Chronic exposure to the anti-M3 muscarinic acetylcholine receptor autoantibody in pemphigus vulgaris contributes to disease pathophysiology.

Content Provider	Europe PMC
Author	Chernyavsky, Alex Khylynskyi, Mykhailo M. Patel, Krupa G. Grando, Sergei A.
Copyright Year	2022
Abstract	Pemphigus vulgaris (PV) is a potentially lethal autoimmune mucocutaneous blistering disease characterized by binding of IgG autoantibodies (AuAbs) to keratinocytes (KCs). In addition to AuAbs against adhesion molecules desmogleins 1 and 3, PV patients also produce an AuAb against the M3 muscarinic acetylcholine (ACh) receptor (M3AR) that plays an important role in regulation of vital functions of KCs upon binding endogenous ACh. This anti-M3AR AuAb is pathogenic because its adsorption eliminates the acantholytic activity of PV IgG; however, the molecular mechanism of its action is unclear. In the present study, we sought to elucidate the mode of immunopharmacologic action of the anti-M3AR AuAb in PV. Short-term exposures of cultured KCs to PV IgG or the muscarinic agonist muscarine both induced changes in the expression of keratins 5 and 10, consistent with the inhibition of proliferation and upregulated differentiation and in keeping with the biological function of M3AR. In contrast, long-term incubations induced a keratin expression pattern consistent with upregulated proliferation and decreased differentiation, in keeping with the hyperproliferative state of KCs in PV. This change could result from desensitization of the M3AR, representing the net antagonist-like effect of the AuAb. Therefore, chronic exposure of KCs to the anti-M3AR AuAb interrupts the physiological regulation of KCs by endogenous ACh, contributing to the onset of acantholysis. Since cholinergic agents have already demonstrated antiacantholytic activity in a mouse model of PV and in PV patients, our results have translational significance and can guide future development of therapies for PV patients employing cholinergic drugs.
ISSN	00219258
Volume Number	298
PubMed Central reference number	PMC8897697
Issue Number	3
PubMed reference number	35143842
Journal	The Journal of Biological Chemistry [J. Biol. Chem]
e-ISSN	1083351X
DOI	10.1016/j.jbc.2022.101687
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2022-02-07
Access Restriction	Open
Rights License	This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). © 2022 The Authors
Subject Keyword	pemphigus vulgaris autoimmunity nondesmoglein pemphigus M3 muscarinic acetylcholine receptor keratinocytes acantholysis tachyphylaxis ACh, acetylcholine AuAb, autoantibody DG, diacylglycerol IP3, inositol 1,4,5-triphosphate KC, keratinocyte M3AR, M3 muscarinic acetylcholine receptor mAChR, muscarinic ACh receptor NIgG, normal IgG PLC, phospholipase C PV, Pemphigus vulgaris qPCR, quantitative PCR
Content Type	Text
Resource Type	Article
Subject	Cell Biology Molecular Biology Biochemistry