Transfer of human serum IgG to nonobese diabetic Igμ ^null mice reveals a role for autoantibodies in the loss of secretory function of exocrine tissues in Sjögren’s syndrome

Abstract

The NOD (nonobese diabetic) mouse has been studied as an animal model for autoimmune insulindependent diabetes and Sjögren's syndrome. NOD.Ig null mice, which lack functional B lymphocytes, develop progressive histopathologic lesions of the submandibular and lachrymal glands similar to NOD mice, but in the absence of autoimmune insulitis and diabetes. Despite the focal appearance of T cells in salivary and lachrymal tissues, NOD.Ig null mice fail to lose secretory function as determined by stimulation of the muscarinic͞cholinergic receptor by the agonist pilocarpine, suggesting a role for B cell autoantibodies in mediating exocrine dryness. Infusion of purified serum IgG or F(ab) 2 fragments from parental NOD mice or human primary Sjögren's syndrome patients, but not serum IgG from healthy controls, alters stimulated saliva production, an observation consistent with antibody binding to neural receptors. Furthermore, human patient IgG fractions competitively inhibited the binding of the muscarinic receptor agonist, [ 3 H]quinuclidinyl benzilate, to salivary gland membranes. This autoantibody activity is lost after preadsorption with intact salivary cells. These findings indicate that autoantibodies play an important part in the functional impairment of secretory processes seen in connection with the autoimmune exocrinopathy of Sjögren's syndrome.

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).…”

“…Antibodies capable of immunoprecipitating muscarinic receptors have been detected in the NOD mouse (70), suggesting that antimuscarinic antibody activity could underlie the pathology responsible for the salivary gland hypofunction. This theory is further supported by the findings that 1) NOD Ig -null mice that lack B cells do not develop salivary gland hypofunction, 2) passive transfer of NOD mouse IgG or of SS patient IgG or IgG F(abЈ) 2 fragments to NOD Ig -null mice results in the development of salivary gland hypofunction in the majority of recipient mice (although a few SS IgG fractions did cause hypersecretion) (see below) (71), and 3) infusion of an anti-M 3 R monoclonal antibody into NOD/SCID mice causes salivary gland hypofunction (72). However, a problem with data from animal whole-body experiments is that they do not demonstrate the precise site or mechanism of action of the infused antibody.…”

“…Therefore, it is impossible to differentiate the M 3 subtype from M 1 or M 4 . In addition, data from studies in which radioligand binding has been used to detect SS IgG recognition of muscarinic receptors present on parotid gland membranes isolated from Ig -null mice suggest that the inhibition is competitive rather than noncompetitive (71).…”

Inhibitory effects of autoantibodies on the muscarinic receptors in Sjögren's syndrome

“…The serum IgG from SS patients is reported to compete the binding of muscarinic receptor agonist to salivary gland membranes. 23 Likewise, persistent loss of sensitivity to Ach was reported in salivary acinar cells that obtained from SS patients. 24 Interestingly, SS IgG induced a similar degree of inhibition in the CChevoked bladder contraction by approximately 50%, 25 suggesting that CICT is also reduced in this tissue, because [Ca 2 þ ] i also plays a putative role in smooth muscle contractions.…”

Biochemical Changes Contributing to Functional Quiescence in Lacrimal Gland Acinar Cells after Chronic Ex Vivo Exposure to a Muscarinic Agonist

“…Antireceptor autoantibodies also have been reported to acutely stimulate smooth muscle contraction but, after a 30 m exposure, to cause a rightward shift and suppress the amplitude of the contraction versus [CCh] dose-response curve [8]. Infusion of IgG from SjS patients inhibited salivary secretion in NOD-Igm null mice [9], and infusion of M3AChR antibodies inhibited salivary secretion in NOD-scid mice [10]. Epithelial cells from SjS patients' labial salivary glands exhibit a rightward displacement of their Ca 2þ responses to acetylcholine [11].…”