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

Abstract

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.

Correlation of IgG autoantibodies against acetylcholine receptors and desmogleins in patients with pemphigus treated with steroid sparing agents or rituximab

“…[12,17,20,25] The development of new techniques for measuring Abs has resulted in the identification of a large number of autoantigens with detectable autoAbs in the sera of patients with pemphigus and other autoimmune diseases. [32] Although numerous in vitro and in vivo animal studies have demonstrated that disruption of acetylcholine receptor function (nicotinic and muscarinic AChR) results in acantholysis similar to that seen in pemphigus, the exact role of these autoAbs in the clinical manifestations of pemphigus in man is unclear. [33] Recently, Lakshmi and co-workers reported that patients with PV and PF had significantly higher titers of IgG anti-M3AChR than normal controls, as well as Abs against DSG1 and DSG3.…”

Tacrolimus reverses the pemphigus vulgaris serum-enhanced expression of desmoglein in HaCaT cells

“…There is growing evidence suggesting that anti-Dsg autoantibodies cannot account for the loss of cellcell adhesion seen in PV, indicating that multiple combinations of pathogenic or subpathogenic autoantibodies may function together to contribute to acantholysis. "Desmoglein compensation hypothesis" and "steric hindrance theory" are the widely recognized pathogenic mechanisms of pemphigus [20][21][22][23].The formation of blisters in PV is due to the synergistic effect of autoantibodies targeting multiple keratinocyte antigens [24,25]. For example, in addition to Dsg, a variety of other autoantibodies have been described in PV, including cholinergic receptors [26], anti-mitochondrial Proteins [27], non-Dsg adhesion proteins (desmocollin and plakophillin) [28,29], and additional targets related to γδ-T lymphocytes, ATP2C1 and IL-36 [30][31][32].…”

Tacrolimus reverses the pemphigus vulgaris serum-enhanced expression of desmoglein in HaCaT cells

“…"Desmoglein compensation hypothesis" and "steric hindrance theory" are the widely recognized pathogenic mechanisms of pemphigus [21][22][23][24]. The formation of blisters in PV is due to the synergistic effect of autoantibodies targeting multiple keratinocytes antigens [25,26]. For example, in addition to Dsg, a variety of other autoantibodies have been described in PV, including cholinergic receptors [27], anti-mitochondrial Proteins [28], non-Dsg adhesion proteins (desmocollin and plakophillin) [29,30], and additional targets concerning γδ-T lymphocytes, ATP2C1 and IL-36 [31][32][33].…”