Antibodies interfering with the type 3 muscarinic receptor pathway inhibit gastrointestinal motility and cholinergic neurotransmission in Sjögren's syndrome

Abstract

Objective. In primary Sjögren's syndrome (SS), impairment of the gastrointestinal (GI) tract is common, and includes reduced esophageal motor function, delayed gastric emptying, and abnormalities in colonic motility; the pathogenesis is as yet unknown. We undertook this study to investigate the role of functional antibodies to the type 3 muscarinic receptor (M3R) in GI dysfunction associated with primary SS.Methods. Muscle strip and whole-organ functional assays were used to determine whether IgG with anti-M3R activity from patients with primary SS disrupted neurotransmission in tissue from throughout the mouse GI tract. Specificity of the autoantibody for the M3R was determined using knockout mice that were deficient in the expression of muscarinic receptor subtypes.Results. Functional antibodies to the M3R inhibited neuronally mediated contraction of smooth muscle from throughout the GI tract and disrupted complex contractile motility patterns in the colon. The autoantibodies were not active on tissue from mice that lacked the M3R, providing compelling evidence of the direct interaction of patient autoantibodies with the M3R.Conclusion. Our results indicate that anti-M3R autoantibodies have the potential to mediate multiple dysfunctions of the GI tract in primary SS, ranging from reduced esophageal motor activity to altered colonic motility. We hypothesize that altered GI motility forms part of a broader autonomic dysfunction mediated by pathogenic anti-M3R autoantibodies in primary SS.

Immune Activation in Irritable Bowel Syndrome: Can Neuroimmune Interactions Explain Symptoms?

“…Interestingly, increased levels of autoantibodies against neuronal channels have been observed in IBS patients; however, the clinical implications of this are yet to be determined ( 105,106 ). Indeed, patients with autoimmune diseases, including Sjogren ' s syndrome and type 1 diabetes, produce autoantibodies that aff ect GI motility via actions on calcium channels or muscarinic receptors, indicating a potential for autoantibody-mediated GI neural dysfunction ( 107,108 ).…”

A Potential Role of Autoantibodies against Muscarinic Type 3 Receptor in Pathogenesis of Sjogren’s Syndrome

“…As in an aforementioned report [27], researchers combined ELISA and functional assay methods to show that having an excitatory or inhibitory effect depends on the binding of anti-M3R autoantibodies to the different epitopes on M3R in SS. In other reports, anti-M3R autoantibodies in SS were shown to have multiple inhibitory effects on the smooth muscle contractions of the gastrointestinal tract including oesophagus, stomach, ileum, and colon to mediate a broader autonomic dysfunction [14,29]. [16] demonstrated that carbacholinduced calcium mobilization was inhibited by long-term incubation of the cells for 12 h with anti-M3R autoantibodies.…”

“…Anti-nuclear autoantibodies (ANA) and rheumatoid factor (RF) are also present with high prevalence in primary SS [6]. In addition, other autoantibodies found in SS patients are cryoglobulins, anti-smooth muscle antibodies (ASMA), anti-mitochondrial antibodies (AMA) [7,8], anti-centromere antibodies (ACA) [9], antibodies against cyclic citrullinated peptides (anti-CCP) [10], anti-carbonic anhydrase antibodies [11], anti-α fodrin antibodies [12] and anti-muscarinic autoantibodies [13][14][15][16][17]. These autoantibodies can be diagnostic or prognostic markers and are associated with some specific extra-glandular manifestations.…”

Mechanisms of Salivary Gland Secretory Dysfunction in Sjögren’s Syndrome

“…Most recently, it has been demonstrated that primary SS IgG with anti-M3R activity inhibited contraction of the smooth muscle of the GI tract and disrupted contractile motility in the colon (Park et al 2011). These data may explain the widespread impairment of the GI tract in SS patients including delayed gastric emptying and abnormalities in colonic motility (Cai et al 2008, ;Kovacs et al 2003).…”