Abstract
Sjögren's syndrome (SjS) is a chronic autoimmune disease that mainly targets the salivary and lacrimal glands. It has been controversial whether anti-muscarinic type 3 receptor (α-M3R) autoantibodies in patients with SjS inhibit intracellular trafficking of aquaporin-5 (AQP5), water transport protein, leading to secretory dysfunction. To address this issue, GFP-tagged human AQP5 was overexpressed in human salivary gland cells (HSG-hAQP5) and monitored AQP5 trafficking to the plasma membrane following carbachol (CCh, M3R agonist) stimulation. AQP5 trafficking was indeed mediated by M3R stimulation, shown in partial blockage of trafficking by M3R-antagonist 4-DAMP. HSG-hAQP5 pre-incubated with SjS plasma for 24 hours significantly reduced AQP5 trafficking with CCh, compared with HSG-hAQP5 pre-incubated with healthy control (HC) plasma. This inhibition was confirmed by monoclonal α-M3R antibody and pre-absorbed plasma. Interestingly, HSG-hAQP5 pre-incubated with SjS plasma showed no change in cell volume, compared to the cells incubated with HC plasma showing shrinkage by twenty percent after CCh-stimulation. Our findings clearly indicate that binding of anti-M3R autoantibodies to the receptor, which was verified by immunoprecipitation, suppresses AQP5 trafficking to the membrane and contribute to impaired fluid secretion in SjS. Our current study urges further investigations of clinical associations between SjS symptoms, such as degree of secretory dysfunction, cognitive impairment, and/or bladder irritation, and different profiles (titers, isotypes, and/or specificity) of anti-M3R autoantibodies in individuals with SjS.
Highlights
Sjogren’s syndrome (SjS), a systemic autoimmune disease primarily targeting the salivary and lacrimal glands, results in severe dry mouth and dry eyes [1,2]
Muscarinic receptor agonist, carbachol, induces recombinant human AQP5 expression vector (rhAQP5) trafficking in human salivary gland (HSG) cells
The purpose of this study was to further define the roles of anti-muscarinic type 3 receptor (M3R) autoantibodies in SjS and their impact on AQP5 trafficking to the plasma membrane, which is critical for fluid secretion in the salivary glands
Summary
Sjogren’s syndrome (SjS), a systemic autoimmune disease primarily targeting the salivary and lacrimal glands, results in severe dry mouth and dry eyes [1,2]. Despite endeavors to define the environmental, genetic, physiological and immunological causes for SjS onset and progression, underlying etiologies remain poorly understood. Possible mechanisms for dry mouth and dry eyes include epithelial cell apoptosis by autoreactive T- or Blymphocytes infiltrating the glands and pro-inflammatory cytokines [3,4]. Another important mechanism underlying secretory dysfunction in SjS involves inhibitory roles of autoantibodies to the acetylcholine muscarinic type 3 receptor (M3R), which is critical for fluid secretion from acinar cells. Studies have demonstrated acute inhibition of parasympathetic neurotransmission in bladder smooth muscle in the presence of SjS anti-M3R autoantibodies [9,10]
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