Critical Role of the Neonatal Fc Receptor (FcRn) in the Pathogenic Action of Antimitochondrial Autoantibodies Synergizing with Anti-desmoglein Autoantibodies in Pemphigus Vulgaris

Chen, Yumay; Chernyavsky, Alexander I.; Webber, Robert J.; Grando, Sergei A.; Wang, Ping H.

doi:10.1074/jbc.m115.668061

Cited by 46 publications

(54 citation statements)

References 51 publications

(59 reference statements)

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“…The levels of pathogenic non-Dsg AuAbs in the Dsg1/3 AuAb-negative PV patient's serum correlate with the stage of disease, which may potentially allow to use certain type(s) of non-Dsg AuAbs as predictors of PV relapse. By analogy with synergy of anti-mitochondrial AuAbs and anti-Dsg3 AuAb in PV patients with conventional immunophenotype (34), in the anti-Dsg1/3 AuAb-negative PV patients, various non-Dsg AuAb species may concur to cause blistering by acting synergistically and thus imposing a simultaneous hit on keratinocytes affecting the intracellular homeostasis to the degree that it can alter the ability of keratinocyte to maintain the integrity of epidermis. The anti-Dsg1/3 AuAbfree PV may become a model for elucidation role of AuAbs to non-Dsg antigens in the physiological regulation of keratinocyte cell-cell adhesion and blister development.…”

Section: Discussionmentioning

confidence: 99%

“…The last but not the least among the most common pathogenic non-Dsg AuAbs characterized in this study was anti-SPCA1 AuAb. Although SPCA1 is located intracellularly, it might be reached by an AuAb in a complex with FcRn ("neonatal" Fc receptor for IgG) that has been shown to bind PVIgGs on the cell membrane of keratinocytes and traffic them to intracellular targets (34). SPCA1 is encoded by the ATP2C1 gene, one copy of which is mutated in patients with HHD who exhibit the clinical and pathological phenocopy of PV (15,16).…”

Section: Autoimmunity Of Non-desmoglein Pemphigusmentioning

confidence: 99%

“…For morphometric assay of acantholysis in vitro, we used the NMSE model described by us in the past (34). Briefly, ϳ3 ϫ 3-mm pieces of trunkal skin of intact neonatal BALB/c mice were incubated at 37°C and 5% CO 2 for 24 h in PBS containing test IgG, after which the skin specimens were fixed, sectioned, and stained with hematoxylin and eosin.…”

Section: Evaluation Of Acantholytic Activities Of Non-dsg Auabsmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 99%

Section: Autoimmunity Of Non-desmoglein Pemphigusmentioning

confidence: 99%

Section: Evaluation Of Acantholytic Activities Of Non-dsg Auabsmentioning

confidence: 99%

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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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“…Numerous signalling molecules and metabolic pathways have been implicated in pemphigus acantholysis, involving, for example, p38 mitogen-activated protein kinase (MAPK) and its downstream effector MAPK-activated protein kinase 2 (MK2) 68–71 , epidermal growth factor receptor 72,73 , RHO GTPases 74 , MYC 75 , caspases 76,77 and mitochondria 78 . However, no signalling event is sufficient to induce the specific histology of pemphigus vulgaris or pemphigus foliaceus epithelial blistering.…”

Section: Mechanisms/pathophysiologymentioning

confidence: 99%

Pemphigus

Kasperkiewicz

Ellebrecht

Takahashi

et al. 2017

Nat Rev Dis Primers

422

429

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Pemphigus is a group of IgG-mediated autoimmune diseases of stratified squamous epithelia, such as the skin and oral mucosa, in which acantholysis (the loss of cell adhesion) causes blisters and erosions. Pemphigus has three major subtypes: pemphigus vulgaris, pemphigus foliaceus and paraneoplastic pemphigus. IgG autoantibodies are characteristically raised against desmoglein 1 and desmoglein 3, which are cell–cell adhesion molecules found in desmosomes. The sites of blister formation can be physiologically explained by the anti-desmoglein autoantibody profile and tissue-specific expression pattern of desmoglein isoforms. The pathophysiological roles of T cells and B cells have been characterized in mouse models of pemphigus and patients, revealing insights into the mechanisms of autoimmunity. Diagnosis is based on clinical manifestations and confirmed with histological and immunochemical testing. The current first-line treatment is systemic corticosteroids and adjuvant therapies, including immunosuppressive agents, intravenous immunoglobulin and plasmapheresis. Rituximab, a monoclonal antibody against CD20+ B cells, is a promising therapeutic option that may soon become first-line therapy. Pemphigus is one of the best-characterized human autoimmune diseases and provides an ideal paradigm for both basic and clinical research, especially towards the development of antigen-specific immune suppression treatments for autoimmune diseases.

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“…Cells were then incubated with 3 mM MMS for 1 hr in the presence of DMSO or PARP inhibitor. At 1 hr after the release from MMS treatment, Seahorse analysis was performed using a Agilent Seahorse XF24 Extracellular Flux Analyzer following the manufacturer's protocol as described previously (35).…”

Section: Measurement Of Mitochondria Respiration: the Seahorse Assaymentioning

confidence: 99%

NAD consumption by PARP1 in response to DNA damage triggers metabolic shift critical for damaged cell survival

Murata

Kong

Moncada

et al. 2018

Preprint

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DNA damage signaling is critical for the maintenance of genome integrity and cell fate decision.Poly(ADP-ribose) polymerase 1 (PARP1) is a DNA damage sensor rapidly activated in a damage dose and complexity-dependent manner playing a critical role in the initial chromatin organization and DNA repair pathway choice at damage sites. However, the cell-wide consequence of its activation in damaged cells is not well delineated. Using the phasor approach to fluorescence lifetime imaging microscopy (FLIM) and fluorescence-based biosensors in combination with laser microirradiation, we found a rapid cell-wide increase of the bound/free NADH ratio in response to nuclear DNA damage, which is triggered by NAD+ depletion by PARP activation. This change is linked to the metabolic balance shift to oxidative phosphorylation (oxphos) over glycolysis. Inhibition of the respiratory chain resulted in rapid PARP-dependent ATP reduction and intracellular acidification, and eventually, PARPdependent, AIF-independent, apoptosis indicating that oxphos becomes critical for damaged cell survival. The results reveal the novel pro-survival effect of PARP activation through a change in cellular metabolism, and demonstrate how unique applications of advanced fluorescence imaging technologies in combination with laser microirradiation can be a powerful tool to interrogate damage-induced metabolic changes at high spatiotemporal resolution in a live cell.

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Critical Role of the Neonatal Fc Receptor (FcRn) in the Pathogenic Action of Antimitochondrial Autoantibodies Synergizing with Anti-desmoglein Autoantibodies in Pemphigus Vulgaris

Cited by 46 publications

References 51 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

Pemphigus

NAD consumption by PARP1 in response to DNA damage triggers metabolic shift critical for damaged cell survival

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