Bullous pemphigoid autoantibodies directly induce blister formation without complement activation

Area of Science:

• Immunodermatology
• Autoimmune Blistering Diseases
• Complement System

Background:

• Bullous pemphigoid (BP) is an autoimmune blistering disease.
• Autoantibodies against type XVII collagen (COL17) are implicated in BP pathogenesis.
• The role of complement activation in BP blister formation is debated.

Purpose of the Study:

• To investigate the necessity of complement activation in BP blister formation.
• To determine whether autoantibodies against COL17 alone can induce blisters.
• To elucidate the mechanism of COL17 involvement in blister pathogenesis.

Main Methods:

• Generation of C3-deficient COL17-humanized mice.
• Passive transfer of autoantibodies from BP patients and generated monoclonal antibodies (mAbs) against COL17.
• Assessment of blister formation, complement deposition, and COL17 levels in mouse skin and cultured keratinocytes.

Main Results:

• Passive transfer of BP autoantibodies induced blister formation in C3-deficient mice, independent of complement activation.
• Antibody deposition, not complement, correlated with blister induction across different antibody isotypes.
• BP autoantibodies reduced COL17 levels via a ubiquitin/proteasome pathway.

Conclusions:

• Complement activation is not essential for blister formation in this experimental model of BP.
• COL17 depletion induced by BP autoantibodies is the key mechanism driving blister formation.
• Findings challenge the traditional view of complement's role and highlight antibody-mediated COL17 depletion.