Correlation of antimuscarinic acetylcholine receptor antibody titers and antidesmoglein antibody titers with the severity of disease in patients with pemphigus

Lakshmi, Manimegalai Jeyasekaran Dhanabhakya; Jaisankar, T J; Rajappa, Medha; Thappa, Devinder Mohan; Chandrashekar, Laxmisha; Divyapriya, Dakshinamurthy; Munisamy, Malathi; Revathy, G.

doi:10.1016/j.jaad.2016.11.039

Cited by 28 publications

(33 citation statements)

References 7 publications

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“…Although the presence of anti-mAR AuAbs in PV patients has been known for 25 years (30), specific targeting of the M3AR subtype was discovered only recently in proteomic studies independently performed by our (10) and Dr. Sinha's groups (31). Yet another group most recently has demonstrated that anti-M3AR AuAb correlates with disease activity and its titer declines with therapy (32), which is consistent with our finding reported herein. The pathogenic activity of anti-M3AR AuAb apparently stems from phosphorylation of classical and desmosomal cadherins in keratinocytes, by analogy with that observed upon functional inactivation of M3AR through the pharmacological approach (reviewed in Ref.…”

Section: Autoimmunity Of Non-desmoglein Pemphigussupporting

confidence: 89%

Synergy among non-desmoglein antibodies contributes to the immunopathology of desmoglein antibody–negative pemphigus vulgaris

Chernyavsky¹,

Amber

Agnoletti³

et al. 2019

Journal of Biological Chemistry

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Edited by Peter Cresswell Pemphigus vulgaris (PV) is a potentially lethal mucocutaneous blistering disease characterized by IgG autoantibodies (AuAbs) binding to epidermal keratinocytes and inducing this devastating disease. Here, we observed that non-desmoglein (Dsg) AuAbs in the sera of patients with Dsg1/3 AuAb-negative acute PV are pathogenic, because IgGs from these individuals induced skin blistering in neonatal mice caused by suprabasal acantholysis. Serum levels of AuAbs to desmocollin 3 (Dsc3), M3 muscarinic acetylcholine receptor (M3AR), and secretory pathway Ca 2؉/ Mn 2؉ -ATPase isoform 1 (SPCA1) correlated with the disease stage of PV. Moreover, AuAb absorption on recombinant Dsc3, M3AR, or SPCA1 both prevented skin blistering in the passive transfer of AuAbs model of PV in BALB/c mice and significantly decreased the extent of acantholysis in a neonatal mouse skin explant model. Although acantholytic activities of each of these immunoaffinity-purified AuAbs could not induce a PV-like phenotype, their mixture produced a synergistic effect manifested by a positive Nikolskiy sign in the skin of neonatal mice. The downstream signaling of all pathogenic non-Dsg AuAbs involved p38 mitogen-activated protein kinase (MAPK)-mediated phosphorylation and elevation of cytochrome c release and caspase 9 activity. Anti-Dsc3 and anti-SPCA1 AuAbs also activated SRC proto-oncogene, nonreceptor tyrosine kinase (SRC). Of note, although a constellation of non-Dsg AuAbs apparently disrupted epidermal integrity, elimination of a single pathogenic AuAb could prevent keratinocyte detachment and blistering. Therefore, anti-Dsg1/3 AuAb-free PV can be a model for elucidating the roles of non-Dsg antigenspecific AuAbs in the physiological regulation of keratinocyte cell-cell adhesion and blister development.

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Section: Autoimmunity Of Non-desmoglein Pemphigussupporting

confidence: 89%

Synergy among non-desmoglein antibodies contributes to the immunopathology of desmoglein antibody–negative pemphigus vulgaris

Chernyavsky¹,

Amber

Agnoletti³

et al. 2019

Journal of Biological Chemistry

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“…Besides desmosomal cadherins, more than 40 antigens were shown to be targeted by autoantibody fractions from patients with pemphigus including muscarinic and nicotinic acetylcholine receptors, pemphaxin, and mitochondrial proteins (Chen et al, 2015;Lakshmi et al, 2017;Marchenko et al, 2010;Nguyen et al, 2000a). Recently, the formation of autoantibodies against different muscarinic receptors subtypes as well as thyroperoxidase, a protein not known to be expressed by keratinocytes, has been confirmed in an HLA-type-dependent fashion (Sajda et al, 2016).…”

Section: Relevance Of Autoantibodies Targeting Antigens Others Than Dmentioning

confidence: 99%

Mechanisms Causing Loss of Keratinocyte Cohesion in Pemphigus

Spindler

Eming

Schmidt

et al. 2018

Journal of Investigative Dermatology

114

102

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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.

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“…In vitro experiments have shown that mAChR activation may prevent, stop, and reverse acantholysis mediated by pemphigus antibodies ( 20 ). Autoantibodies against mAChRs have been identified in the serum of 85–100% of pemphigus patients ( 21 , 22 ). Lakshmi et al prospectively evaluated the disease severity of 45 patients with pemphigus who were followed up at baseline, 3 months, and 15 months.…”

Section: Major Defined Autoantigensmentioning

confidence: 99%

“…They collected sera from these patients to assess the titers of antibodies against Dsg1/Dsg3 and anti-M3 mAChR to correlate them with disease severity and response to therapy. They found that antibody titers correlated significantly with disease activity and that anti-M3 mAChR antibodies were present in all cases ( 22 ).…”

Section: Major Defined Autoantigensmentioning

confidence: 99%

Non-Desmoglein Antibodies in Patients With Pemphigus Vulgaris

2018

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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 Ca2+-dependent cell adhesion molecule belonging to the cadherin family, has been considered the “primary” autoantigen in PV. Proteomic studies have identified numerous autoantibodies in patients with PV that have known roles in the physiology and cell adhesion of keratinocytes. Antibodies to these autoantibodies include desmocollins 1 and 3, several muscarinic and nicotinic acetylcholine receptor subtypes, mitochondrial proteins, human leukocyte antigen molecules, thyroid peroxidase, and hSPCA1—the Ca2+/Mn2+-ATPase encoded by ATP2C1, which is mutated in Hailey–Hailey disease. Several studies have identified direct pathogenic roles of these proteins, or synergistic roles when combined with Dsg3. We review the role of these direct and indirect mechanisms of non-desmoglein autoantibodies in the pathogenesis of PV.

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Correlation of antimuscarinic acetylcholine receptor antibody titers and antidesmoglein antibody titers with the severity of disease in patients with pemphigus

Cited by 28 publications

References 7 publications

Synergy among non-desmoglein antibodies contributes to the immunopathology of desmoglein antibody–negative pemphigus vulgaris

Synergy among non-desmoglein antibodies contributes to the immunopathology of desmoglein antibody–negative pemphigus vulgaris

Mechanisms Causing Loss of Keratinocyte Cohesion in Pemphigus

Non-Desmoglein Antibodies in Patients With Pemphigus Vulgaris

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