Antiidiotypic antibodies neutralize autoantibodies that inhibit cholinergic neurotransmission.
OBJECTIVE
Functional autoantibodies that inhibit M(3) muscarinic receptor (M3R)-mediated neurotransmission have been reported in patients with Sjögren's syndrome (SS) and in patients with scleroderma. Because of limited reports that intravenous immunoglobulin (IVIG) improves dysautonomia in primary SS, we investigated whether IVIG neutralizes the effect of anti-M3R antibodies on colon smooth muscle contractions, in an in vitro functional assay.


METHODS
IgG obtained from patients with primary SS, patients with rheumatoid arthritis and secondary SS, and patients with scleroderma was tested, before and after coincubation with equimolar amounts of IVIG or its F(ab')(2) and Fc fractions, for the ability to inhibit carbachol-evoked colon smooth muscle contractions. In addition, patient IgG was passed through an IVIG F(ab')(2) column, and unretained IgG was tested for functional activity on colon smooth muscle strips. Purified IgG obtained from healthy adults was also examined for a neutralizing effect on anti-M3R antibody activity.


RESULTS
Inhibition of colon contractions was mediated by the Fab fraction of patient IgG. Coincubation of IgG from the 3 patient groups with IVIG or its F(ab')(2) fragment neutralized anti-M3R antibody-mediated inhibition of cholinergic smooth muscle contractions. Preabsorption of patient IgG with Sepharose-bound IVIG F(ab')(2) removed the anti-M3R inhibitory activity. In addition, purified IgG from each of 4 healthy adults neutralized the functional autoantibodies.


CONCLUSIONS
Anti-M3R antibody activity does not require receptor crosslinking. Antiidiotypic antibodies present in pooled IgG neutralize patient IgG-mediated inhibition of M3R cholinergic neurotransmission, providing a rationale for IVIG as a treatment of autonomic dysfunction in patients with SS and patients with scleroderma. Furthermore, antiidiotypic antibodies in healthy individuals may prevent the emergence of pathogenic anti-M3R autoantibodies.
Cavill
Dana
D
Flinders University of South Australia, Bedford Park, Australia.
Waterman
Sally A
SA
Gordon
Tom P
TP
D000109:Acetylcholine / Q000276:immunology*; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology*; D003106:Colon / Q000276:immunology; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D007074:Immunoglobulin G; D016756:Immunoglobulins, Intravenous; D066298:In Vitro Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D009119:Muscle Contraction / Q000276:immunology; D009130:Muscle, Smooth / Q000276:immunology; D009500:Neutralization Tests; D012595:Scleroderma, Systemic / Q000276:immunology*; D012859:Sjogren's Syndrome / Q000276:immunology*; D009435:Synaptic Transmission / Q000276:immunology*
D000888:Antibodies, Anti-Idiotypic; D001323:Autoantibodies; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D016756:Immunoglobulins, Intravenous; D000109:Acetylcholine