Antimuscarinic antibodies in primary Sjögren's syndrome reversibly inhibit the mechanism of fluid secretion by human submandibular salivary acinar cells

Abstract

Objective. Sjögren's syndrome (SS) is an autoimmune condition affecting salivary glands, for which a clearly defined pathogenic autoantibody has yet to be identified. Autoantibodies that bind to the muscarinic M 3 receptors (M 3 R), which regulate fluid secretion in salivary glands, have been proposed in this context. However, there are no previous data that directly show antisecretory activity. This study was undertaken to investigate and characterize the antisecretory activity of anti-M 3 R. Methods. Microfluorimetric Ca 2؉ imaging and patch clamp electrophysiologic techniques were used to measure the secretagogue-evoked increase in [Ca 2؉] i and consequent activation of Ca 2؉ -dependent ion channels in individual mouse and human submandibular acinar cells. Together, these techniques form a sensitive bioassay that was used to determine whether IgG isolated from patients with primary SS and from control subjects has antisecretory activity.Results. IgG (2 mg/ml) from patients with primary SS reduced the carbachol-evoked increase in [Ca 2؉ ] i in both mouse and human acinar cells by ϳ50%. IgG from control subjects had no effect on the Ca 2؉ signal. Furthermore, the inhibitory action of primary SS patient IgG on the Ca 2؉ signal was acutely reversible. We repeated our observations using rabbit serum containing antibodies raised against the second extracellular loop of M 3 R and found an identical pattern of acutely reversible inhibition. Anti-M 3 R-positive serum had no effect on Ca 2؉-dependent ion channel activation evoked by the direct intracellular infusion of inositol 1,4,5-triphosphate.Conclusion. These observations show for the first time that IgG from patients with primary SS contains autoantibodies capable of damaging saliva production and contributing to xerostomia. The unusual but not unprecedented acute reversibility of the effects of anti-M 3 autoantibodies is the subject of further research.

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

“…While longitudinal studies correlating results from the functional assays with manometry, GI imaging, and clinical features in patients are needed to clarify the relationship between anti-M3R autoantibodies and GI symptoms in primary SS, these autoantibodies have also been implicated in primary SS-associated dysfunction of bladder detrusor and secretomotor activity in lacrimal and salivary glands (3,11,13,31,36,37). Thus, we hypothesize that GI transit abnormalities form part of a broad spectrum of autonomic dysfunction that is mediated by anti-M3R autoantibodies in primary SS.…”

“…In addition, the inability of IgG from patients with primary SS to alter spontaneous, neuronally mediated CMMC activity in M3R-knockout mice provides evidence against the presence of other pathogenic autoantibodies against targets that regulate CMMC activity in these animals. Presumably, the use of muscarinic receptor-knockout mice would also be a suitable strategy for determining the specificity of autoantibodymediated pathogenesis in other autonomic features of primary SS, including secretory function in salivary acinar cells (31,43,44).…”

Olho seco: etiopatogenia e tratamento

“…O processo inflamatório nas glândulas leva à expressão de autoantígenos na superfície das células epiteliais (fodrin, Ro e La) e retenção de células CD-4 e CD-8 tecidoespecíficas. Além disso, a hiposecreção é amplificada através de um bloqueio neurossecretor contra receptores muscarínicos dentro das glândulas (15) .…”

Sjögren’s syndrome

“…Antimuscarinic receptor antibodies are currently a proposed explanation for this functional impairment. 5 …”