyes and mouth, but it can affect lungs, kidneys, skin, and thyroid. Genetic defects in the epithelial barrier cells are linked to a spectrum of allergic and autoimmune diseases [6,7,8,9,10,11,12,13,14,15,16,17]. In this respect, the etiology of pSS is still incompletely understood and both epithelial dysfunction and primary immune defects have been proposed as initiating factors
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