Inhibitory effects of muscarinic receptor autoantibodies on parasympathetic neurotransmission in Sjögren's syndrome

Abstract

Objective. Sjögren's syndrome (SS) is an auto-immune disorder characterized by dry eyes and mouth (sicca syndrome) and lymphocytic infiltration of the lacrimal and salivary glands. Abnormalities of para-sympathetic neurotransmission may contribute to the glandular dysfunction. In this study, we used a functional assay to investigate autoantibody-mediated effects on parasympathetic neurotransmission and smooth muscle contraction. Methods. Serum and purified IgG were obtained from patients with primary and secondary SS and from control subjects. Contraction of isolated bladder strips in response to stimulation of M 3-muscarinic receptors by a muscarinic receptor agonist, carbachol, or by endogenous acetylcholine released from postganglionic parasympathetic nerves was measured before and after the addition of patient serum or IgG. Results. Sera from 5 of 9 patients with primary SS and from 6 of 6 patients with secondary SS inhibited carbachol-evoked bladder contraction by 50%. Sera from these patients also inhibited the action of neuro-nally released acetylcholine at M 3-muscarinic receptors. Sera from 7 of 8 healthy individuals, from patients with rheumatoid arthritis without sicca symptoms, and from patients with systemic lupus erythematosus had no effect. The anti-muscarinic receptor activity was localized in the IgG fraction, since purified IgG from patients with SS also inhibited agonist-and nerve-evoked contractions. In this preliminary study, the autoanti-bodies seemed to be associated with the presence of bladder symptoms and other autonomic features. Conclusion. Autoantibodies that act as antagonists at M 3-muscarinic receptors on smooth muscle occur in a subset of patients with primary and secondary SS. Their presence in secondary SS was unexpected and provides new evidence for a common pathogenetic link between primary and secondary SS. These auto-antibodies appear to contribute to sicca symptoms and may explain associated features of autonomic dysfunc-tion in some patients.

A case of interstitial cystitis accompanying Sj�gren?s syndrome

“…Recent studies suggest that autoantibody to M3R may cause secretory dysfunction that leads to dry mouth in patients with Sjögren's syndrome. 10,25,26 Studies have also shown that sera from patients with Sjögren's syndrome inhibit smooth muscle contraction of isolated bladder strips in response to stimulation of M3R by a muscarinic receptor agonist. Autoantibody to M3R may explain manifestations of autonomic dysfunction, such as interstitial cystitis, in some patients with Sjögren's syndrome.…”

“…Recent studies suggest that autoantibody to type 3 muscarinic acetylcholine receptor (M3R) may contribute to sicca symptoms and may explain associated features of autonomic dysfunction in some patients. 10 Interstitial cystitis accompanying Sjögren's syndrome was first reported by Van De Merwe and colleagues in 1993. 7 To the best of our knowledge, only three reports on interstitial cystitis accompanying Sjögren's syndrome have been published in Japan over the last 10 years.…”

Generation and functional analysis of monoclonal antibodies against the second extracellular loop of human M3 muscarinic acetylcholine receptor

“…Several methods have been used to functionally analyze anti-M3R antibodies. For example, assays of smooth muscle showed that IgG fractions from patients with SS (SS-IgG) inhibited carbachol-evoked or nerveevoked bladder or colon contractions, respectively [5,6]. In salivary gland cells, SS-IgG inhibited both the rise in [Ca 2?…”

Pathogenesis and diagnosis of Sjögren’s syndrome

“…Die Autoantikörper können für den Verlust der sekretorischen Funktion der Drüsen z. T. verantwortlich sein. Die Prä-valenz der Autoantikörper beim primären Sjögren-Syndrom beträgt etwa 60%, die Spezifität ist bei einer Prävalenz von 12% bei Blutspendern aber gering [25]. Der Marker wird momentan nur aus Forschungsindikation bestimmt.…”