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

The importance of acetylcholine (ACh) in keratinocyte adhesion and acantholysis has been investigated over the last three decades, particularly in the pathophysiology of autoimmune blistering dermatoses. Pemphigus vulgaris (PV) is an autoimmune blistering skin disease where autoantibody-mediated suprabasilar intraepidermal splitting causes flaccid blisters and non-healing erosions of the oral mucosa and sometimes also of the skin. Historically, acantholysis in PV was thought to be driven by anti-desmoglein (Dsg) antibodies.

Botulinum Neurotoxin Type A Directly Affects Sebocytes and Modulates Oleic Acid-Induced Lipogenesis.

Excess sebum (seborrhea) results in oily skin and is associated with large pore size and acne. Studies in healthy, seborrheic volunteers have reported that intradermal injection of commercial preparations of botulinum neurotoxin type A (BoNT/A) (onabotulinumtoxinA, abobotulinumtoxinA, and incobotulinumtoxinA) reduced sebum production, and thus, skin oiliness and pore size. The mechanism for these effects has not been fully elucidated; however, several theories involving direct or indirect effects of BoNT/A on neuronal and/or dermal cells (e.

Mitochondrial Autoantibodies and the Role of Apoptosis in Pemphigus Vulgaris.

Pemphigus vulgaris (PV) is an IgG autoantibody-mediated, potentially fatal mucocutaneous disease manifested by progressive non-healing erosions and blisters. Beyond acting to inhibit adhesion molecules, PVIgGs elicit a unique process of programmed cell death and detachment of epidermal keratinocytes termed apoptolysis. Mitochondrial damage by antimitochondrial antibodies (AMA) has proven to be a critical link in this process.

The M3 Muscarinic Acetylcholine Receptor Promotes Epidermal Differentiation.

The M3 muscarinic acetylcholine receptor is predominantly expressed in the basal epidermal layer where it mediates the effects of the autocrine/paracrine cytotransmitter acetylcholine. Patients with the autoimmune blistering disease pemphigus develop autoantibodies to M3 muscarinic acetylcholine receptor and show alterations in keratinocyte adhesion, proliferation, and differentiation, suggesting that M3 muscarinic acetylcholine receptor controls these cellular functions. Chmr3 mice display altered epidermal morphology resembling that seen in patients with pemphigus vulgaris.

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

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.

Transient lymphadenopathy during intravenous immunoglobulin (IVIg) in a patient with pemphigus vulgaris.

This is the first case of transient cervical lymphadenopathy as an adverse event during IVIg infusion. IVIg plays a vital role in the treatment of many dermatological conditions and identification of adverse events can facilitate patient counseling.

Atypical pemphigus: autoimmunity against desmocollins and other non-desmoglein autoantigens.

In this review, we recap current knowledge about non-desmoglein autoantigens in atypical forms of autoimmune pemphigus. More than 50 keratinocyte proteins, including adhesion molecules, receptors and enzymes as well as mitochondrial proteins can be targeted, leading to alterations in numerous intracellular signaling pathways. Patients with pemphigus herpetiformis feature various combinations of antibodies to desmogleins 1 and 3 and desmocollins 1-3.

Protective Effects of Bark Extract and Nicotine on Cigarette Smoke-induced Oxidative Stress in Keratinocytes.

Background/aim: Cigarette smoke (CS) is a major environmental health threat. The oxidative stress induced by CS on keratinocytes and the possible protective effect of nicotine, its receptor inhibitors, and Pinus halepensis bark extract in relation to known antioxidants were investigated.

Materials And Methods: Primary mouse keratinocytes were exposed to cigarette smoke in the presence and absence of Pinus halepensis bark extract (1 μg/ml), rutin (50 μM) and ascorbic acid (250 μM), nicotine (1 μM) with or without mecamylamine (5 μM) and α-bungarotoxin (0.

Rationale for including intravenous immunoglobulin in the multidrug protocol of curative treatment of pemphigus vulgaris and development of an assay predicting disease relapse.

Analysis of reported outcomes of treatment of pemphigus vulgaris (PV) patients demonstrated that the multidrug approach offers a lower relapse rate compared to the FDA-approved prednisone/rituximab regimen. The multidrug protocol protects keratinocytes from autoantibody attack by systemic corticosteroids and mitochondrion-protecting drugs, selectively eliminates pathogenic autoantibodies by intravenous immunoglobulin (IVIg) and inhibits autoantibody production by cytotoxic immunosuppressors. Therefore, IVIg should be always added to the prednisone/rituximab regimen that does not eliminate circulating autoantibodies.

A historic perspective on the current progress in elucidation of the biologic significance of non-neuronal acetylcholine.

The "5 International Symposium on Non-neuronal Acetylcholine: from bench to bedside" was held on September 27-29, 2019 in Hyatt Regency, Long Beach, CA, USA. Approximately 50 scientists from 11 countries over 6 continents participated in this meeting. The major topics included an overall biologic significance of non-neuronal acetylcholine (ACh) and the roles of the non-neuronal cholinergic systems in mucocutaneous, respiratory, digestive, immunologic, endocrine, cardiovascular, musculoskeletal and kidney diseases, and cancer.

Mechanisms of synergy of autoantibodies to M3 muscarinic acetylcholine receptor and secretory pathway Ca/Mn-ATPase isoform 1 in patients with non-desmoglein pemphigus vulgaris.

Pemphigus vulgaris (PV) is a potentially lethal mucocutaneous blistering disease characterized by IgG autoantibodies (AuAbs) binding to epidermal keratinocytes and inducing a devastating blistering disease affecting oral and/or esophageal surfaces and, sometimes, also the skin. Anti-keratinocyte AuAbs developed by the desmoglein (Dsg) 1/3 AuAb-negative acute PV patients are pathogenic, as they induced acantholysis and epidermal split in the experimental models of PV in vitro and in vivo. These PV patients have various combinations of AuAbs to keratinocyte muscarinic acetylcholine receptor subtype M3 (M3AR), the secretory pathway Ca/Mn-ATPase isoform 1 (SPCA1), and desmocollin 3 whose relative concentrations correlate with the disease activity.

Real-world experience of dupilumab treatment for atopic dermatitis in adults: a retrospective analysis of patients' records.

Background: Clinical trial data for dupilumab, a monoclonal antibody against the interleukin-4 receptor (IL-4Rα), have shown that it is safe and effective for the treatment of moderate to severe atopic dermatitis in patients whose disease is resistant to other therapies. However, little real-world experience with dupilumab use has been reported thus far. The aim of this retrospective study was to assess overall outcomes in adult patients with atopic dermatitis (AD) treated with dupilumab.

Keratosis pilaris rubra with mucin deposition.

Keratosis pilaris (KP) is a benign cutaneous disorder characterized by folliculocentric hyperkeratotic papules most often occurring on the proximal extremities. Erythema is usually limited to perifollicular skin, but when keratosis pilaris presents on a background of confluent erythema, the term keratosis pilaris rubra (KPR) is used. The histological findings associated with KP have not been well described in the literature.

Mechanisms of pathogenic effects of eosinophil cationic protein and eosinophil-derived neurotoxin on human keratinocytes.

Cutaneous deposition of eosinophil degranulation proteins is a major feature of eosinophil-rich cutaneous diseases including bullous pemphigoid (BP). We sought to better understand the effect of two of these proteins - eosinophil cationic protein (ECP) and eosinophil-derived neurotoxin (EDN), on human keratinocytes using the Het-1A cell line. To evaluate expression of key cytokines and chemokines observed in BP as well as metal metalloprotease 9 (MMP9), we performed qPCR and in-cell Western assays on cells treated with either ECP or EDN.

Paraneoplastic autoimmune multiorgan syndrome (PAMS): Beyond the single phenotype of paraneoplastic pemphigus.

Paraneoplastic autoimmune multiorgan syndrome (PAMS) is characterized by a heterogenous group of signs and symptoms including severe desquamative stomatitis, a polymorphous cutaneous eruption, humoral immunity against plakin proteins, contribution of cell-mediated autoimmunity and commonly a progressive respiratory failure. Autoantibodies in PAMS target a wide array of antigens including plakins, cadherins, alpha-2-macroglobulin like 1 (A2ML1), BP180, plakophilin-3, and several neuromuscular antigens. Originally described as paraneoplastic pemphigus in 1990 due to some of its clinical and immunologic similarities to classic pemphigus (pemphigus vulgaris and pemphigus foliaceus), PAMS is a multiorganopathy with several distinct features from these classic forms of pemphigus.

Retrospective analysis of a single-center clinical experience toward development of curative treatment of 123 pemphigus patients with a long-term follow-up: efficacy and safety of the multidrug protocol combining intravenous immunoglobulin with the cytotoxic immunosuppressor and mitochondrion-protecting drugs.

Background: Pemphigus vulgaris (PV) is a life-long IgG autoantibody-mediated blistering disease affecting the mucosal surfaces lined by the stratified epithelium (oral, nasal, genital) and sometimes also the skin. While corticosteroid treatment is life saving, the high dose and prolonged courses required for disease control are associated with significant adverse effects, including death. Although introduction of rituximab (RTX) provided for a favorable outcome, the high relapse rate, that is, up to 80%, precludes successful use of RTX as a monotherapy.

The Role of Eosinophils in Bullous Pemphigoid: A Developing Model of Eosinophil Pathogenicity in Mucocutaneous Disease.

Bullous pemphigoid (BP) is an autoimmune blistering disease which carries a significant mortality and morbidity. While historically BP has been characterized as an IgG driven disease mediated by anti-BP180 and BP230 IgG autoantibodies, developments in recent years have further elucidated the role of eosinophils and IgE autoantibodies. In fact, eosinophil infiltration and eosinophilic spongiosis are prominent features in BP.

Non-Desmoglein Antibodies in Patients With Pemphigus Vulgaris.

Pemphigus vulgaris (PV) is a potentially life-threatening mucocutaneous autoimmune blistering disease. Patients develop non-healing erosions and blisters due to cell-cell detachment of keratinocytes (acantholysis), with subsequent suprabasal intraepidermal splitting. Identified almost 30 years ago, desmoglein-3 (Dsg3), a Ca-dependent cell adhesion molecule belonging to the cadherin family, has been considered the "primary" autoantigen in PV.

Diagnosis and management of pemphigus: Recommendations of an international panel of experts.

Background: Several European countries recently developed international diagnostic and management guidelines for pemphigus, which have been instrumental in the standardization of pemphigus management.

Objective: We now present results from a subsequent Delphi consensus to broaden the generalizability of the recommendations.

Methods: A preliminary survey, based on the European Dermatology Forum and the European Academy of Dermatology and Venereology guidelines, was sent to a panel of international experts to determine the level of consensus.

Mechanisms Causing Loss of Keratinocyte Cohesion in Pemphigus.

The autoimmune blistering skin disease pemphigus is caused by IgG autoantibodies against desmosomal cadherins, but the precise mechanisms are in part a matter of controversial discussions. This review focuses on the currently existing models of the disease and highlights the relevance of desmoglein-specific versus nondesmoglein autoantibodies, the contribution of nonautoantibody factors, and the mechanisms leading to cell dissociation and blister formation in response to autoantibody binding. As the review brings together the majority of laboratories currently working on pemphigus pathogenesis, it aims to serve as a solid basis for further investigations for the entire field.

Meeting Report of the Pathogenesis of Pemphigus and Pemphigoid Meeting in Munich, September 2016.

Autoimmune blistering diseases are a heterogeneous group of about a dozen complex disorders that are characterized by intraepidermal (pemphigus) and subepidermal blistering (pemphigoid diseases and dermatitis herpetiformis). The Pathogenesis of Pemphigus and Pemphigoid Meeting, organized by the Departments of Dermatology in Lübeck and Marburg and the Institute of Anatomy and Cell Biology, Munich, was held in September 2016 in Munich. The meeting brought together basic scientists and clinicians from all continents dedicating their work to autoimmune blistering diseases.