Role of different pathways of the complement cascade in experimental bullous pemphigoid
Kelly C. Nelson, … , Luis A. Diaz, Zhi Liu
Kelly C. Nelson, … , Luis A. Diaz, Zhi Liu
Published November 1, 2006
Citation Information: J Clin Invest. 2006;116(11):2892-2900. https://doi.org/10.1172/JCI17891.
View: Text | PDF
Research Article Dermatology

Role of different pathways of the complement cascade in experimental bullous pemphigoid

Abstract

Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease associated with autoantibodies directed against the hemidesmosomal proteins BP180 and BP230 and inflammation. Passive transfer of antibodies to the murine BP180 (mBP180) induces a skin disease that closely resembles human BP. In the present study, we defined the roles of the different complement activation pathways in this model system. Mice deficient in the alternative pathway component factor B (Fb) and injected with pathogenic anti-mBP180 IgG developed delayed and less intense subepidermal blisters. Mice deficient in the classical pathway component complement component 4 (C4) and WT mice pretreated with neutralizing antibody against the first component of the classical pathway, C1q, were resistant to experimental BP. These mice exhibited a significantly reduced level of mast cell degranulation and polymorphonuclear neutrophil (PMN) infiltration in the skin. Intradermal administration of compound 48/80, a mast cell degranulating agent, restored BP disease in C4–/– mice. Furthermore, C4–/– mice became susceptible to experimental BP after local injection of PMN chemoattractant IL-8 or local reconstitution with PMNs. These findings provide the first direct evidence to our knowledge that complement activation via the classical and alternative pathways is crucial in subepidermal blister formation in experimental BP.

Authors

Kelly C. Nelson, Minglang Zhao, Pamela R. Schroeder, Ning Li, Rick A. Wetsel, Luis A. Diaz, Zhi Liu

×

Figure 1

Clinical, IF, and histological examination of neonatal WT, C4–/–, and Fb–/– mice injected with pathogenic anti-mBP180 IgG.

Options: View larger image (or click on image) Download as PowerPoint
Clinical, IF, and histological examination of neonatal WT, C4–/–, and Fb...
Neonatal WT, C4–/–, and Fb–/– mice were injected i.d. with pathogenic rabbit anti-mBP180 IgG R530 or control rabbit IgG R50 (2.64 mg/g body weight) and examined 12 hours after injection. The pathogenic IgG-injected WT (A) and Fb–/– (I) mice developed extensive epidermal disease. The skin of these animals showed linear deposition of rabbit IgG (B and J) and mouse C3 (C and K) at the BMZ by direct IF. (D and L) H&E-stained sections from these mice showed a subepidermal vesicle with PMN infiltrate. (E) In contrast, anti-mBP180 IgG–injected C4–/– mice showed no clinical evidence of skin disease. Direct IF studies showed rabbit IgG (F), but no mouse C3 (G) deposition at the BMZ. (H) These animals showed no evidence of subepidermal vesiculation at the light microscopic level. Skin from mice injected with anti-mBP180 IgG was negative for BMZ staining with negative control antibody (FITC-conjugated goat anti-human IgG), and skin from mice injected with control rabbit IgG showed negative BMZ staining with FITC-conjugated goat anti-rabbit IgG and anti-mC3 IgG (data not shown). Four independent experiments were performed per group. Arrowheads denote sites of antibody labeling and basal keratinocytes. D, dermis; E, epidermis; V, vesicle. Magnification, ×200 (B–D, F–H, and J–L).