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

Abstract

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The M3 Muscarinic Acetylcholine Receptor Promotes Epidermal Differentiation

“…These findings support the idea that the cytotransmitter ACh—produced and released by epidermal KCs and signaling through the CHRM3 subtype expressed in epidermal stem cells—has an important epidermal developmental role. This study also sheds new light on the pathophysiology of pemphigus vulgaris where some patients develop autoantibodies inactivating CHRM3 through receptor desensitization ( Chernyavsky et al, 2022 ). Patients with pemphigus vulgaris feature some of the same alterations in adhesion, epidermal stem cell proliferation, and differentiation as observed in the experimental model of Chrm3 inactivation.…”

“…Patients with pemphigus vulgaris feature some of the same alterations in adhesion, epidermal stem cell proliferation, and differentiation as observed in the experimental model of Chrm3 inactivation. Similar to the epidermal changes in Chrm3 −/− mice, anti-CHRM3 pemphigus autoantibodies upregulate K5 and downregulate K10 ( Chernyavsky et al, 2022 ) in mice—findings that are mirrored in the epidermis of patients with pemphigus vulgaris ( Williamson et al, 2006 ).…”

The Role of Non-Neuronal Acetylcholine in the Autoimmune Blistering Disease Pemphigus Vulgaris

“…Autoantibodies against mAChRs in patients with PV have been known for many years, but more recently, the role of the M3 subtype of AChRs in pemphigus has been elucidated specifically [ 24 , 25 , 26 , 27 ]. M3 mAChR is found predominantly in the basal layer of the epidermis and is involved in the regulation of keratinocyte proliferation, migration, adhesion, and terminal differentiation by endogenous ACh [ 17 ].…”

“…More recently, the long-term incubation of cultured keratinocytes with the anti-M3 mAChR antibody resulted in the decreased expression of M3 mAChR and an agonist-like effect on M3 mAChR signaling [ 26 ]. PV IgGs cause acantholysis via a receptor/ligand interaction titled the “Inactivation/Activation of Biologically Active Molecules”, mitigating the participation of complement and inflammatory cells.…”

In Vitro, Ex Vivo, and In Vivo Models for the Study of Pemphigus

“…Although DSG3 and DSG1 are the cadherins mainly targeted by autoantibodies, other cadherins, such as Desmocollin1 (DSC1), DSC2 and DSC3, are involved in nonclassical forms of Pemphigus [7]. Beyond cadherins, other proteins, such as anti-cholinergic receptors, have been described as targets for autoantibodies in Pemphigus patients [8]. The role of autoantibodies against non-cadherin autoantigens in the disease has not been completely clarified yet, but their presence further highlights the complexity of this disease.…”