What is the pathophysiology of pemphigus?

Pathophysiology of Pemphigus

Pemphigus is an acquired autoimmune disease characterized by IgG antibodies targeting desmosomal proteins, primarily desmoglein 3 (Dsg3) and desmoglein 1 (Dsg1), leading to intraepithelial blistering and mucocutaneous erosions. 1

Autoimmune Mechanisms

Autoantibody Production

• IgG autoantibodies primarily target:
  • Desmoglein 3 (Dsg3) - major antigen in pemphigus vulgaris
  • Desmoglein 1 (Dsg1) - present in 50-60% of pemphigus vulgaris patients, primary antigen in pemphigus foliaceus 1

Antibody Profile and Clinical Phenotype

• The specific antibody profile determines the clinical presentation:
  • Anti-Dsg3 antibodies alone → predominantly mucosal involvement
  • Anti-Dsg3 + anti-Dsg1 antibodies → mucocutaneous involvement 1
• Mucocutaneous disease tends to be more severe than purely mucosal disease, with:
  • Slower response to treatment
  • Lower likelihood of achieving remission off-treatment 1

Mechanisms of Acantholysis (Loss of Cell Adhesion)

The pathogenic antibodies cause blister formation through multiple mechanisms:

1. Direct interference with desmosomal adhesion:

   • Steric hindrance of homophilic desmoglein interactions 2
   • Targeting of the cis-adhesive interface of Dsg3, particularly the EC1 and EC2 subdomains 3

2. Cellular internalization of desmogleins:

   • Antibody binding triggers internalization of desmogleins
   • Prevents integration of desmogleins into desmosomes
   • Results in Dsg3-depleted desmosomes in pemphigus vulgaris 2

3. Signaling-dependent pathways:

   • "Outside-in" signaling cascade activation 2
   • Activation of p38MAPK, ERK, and PLC/Ca²⁺ pathways 4
   • Phosphorylation of desmosomal proteins including Dsg3 2
   • Disassembly of desmosomal components from inside the cells

Ultrastructural Changes

Characteristic ultrastructural hallmarks include:

• Reduction in desmosome number and size
• Formation of split desmosomes
• Uncoupling of keratin filaments from desmosomes 4

Cellular Immune Regulation

The production of pathogenic autoantibodies involves:

• T cell-dependent B cell activation
• Somatic hypermutation of B cells (high levels of mutations in complementarity-determining regions)
• Loss of binding to Dsg3 when somatic mutations are reverted to germline sequences, suggesting that autoreactivity depends on these mutations 3

Clinical Implications

• Mortality was historically high (75%) before the introduction of corticosteroids in the 1950s 1
• Current mortality rates differ by phenotype:
  • Predominantly mucosal PV: 1-17% mortality
  • Mucocutaneous PV: 8-42% mortality 1

Understanding the pathophysiology has led to targeted therapies, including rituximab (anti-CD20 monoclonal antibody), which depletes B cells responsible for autoantibody production 5.

Diagnostic Considerations

The pathophysiological understanding guides diagnostic approaches:

• Direct immunofluorescence showing IgG deposition in intercellular spaces of the epidermis
• Enzyme-linked immunosorbent assays (ELISA) for direct measurement of Dsg1 and Dsg3 antibodies in serum 1
• Histopathology showing suprabasal acantholysis and blister formation 1

The pathophysiological understanding of pemphigus continues to evolve, offering opportunities for the development of more targeted therapies aimed at specific mechanisms of disease.