Humoral Epitope Spreading in Autoimmune Bullous Diseases

Abstract

Autoimmune blistering diseases are characterized by autoantibodies against structural adhesion proteins of the skin and mucous membranes. Extensive characterization of their autoantibody targets has improved understanding of pathogenesis and laid the basis for the study of antigens/epitopes diversification, a process termed epitope spreading (ES). In this review, we have reported and discussed ES phenomena in autoimmune bullous diseases and underlined their functional role in disease pathogenesis. A functional ES has been proposed: (1) in bullous pemphigoid patients and correlates with the initial phase of the disease, (2) in pemphigus vulgaris patients with mucosal involvement during the clinical transition to a mucocutaneous form, (3) in endemic pemphigus foliaceus, underlining its role in disease pathogenesis, and (4) in numerous cases of disease transition associated with an intermolecular diversification of immune response. All these findings could give useful information to better understand autoimmune disease pathogenesis and to design antigen/epitope specific therapeutic approaches.

Keywords: BP180; antigen; autoantibody; desmoglein; epitope; epitope spreading; pathogenesis; specific therapy.

Figure 1

Epitope spreading (ES) in bullous pemphigoid (BP) patients. A schematic representation of BP antigens (BP180 and BP230). Findings support the idea that IgG recognition of the BP180 ectodomain is an early event in BP disease, followed by variable intramolecular ES (red and blue lines in BP180 ectodomain) and intermolecular ES events (orange lines), which likely shape the individual course of BP (22, 58).

Figure 2

Clinical transition between mucosal pemphigus vulgaris (PV) to mucocutaneous PV as proposed by Salato et al. Survey and schematic representation of the antigenic regions recognized by autoantibodies of a representative PV patient with only mucosal involvement (mPV) that shift clinical phenotype to mucocutaneous one (mcPV) (76). PV antigens (Dsg1 and Dsg3) with relative subdomains (EC1–EC5) of Dsg1 and 3 and their amino acid sequences are illustrated. Red arrows indicate the regions recognized by patient autoantibodies during the course of the disease (76). The mPV patient at an early stage of disease has autoantibodies specific for ectodomain (EC5) subdomain. At this time the circulating autoantibodies are not able to bind human skin by [indirect immunofluorescence (IIF)]. Several years later, the patient produces autoantibodies directed to EC1 by an intramolecular ES phenomenon. At this stage the autoantibodies start to bind the human skin and an intermolecular ES toward Dsg1 occurred with development of cutaneous as well as mucosal blisters (76).

Figure 3

Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) patients present Dsg3 and Dsg1 epitope profiles stable over the disease course. A schematic representation of the antigenic regions recognized by autoantibodies of a PV (A) and PF (B) patients at diagnosis, with relative percentage of reactivity, and during the disease course (20, 21). Only two patients (for PV and PF) in whom epitope spreading (ES) phenomenon occurred have been shown. In most PV and PF patients, the major Dsg3 and Dsg1 epitopes are localized in the EC1–2 subdomains. In the vast majority of PV and PF patients, the epitope profile remained stable during the course of the disease. Of note, two patients (PV patient 1 and PF patient 2) in active stage reacted to EC1 and shifted with an intramolecular ES to other subdomains (EC2/EC3 and EC2) (20, 21).

Figure 4

Current etiopathogenetic model for endemic pemphigus foliaceus (EPF). A schematic representation of the antigenic regions recognized by autoantibodies of normal individuals and EPF patients. (A) Patients in the preclinical stage and healthy individuals from endemic areas possess IgG1 circulating autoantibodies that recognize non-pathogenic epitopes in the EC5, whereas when the disease developed appeared pathogenic IgG4 antibodies to EC1 and EC2 through class switch and ES (–98). (B) In parallel, antigen mimicry that induces with or without ES an antibody switch from an epitope of salivary gland fly antigen (IgE) to a pathogenic epitope on the EC1 subdomain of Dsg1 (IgG4) is shown (102).