Antibody-mediated gastrointestinal dysmotility in scleroderma☆☆☆

Abstract 

Background & Aims: Defects in enteric excitatory neurotransmission have been proposed to underlie the gastrointestinal dysmotility associated with scleroderma (systemic sclerosis). This study investigated whether patients with scleroderma produce antibodies that inhibit M3-muscarinic or neurokinin receptor–mediated intestinal contractions, either directly or via an effect on L-type voltage-gated calcium channels (VGCCs). Methods: Responses of mouse colon longitudinal muscle to stimulation by the muscarinic agonist carbachol (1–300 μmol/L) and neurokinin-1 and -2 receptor agonists were measured in the absence and presence of serum (2%) or immunoglobulin G (IgG) (0.3–1.0 mg/mL) from patients with scleroderma, those with other autoimmune disorders, and healthy controls. The role of L-type VGCCs in carbachol- and tachykinin-evoked contractions was assessed using nicardipine. Results: M3-muscarinic receptor–mediated contractions were inhibited by Ig fractions from 7 of 9 patients with scleroderma (limited and diffuse forms), 4 of 4 patients with primary Sjögren's syndrome, and 3 of 3 patients with secondary Sjögren's syndrome. Ig fractions from healthy controls did not inhibit the M3-muscarinic receptor–mediated contractions. Inhibition by Ig was concentration-dependent; a maximum inhibition of approximately 40% occurred at 0.6 mg/mL IgG. Both M3-muscarinic and neurokinin receptor–mediated contractions were L-type VGCC dependent. Patient sera had no effect on responses to neurokinin receptor stimulation, demonstrating the lack of antibodies inhibiting L-type VGCCs. Conclusions: Functional antibodies specifically inhibiting M3-muscarinic receptor–mediated enteric cholinergic neurotransmission may provide a pathogenic mechanism for the gastrointestinal dysfunction seen in patients with scleroderma.

GASTROENTEROLOGY 2002;123:1144-1150

Abbreviations:  NK , neurokinin, RA , rheumatoid arthritis, RF , rheumatoid factor, VGCC , voltage-gated calcium channel