Antimyenteric neuronal antibodies in scleroderma.

Abstract

The pathogenesis of gastrointestinal (GI) dysmotility in scleroderma is incompletely understood, although previous studies have proposed a neuropathic mechanism. We studied patients with scleroderma as compared with other connective tissue disease patients and normal controls for the presence of circulating antibodies to myenteric neurons. Serial dilutions of sera were overlaid on rat intestine, doublelabeled with antineurofilament antibody as a myenteric plexus marker, and imaged using indirect immunofluorescence techniques. High titer sera ( -1:50) from 19 out of 41 scleroderma patients stained myenteric neurons, whereas none of 22 normals or 5 patients with idiopathic GI dysmotility were positive. Although 6 out of 20 SLE and 6 out of 10 mixed connective tissue disease patients' sera stained myenteric plexus neurons, when positive sera were absorbed with calf thymus extract to remove antinuclear antibody, 15 scleroderma sera, 0 SLE, and 2 mixed connective tissue disease patients retained positive staining of myenteric neurons. Western blotting using actin and neuronal intermediate filament preparations failed to show immunoreactivity with scleroderma sera containing antimyenteric neuronal antibodies. Paraneoplastic sera associated with GI dysmotility stained myenteric neurons in a different pattern than seen with scleroderma sera. A positive correlation between the presence of Raynaud's phenomenon and antimyenteric neuronal antibodies was observed in scleroderma patients. Our results indicate that IgG antibodies reacting with myenteric neurons are present in many patients with scleroderma. Although the neuronal antigen has not yet been identified, the presence of myenteric neuronal antibodies in patients with GI dysmotility and scleroderma suggests a neuropathic process. (J. Clin. Invest. 1994. 94:761-770.)

Gastrointestinal Manifestations of Systemic Sclerosis

“…2). Howe et al identified autoantibodies to enteric neurons in 15 of 41 patients, suggesting a possible immune-mediated dysfunction of enteric neurons [14]. Antibodies against the muscarinic M3 receptor have been identified in a small group of patients with scleroderma and severe gastrointestinal complications.…”

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

“…A recent study has found a high incidence of antimyenteric neuronal antibodies in the sera of SSc patients with GI symptoms (22). A follow-up study showed that passive transfer of these antibodies into a rat model significantly disrupts intestinal myoelectric activity (15), further supporting a neuropathic etiology to dysmotility in SSc patients.…”

The role of humoral autoimmunity in gastrointestinal neuromuscular diseases

“…However, 19 of 25 patients without anti-myenteric antibodies also had GI dysfunction, casting doubt on a direct causative role (Howe et al 1994). IgG against mAChRs were detected by radioimmunoprecipitation in 7 of 9 scleroderma patients with gastrointestinal symptoms.…”

“…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).…”