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

Abstract

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.

Pemphigus vulgaris possibly associated with application of a tissue expander in a patient with Crohn’s disease and primary sclerosing cholangitis

“…These non-Dsg autoantibodies might be of importance in the pathogenesis of PV. Indeed, Chernyavsky et al (33) found that non-Dsg autoantibodies in the sera of patients with Dsg1/3-negative acute PV are pathogenic because IgGs from these individuals induced skin blistering in neonatal mice subsequent to suprabasal acantholysis. Moreover, serum levels of autoantibodies to desmocollin 3 (Dsc3), M3 muscarinic acetylcholine receptor (M3AR), and secretory pathway Ca2+/Mn2+-ATPase isoform 1 (SPCA1) correlated with the disease stage of PV, whereas absorption of these autoantibodies on recombinant Dsc3, M3AR, or SPCA1 prevented skin blistering after passive transfer to BALB/c mice.…”

From bench to bedside: evolving therapeutic targets in autoimmune blistering disease

“…A great advantage of this method is the ability to deplete pathogenic memory B cells and plasma cells without inducing generalized immunosuppression. However, as pemphigus often involves other autoantigens it remains to be seen whether this depletion would be sufficient outside of experimental setting …”

“…However, as pemphigus often involves other autoantigens it remains to be seen whether this depletion would be sufficient outside of experimental setting. 10,11 Ianalumab B-cell activating factor (BAFF) receptors are primarily expressed on B cells and function in B-cell activation, maturation, class switching in response to T-cell stimulation and survival. 69,70 Ianalumab (VAY736) is a human IgG1 mAB which competitively inhibits the BAFF receptor.…”

“…Subsequent apoptolysis leads to the formation of flaccid blisters and erosions on the skin and mucous membranes . Autoantibodies to several other keratinocyte proteins can additionally lead to subsequent acantholysis . Paraneoplastic autoimmune multiorgan syndrome (PAMS) is a distinct multiorganopathy, once thought to be related to PV.…”

“…8,9 Autoantibodies to several other keratinocyte proteins can additionally lead to subsequent acantholysis. 10,11 Paraneoplastic autoimmune multiorgan syndrome (PAMS) is a distinct multiorganopathy, once thought to be related to PV. Underlying malignancy or lymphoproliferative disorders are frequently found in affected patients, along with autoantibodies to numerous proteins including desmoplakin 1 or 2, envoplakin, BP180, BP230, desmoglein 1 or 3, desmocollin 1 or 2 or 3.…”