Antibody-mediated gastrointestinal dysmotility in scleroderma

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).

Responses of mouse colon longitudinal muscle to stimulation by the muscarinic agonist carbachol (1-300 micromol/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.

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.

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.