Circulating antibodies against rat parotid gland M3 muscarinic receptors in primary Sjögren’s syndrome

Abstract

SUMMARYIn this study we demonstrate that IgG present in the sera of patients with primary Sjögren's syndrome (PSS) could bind and activate muscarinic acetylcholine receptors (mAChRs) of rat parotid gland. These antibodies were able to inhibit in a non-competitive manner the binding of 3 H-quinuclidinyl benzilate (QNB) to mAChRs of purified rat parotid gland membranes. Moreover, IgG from PSS could modify biological effects mediated by mAChR activation; i.e. decrease cAMP, increase phosphoinositide turnover without affecting cGMP. Atropine and 4-DAMP blocked all of these effects, and carbachol mimicked them, confirming the M 3 subtype mAChRs mediated PSS IgG action. Neither binding nor biological effect were obtained with IgG from sera of normal women. The prevalence of cholinergic antibody was 100% in PSS, and was independent of Ro/SS-A and La/SS-B antibodies. It could be concluded that antibody against mAChRs may be another serum factor to be considered in the pathophysiology of the development of PSS.

Antimuscarinic antibodies in Sjögren's syndrome: Where are we, and where are we going?

“…The reversibility of the binding observed when mouse or human submandibular acinar cells are exposed to SS IgG or rabbit polyclonal anti-M 3 R is intriguing since it confirms the previous findings in Ig -null mice (71) but is contradictory with data obtained from smooth muscle bioassay (15,62,64) and radioligand binding studies (14,73). In myasthenia gravis it is established that, in vitro, the reversibility of the interaction between the autoantibodies and the nicotinic cholinergic receptors is highly dependent on the length of time of exposure and the concentration of the autoantibody (85).…”

“…Findings of radioligand binding studies have suggested that serum from a large proportion of patients with SS, but not from controls, contains IgG antibodies that can noncompetitively bind to the M 3 R of rat parotid gland (14) or rat exorbital lacrimal gland membranes (73), as well as salivary IgA antibodies that can noncompetitively bind to the M 3 R of rat parotid salivary gland membranes (74). While these data suggest that antimuscarinic antibodies may have a pathologic role in SS, they do not conclusively demonstrate that the interaction is exclusively with M 3 R. This is because experimental differentiation between the muscarinic receptor subtypes present in a tissue is difficult since there are no specific selective antagonists available and, in rodent salivary glands, M 3 R, M 4 R (75), and M 1 R (76) are all present.…”

“…In only one of the radioligand binding studies examining the ability of SS patient IgG or IgA to bind to muscarinic receptors (14,73,74) did the investigators attempt to use a rank order of antagonists to characterize the site of SS IgG interaction with muscarinic receptors (14). Unfortunately, only 4 antagonists were used, and these included AF-DX 116, a compound known to produce variable results with M 3 R (77).…”

“…Although SS is classified as an autoimmune disease, no specific pathologic autoantibody has been found (3,13). However, data from recent studies have suggested that patients with primary SS and patients with secondary SS may have inhibitory autoantibodies directed against muscarinic receptors (14)(15)(16). The presence of inhibitory autoantibodies directed against salivary gland muscarinic receptors would serve to unite the pathologies underlying the glandular hypofunction of both primary and secondary SS, explaining why the degree of glandular hypofunction is equivalent in the two (17).…”

Diagnostic performance of tear function tests in Sjogren's syndrome patients

“…33 A reduced tear secretion, consequent to reduced corneal sensitivity, could also be in relation with an impairment in the parasympathetic control of lachrymal gland, as demonstrated in other exocrine gland, 34,35 as a consequence of the presence of anti M3 muscarinic receptors 36 independently from the concurrent presence of anti-SSA and anti-SSB, 37 as it has been demonstrated in an animal model. 38 A reduced tear clearance rate results in accumulation of corneal metabolism products, including the inflammatory cytokines present in the tear fluid of SS-I patients 39,40 maintaining the ocular surface inflammation within a vicious circle.…”