The Autoimmune Skin Disease Bullous Pemphigoid: The Role of Mast Cells in Autoantibody-Induced Tissue Injury

Abstract

Bullous pemphigoid (BP) is an autoimmune and inflammatory skin disease associated with subepidermal blistering and autoantibodies directed against the hemidesmosomal components BP180 and BP230. Animal models of BP were developed by passively transferring anti-BP180 IgG into mice, which recapitulates the key features of human BP. By using these in vivo model systems, key cellular and molecular events leading to the BP disease phenotype are identified, including binding of pathogenic IgG to its target, complement activation of the classical pathway, mast cell degranulation, and infiltration and activation of neutrophils. Proteinases released by infiltrating neutrophils cleave BP180 and other hemidesmosome-associated proteins, causing DEJ separation. Mast cells and mast cell-derived mediators including inflammatory cytokines and proteases are increased in lesional skin and blister fluids of BP. BP animal model evidence also implicates mast cells in the pathogenesis of BP. However, recent studies questioned the pathogenic role of mast cells in autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, and epidermolysis bullosa acquisita. This review highlights the current knowledge on BP pathophysiology with a focus on a potential role for mast cells in BP and mast cell-related critical issues needing to be addressed in the future.

Keywords: autoantibodies; bullous pemphigoid; hemidesmosome; mast cells; skin autoimmunity.

Figure 1

Human bullous pemphigoid (BP). (A) Large, tense bullae, and erythematous patches seen in BP patient. (B) Histology reveals dermal–epidermal junction separation with inflammatory cell infiltration. Immunofluorescence shows linear deposition of IgG (C) and complement C3 (D) at the basement membrane zone (BMZ). d, dermis; e, epidermis. Arrow, the BMZ. Original magnification, 100× for panels (B–D).

Figure 2

Mouse bullous pemphigoid. The anti-BP180 IgG induce extensive blistering disease in neonatal B6 mice clinically (A) and histologically (B). The skin of these animals shows linear deposition of anti-BP180 IgG (C) and murine C3 (D) at the BMZ, as determined by direct IF. Toluidine blue staining shows resting and degranulating mast cells in the dermis (E). d, dermis; e, epidermis; v, vesicle; arrow, the BMZ. Original magnification, 200× for panels (B–D), 400× for panel (E). (E) Arrows for degranulating mast cells, and arrow heads for normal resting mast cells.

Figure 3

Proposed role of mast cells (MCs) in bullous pemphigoid (BP). Anti-BP180 IgG binding to BP180 on the surface of basal keratinocytes activates the complement (C), generating C5a. C5a acts on C5a receptor (C5aR) to cause MCs to degranulate and release pro-inflammatory cytokines/chemokines (e.g., TNFα) and proteolytic enzymes including mouse MC protease-4 (mMCP-4). Anti-BP180 IgE could also activate MCs. The released pro-inflammatory mediators interact with local cells to recruit neutrophils (PMN) and eosinophils (Eos). Infiltrating PMN and Eos, upon activation through interactions between immobilized anti-BP180 IgG/IgE and FcγR/FcεR, release neutrophil elastase (NE), MMP-9, and other proteolytic enzymes. mMCP-4 activates MMP-9 and also directly cleaves BP180 and other BP180-associated proteins in concert with MMP-9 and NE, resulting in subepidermal blistering.