Advances in pemphigus and its endemic pemphigus foliaceus (Fogo Selvagem) phenotype: a paradigm of human autoimmunity

Abstract

Pemphigus encompasses a group of organ specific, antibody mediated autoimmune diseases of the skin characterized by keratinocyte detachment that leads to the development of blisters and erosions, which can become life-threatening. The pathogenic autoantibodies recognize desmogleins, which are members of the desmosomal cadherin family of cell adhesion molecules. Desmoglein 3 is targeted in pemphigus vulgaris while desmoglein 1 is targeted in pemphigus foliaceus and its endemic form, Fogo Selvagem. This review will briefly define the salient features of pemphigus and the proposed steps in pathogenesis. We will then summarize the most recent advances in three important areas of investigation: (i) epidemiologic, genetic, and immunologic features of Fogo Selvagem, (ii) molecular mechanisms of injury to the epidermis, and (iii) novel therapeutic strategies targeting specific steps in disease pathogenesis. The advances in each of these three seemingly separate areas contribute to the overall understanding of the pemphigus disease model. These recent advancements also underscore the dynamic interplay between the treatment of patients in a clinical setting and basic science research and have led to an integrative understanding of disease pathogenesis and treatment, allowing pemphigus to serve as a paradigm of human autoimmunity.

Figure 1

Clinical presentation of Fogo Selvagem with (a) spontaneous generalized blisters and erosions. (b) Biopsies of these lesions demonstrate intra-epidermal subcorneal vesicles due to cell detachment (acantholysis). (c) Direct immunofluorescence locates the total IgG or IgG4 to the surface of detached epidermal cells.

Figure 2

The endemic regions of FS. The endemic regions of FS are located in the central planes of Brazil, comprising the following states: Sao Paulo, Parana, Minas Gerais, Goias, Mato Grosso and Mato Grosso do Sul and the Distrito Federal de Brasilia. Hospitals specialized to treat FS are located in cities of Sao Paulo, Goiania and Campo Grande. The Limao Verde Amerindian reservation is one of six Terena Indians settled in the state of Mato Grosso do Sul. The Limao Verde reservation shows a 3% prevalence of FS and is under investigation by our group since 1993.

Figure 3

Anti-Dsg1 IgG4 antibodies from FS patients are pathogenic in neonatal mice. IgG4 purified from FS patients was injected intraperitoneally to neonatal Blab/c mice. (a) In the course of 8–24 hours, these animals develop superficial vesicles and erosions. (b) Histologic examination reveals subcorneal vesicles and (c) direct IF shows the human IgG4 bound to the epidermal intercellular spaces.

Figure 4

Molecular homology between Dsg1, Dsg3 and E-cadherin. The desmogleins 1 and 3 are desmosomal transmembrane proteins sharing the same cadherin-like domain structure of E-cadherin. The EC1-EC2 domains of Dsg1 are recognized by pathogenic autoantibodies of FS patients whereas Dsg3 is bound by autoantibodies from pemphigus vulgaris patients. Autoantibodies against E-cadherin have also been described in mucocutaneous PV, PF and FS [95].

Figure 5

Molecular mechanisms of acantholysis in pemphigus. Desmoglein 1 and 3 are linked to the intermediate filament keratin network of the keratinocyte whereas E-cadherin links to the actin cytoskeleton. Pathogenic autoantibodies in PV and PF bind the ectodomain of Dsg3 or Dsg1 and trigger intracellular signaling that leads to acantholysis. Keratinocyte apoptosis also results from this immunopathological process.

Figure 6

Rationale of pemphigus therapies. The five targeted areas where immuno-intervention may play a role in controlling disease activity in PV, PF and FS are shown in this figure. A PV patient is depicted with the targeted sites: (1) elimination of the autoantigen or triggering environmental antigen, (2) deletion of autoreactive and regulatory T cell activation, (3) deletion of autoreactive B cell responses, (4) elimination of circulating autoantibody and (5) altering the keratinocyte responses to pathogenic autoantibodies (epidermis becomes “resistant” to these autoantibodies).