The mitochondrion is a common target of disease pathophysiology in pemphigus and pemphigoid

Grando, Sergei A.

doi:10.1111/exd.12772

Cited by 7 publications

(6 citation statements)

References 12 publications

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“…Using our model, however, the known ability of ROS to affect KIF and actin cytoskeletons as well as PKC, Src, p38MAPK, and RhoA signaling ( 162 – 167 ) potentially demonstrates how ROS may contribute to blister formation in a number of ways. As a result, our model can also explain how anti-mitochondrial autoAbs, which have been suggested to play a role in PV and shown to increase ROS production, can directly mediate disease pathogenesis ( 50 , 168 – 172 ). Furthermore, the activation of pro-apoptotic pathways by autoAb binding has been shown to modulate p38MAPK ( 50 ) and may further contribute to the signaling pathologies that drive acantholysis.…”

Section: Integrated Model Of Pv Autoab-induced Signalingmentioning

confidence: 84%

Autoantibody Signaling in Pemphigus Vulgaris: Development of an Integrated Model

Sajda

Sinha

2018

Front. Immunol.

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Pemphigus vulgaris (PV) is an autoimmune skin blistering disease effecting both cutaneous and mucosal epithelia. Blister formation in PV is known to result from the binding of autoantibodies (autoAbs) to keratinocyte antigens. The primary antigenic targets of pathogenic autoAbs are known to be desmoglein 3, and to a lesser extent, desmoglein 1, cadherin family proteins that partially comprise the desmosome, a protein structure responsible for maintaining cell adhesion, although additional autoAbs, whose role in blister formation is still unclear, are also known to be present in PV patients. Nevertheless, there remain large gaps in knowledge concerning the precise mechanisms through which autoAb binding induces blister formation. Consequently, the primary therapeutic interventions for PV focus on systemic immunosuppression, whose side effects represent a significant health risk to patients. In an effort to identify novel, disease-specific therapeutic targets, a multitude of studies attempting to elucidate the pathogenic mechanisms downstream of autoAb binding, have led to significant advancements in the understanding of autoAb-mediated blister formation. Despite this enhanced characterization of disease processes, a satisfactory explanation of autoAb-induced acantholysis still does not exist. Here, we carefully review the literature investigating the pathogenic disease mechanisms in PV and, taking into account the full scope of results from these studies, provide a novel, comprehensive theory of blister formation in PV.

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Section: Integrated Model Of Pv Autoab-induced Signalingmentioning

confidence: 84%

Autoantibody Signaling in Pemphigus Vulgaris: Development of an Integrated Model

Sajda

Sinha

2018

Front. Immunol.

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“…This results in increased cytochrome c release, disruption of inner membrane of the mitochondrial electron transport chain, decreased ATP production and consequent increase in reactive oxygen species (ROS) production. 15 Ultimately, damage to the mitochondrial power chain triggers apoptosis. The administration of mitochondrial protecting medications (minocycline, nicotinamide and cyclosporine) can eradicate acantholysis in a PV-IgG-induced mouse model.…”

Section: Other Moleculesmentioning

confidence: 99%

“…This monopathogenic theory suggests that binding of anti‐Dsg autoantibodies drives steric hindrance, keratinocyte dissociation and acantholysis 13 . However, PVIgG specificity is not limited to Dsg as these autoantibodies target other molecules including mitochondrial antigens and ACh receptors and act synergistically with anti‐Dsg autoantibodies 14‐16 . In addition to steric hindrance, it is now accepted that binding of PVIgG to keratinocytes alters signalling of various intracellular molecules, including p38 mitogen‐activated protein kinase (p38MAPK), Phosphokinase C (PKC), Rho A and Caspase 3, 6, 8 and 9 17 .…”

Section: Introductionmentioning

confidence: 99%

Mechanism‐based therapeutic targets of pemphigus vulgaris: A scoping review of pathogenic molecular pathways

Kaur

Kerbrat

Kho

et al. 2021

Experimental Dermatology

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Pemphigus vulgaris (PV) is an autoimmune blistering condition affecting 0.1 to 0.5 per 100,000 people worldwide. 1 Before the advent of corticosteroids, PV was invariably fatal and even when treated, mortality rates are as high as 15%. 2 PV is characterised by painful flaccid bullae with mucosal or mucocutaneous distribution and commonly manifests orally. 3,4 Histologically, intraepithelial splitting of

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“…Anti-mitochondrial autoAbs are found in several other autoimmune disorders in addition to PV, such as primary biliary sclerosis and systemic scleroderma ( 67 , 75 , 94 – 96 ). Despite a lack of specificity to PV, a preponderance of evidence exists that links anti-mitochondrial autoAbs to pathogenesis in PV.…”

Section: Functional Role Of Non-desmoglein Autoantibodies In Pvmentioning

confidence: 99%

The Evolving Story of Autoantibodies in Pemphigus Vulgaris: Development of the “Super Compensation Hypothesis”

Sinha

Sajda

2018

Front. Med.

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Emerging data and innovative technologies are re-shaping our understanding of the scope and specificity of the autoimmune response in Pemphigus vulgaris (PV), a prototypical humorally mediated autoimmune skin blistering disorder. Seminal studies identified the desmosomal proteins Desmoglein 3 and 1 (Dsg3 and Dsg1), cadherin family proteins which function to maintain cell adhesion, as the primary targets of pathogenic autoAbs. Consequently, pathogenesis in PV has primarily considered to be the result of anti-Dsg autoAbs alone. However, accumulating data suggesting that anti-Dsg autoAbs by themselves cannot adequately explain the loss of cell-cell adhesion seen in PV, nor account for the disease heterogeneity exhibited across PV patients has spurred the notion that additional autoAb specificities may contribute to disease. To investigate the role of non-Dsg autoAbs in PV, an increasing number of studies have attempted to characterize additional targets of PV autoAbs. The recent advent of protein microarray technology, which allows for the rapid, highly sensitive, and multiplexed assessment of autoAb specificity has facilitated the comprehensive classification of the scope and specificity of the autoAb response in PV. Such detailed deconstruction of the autoimmune response in PV, beyond simply tracking anti-Dsg autoAbs, has provided invaluable new insights concerning disease mechanisms and enhanced disease classification which could directly translate into superior tools for prognostics and clinical management, as well as the development of novel, disease specific treatments.

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The mitochondrion is a common target of disease pathophysiology in pemphigus and pemphigoid

Cited by 7 publications

References 12 publications

Autoantibody Signaling in Pemphigus Vulgaris: Development of an Integrated Model

Autoantibody Signaling in Pemphigus Vulgaris: Development of an Integrated Model

Mechanism‐based therapeutic targets of pemphigus vulgaris: A scoping review of pathogenic molecular pathways

The Evolving Story of Autoantibodies in Pemphigus Vulgaris: Development of the “Super Compensation Hypothesis”

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