Mechanisms of Disease: Pemphigus and Bullous Pemphigoid

Abstract

Pemphigus and bullous pemphigoid are autoantibody-mediated blistering skin diseases. In pemphigus, keratinocytes in epidermis and mucous membranes lose cell-cell adhesion, and in pemphigoid, the basal keratinocytes lose adhesion to the basement membrane. Pemphigus lesions are mediated directly by the autoantibodies, whereas the autoantibodies in pemphigoid fix complement and mediate inflammation. In both diseases, the autoantigens have been cloned and characterized; pemphigus antigens are desmogleins (cell adhesion molecules in desmosomes), and pemphigoid antigens are found in hemidesmosomes (which mediate adhesion to the basement membrane). This knowledge has enabled diagnostic testing for these diseases by enzyme-linked immunosorbent assays and dissection of various pathophysiological mechanisms, including direct inhibition of cell adhesion, antibody-induced internalization of antigen, and cell signaling. Understanding these mechanisms of disease has led to rational targeted therapeutic strategies.

Keywords: autoantibody; autoimmune; blistering; skin.

Figure 1

Clinical, histological, and immunopathological findings in pemphigus and pemphigoid. Clinical images of (a) PV with large erosions, (b) PF with scaly crusted lesions, and (c) BP with tense blisters. (d) Histology of PV shows suprabasilar blister, (e) PF shows acantholysis in the granular layer of the epidermis, and (f) BP shows a subepidermal blister with eosinophils. Indirect immunofluorescence of (g) PV on monkey esophagus and (h) BP on normal human skin shows presence of circulating IgG binding cell surface and epidermal basement membrane, respectively. (i) Direct immunofluorescence of perilesional skin in a BP patient shows C3 at the epidermal basement membrane. Abbreviations: BP, bullous pemphigoid; C3, third component of complement; IgG, immunoglobulin G; PF, pemphigus foliaceus; PV, pemphigus vulgaris.

Figure 2

Schematics of the intercellular keratinocyte desmosome and the basal keratinocyte hemidesmosome at the basement membrane. Dsgs, the targets of pemphigus antibodies, mediate cell-cell contact by trans- and cis-adhesion. Adhesion is also provided by Dscs, which, like Dsgs, are in the cadherin adhesion molecule supergene family. Intracellular proteins of desmosomes, such as PG, PKP-1, and DP, link Dsgs and Dscs to KIFs. The hemidesmosome links basal keratinocytes to the epidermal basement membrane zone. BP180 and BP230 are the molecules targeted by autoantibodies in BP patients. BP230 and plectin link the hemidesmosome to KIFs. DP, BP230, and plectin, all of which link the KIFs to the desmosome or hemidesmosome, are in the same gene family of plakins. Abbreviations: BP, bullous pemphigoid; Col, collagen; DP, desmoplakin; Dsc, desmocollin; Dsg, desmoglein; KIF, keratin intermediate filament; Lam332, laminin 332; LD, lamina densa; LL, lamina lucida; PG, plakoglobin; PKP-1, plakophilin 1; SLD, sublamina densa.

Figure 3

Desmoglein compensation in pemphigus. Triangles show the usual localization of Dsg1 (green) and Dsg3 (yellow) in the epidermis (skin) and mucous membrane. Triangle width indicates the relative amount of Dsg present at each cell level. Loss of color in a triangle represents loss of function of that particular Dsg due to the presence of αDsg1 or αDsg3. In any area in which Dsg1 or Dsg3 function has been inactivated and the other Dsg is not present to compensate, a blister (shown as loss of cell-cell adhesion) occurs. Abbreviations: αDsg1, anti-Dsg1 antibodies; αDsg3, anti-Dsg3 antibodies; Dsg, desmoglein.

Figure 4

Pathophysiological pathways in bullous pemphigoid. Many of these pathways have been demonstrated in mouse models. Although neutrophils are critical for subepidermal blisters in the mouse, in humans the infiltrate is usually eosinophil rich, with many fewer neutrophils. Abbreviations: BMZ, basement membrane zone; BP, bullous pemphigoid; EC, ectodomain; Ig, immunoglobulin; MC, mast cell; NE, neutrophil elastase.