Role of different pathways of the complement cascade in experimental bullous pemphigoid
Kelly C. Nelson, Minglang Zhao, Pamela R. Schroeder, Ning Li, Rick A. Wetsel, Luis A. Diaz, Zhi Liu
Kelly C. Nelson, Minglang Zhao, Pamela R. Schroeder, Ning Li, Rick A. Wetsel, Luis A. Diaz, Zhi Liu
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 6

Effect of MC degranulating agent on PMN infiltration and subepidermal blistering in pathogenic IgG–injected C4–/– mice.

Options: View larger image (or click on image) Download as PowerPoint
Effect of MC degranulating agent on PMN infiltration and subepidermal bl...
WT and C4–/– mice were injected with pathogenic anti-mBP180 R530 IgG (2.6 mg/g body weight) with or without pretreatment of the MC degranulating agent compound 48/80 (C48/80) and were examined 2 hours (for toluidine blue staining) and 12 hours (for clinical examination and MPO assay) after IgG injection. (A–C) Clinical examination and toluidine blue staining of the mouse skin showed subepidermal blisters and MC degranulation in WT (A) and C4–/– mice with compound 48/80 pretreatment (C). (B) In contrast, C4–/– mice without compound 48/80 treatment exhibited no skin lesions and minimal MC degranulation. (D) MCs in the dermis of the skin were counted and classified as degranulated or normal. Total MCs in 5 random fields were counted (mean, 31.72 ± 8.41), and percent MC degranulation was calculated. As expected, MC degranulation was significantly reduced in C4–/– mice compared with WT mice. However, a significant increase of MC degranulation was seen in the skin of compound 48/80–treated C4–/– mice. n = 6 per group. (E) MPO activity assay revealed significantly higher levels of PMN infiltration in WT and C4–/– mice with compound 48/80 pretreatment than those without it. Tissue MPO activity at the injection sites was expressed as relative MPO activity. Three independent experiments were performed per group. n = 6 per group. **P < 0.01 versus WT and pretreated C4–/– mice.