Antibody-mediated gastrointestinal dysmotility in scleroderma

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).…”

Immunoglobulins from scleroderma patients inhibit the muscarinic receptor activation in internal anal sphincter smooth muscle cells

“…Functional autoantibodies in SSc have been identified that specifically inhibit animal colonic smooth muscle (7,19). These studies have shown that the SSc IgGs inhibit the smooth muscle contraction caused by carbachol-induced activation of M 3 -R. The data were interpreted to indicate that M 3 -R antibodies from the SSc patients' sera may lead to failure of the cholinergic neurotransmission and, in turn, result in GI motility dysfunction.…”

The role of humoral autoimmunity in gastrointestinal neuromuscular diseases

“…Indeed this issue is highlighted by a similar study of GI dysmotility secondary to scleroderma (Goldblatt et al 2002). Circulating autoantibodies which modify in vitro events associated with muscarinic antagonism have been detected in such patients, and have been postulated, as a result of indirect pharmacological evidence, to exert a functional effect, via the M 3 mAChR.…”

“…The sera of scleroderma patients has also been found to contain antibodies capable, in immunofluorescent assays, of binding myenteric neurons (Howe et al 1994). Anti-muscarinic AChR (mAChR) autoantibodies have also been identified in patients with SSc and GI dysfunction (see below for further discussion) (Goldblatt et al 2002;Kawaguchi et al 2009). …”

“…However, from this observation alone the IgG effect cannot be attributed solely to M 3 mAChR antagonism as the agent used to evoke the contractions, carbachol (a muscarinic receptor agonist) also activates the M 2 receptor subclass. Futhermore, the authors note in their discussion that they have failed to show direct binding to M 3 mAChRs transfected and expressed on the surface of mammalian cells or to virally produced recombinant receptors (Goldblatt et al 2002) (see section 1.5.4 for further description). Nevertheless, the presence of antibodies against the M 3 mAChR was investigated using an ELISA to screen for binding to a synthetic peptide corresponding to the second extraellular loop domain of the human receptor.…”