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.

Keywords: acetylcholine receptor; autoantibodies; desmocollin; desmoglein; mitochondria; plakophilin; protein array technology; thyroid peroxidase.

Figure 1

Timeline of significant findings regarding autoantibodies in Pemphigus vulgaris. Important developments in the field are depicted in chronological order (see text for detailed description).

Figure 2

Use of protein array technology in Pemphigus vulgaris. To date, protein array technology has been used by 2 groups with differing sets of antigens printed, patient and control populations used, and varying approaches to analysis. Both groups found some overlap in the autoantibody response in PV for both anti-Dsg and non-Dsg targets.

Figure 3

The super-compensation hypothesis. We hypothesize the binding of specific autoAbs in combination with the unique epidermal expression of the various autoantigens results in the characteristic alteration of signaling pathways and the development of acantholysis only if the sum of these effects exceeds a set threshold. In this theory, highly pathogenic antibodies to either anti-Dsg3 alone, or anti-Dsg3 and−1 together can exceed the blistering threshold. Similarly, multiple combinations of subpathogenic anti-Dsg3/1 autoAbs together with non-Dsg autoAbs could potentially exceed this threshold. However, weakly pathogenic anti-Dsg or non-Dsg autoAbs alone, or sometimes even in combination, do not breach the threshold for triggering acantholysis.