Antibodies Against Cerebral M1 Cholinergic Muscarinic Receptor from Schizophrenic Patients: Molecular Interaction

Abstract

We demonstrated the presence of circulating Abs from schizophrenic patients able to interact with cerebral frontal cortex-activating muscarinic acetylcholine receptors (mAChR). Sera and purified IgG from 21 paranoid schizophrenic and 25 age-matched normal subjects were studied by indirect immunofluorescence, flow cytometry, immunoblotting, dot blot, ELISA, and radioligand competition assays. Rat cerebral frontal cortex membranes and/or a synthetic peptide, with an amino acid sequence identical with that of human M1 mAChR, were used as Ags. By indirect immunofluorescence and flow cytometry procedures, we proved that serum-purified IgG fraction from schizophrenic patients reacted to neural cell surfaces from rat cerebral frontal cortex. The same Abs were able to inhibit the binding of the specific M1 mAChR radioligand [3H]pirenzepine. Immunoblotting experiments showed that IgG from schizophrenic patients revealed a band with a molecular mass coincident to that labeled by an anti-M1 mAChR Ab. Using synthetic peptide for dot blot and ELISA, we demonstrated that these Abs reacted against the second extracellular loop of human cerebral M1 mAChR. Also, the corresponding affinity-purified antipeptide Ab displayed an agonistic-like activity associated to specific receptor activation, increasing cyclic GMP production and inositol phosphate accumulation, and protein kinase C translocation. This paper gave support to the participation of an autoimmune process in schizophrenia.

Towards a muscarinic hypothesis of schizophrenia

“…193,194 These antibodies are functionally active as they activate muscarinic receptors on astrocytes 195 and induce an increase in M 1 muscarinic receptor mRNA. 196 These findings, while still preliminary, suggest an interesting possible link between the immune system and muscarinic receptors in schizophrenia.…”

Cholinergic Circuits and Signaling in the Pathophysiology of Schizophrenia

“…These antibodies displace tritiated pirenzapine and have agonist-like properties at the M1 receptor in in vitro assays (Borda et al, 2002).…”

Anti-μ-opioid-receptor IgG antibodies are commonly present in serum from healthy blood donors: evidence for a role in apoptotic immune cell death

“…32 Accordingly, it has been considered that disease-associated autoantibodies may emerge from the natural autoantibody repertoire. 33 In this context, characterization of agonistic anti-G protein-coupled receptor autoantibodies in several pathologic conditions, including Graves disease, 34 preeclampsia, 35 neonatal lupus congenital heart block, 36 and schizophrenia, 37 may presume that these kinds of autoantibodies, including anti-hMOR autoantibodies, are a common feature of the natural autoantibody repertoire.…”