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.
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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

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Figure 5

Relative contribution of the classical and alternative pathways of complement in anti-mBP180–induced subepidermal blister formation.

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Relative contribution of the classical and alternative pathways of compl...
WT, C4–/–, and Fb–/– mice (n = 12 per group) were injected with an optimal or suboptimal dose (2.64 or 2.0 mg/g body weight, respectively) of pathogenic anti-mBP180 IgG or with control IgG (2.64 mg/g body weight) in the absence (A) or presence (B) of anti-mC1q monoclonal antibody and examined at 12, 24, and 48 hours after IgG injection. Disease severity was quantified by measuring tissue MPO activities (mean + SEM) in the injection sites as an indicator of PMN recruitment. (A) Without C1q inhibition, significant reduction of PMN infiltration was seen in the skin of C4–/– mice at all time points and in Fb–/– mice at 24 and 48 hours compared with WT mice. ΧP < 0.001. (B) Anti-mC1q antibody treatment significantly reduced PMN infiltration in all 3 strains of mice. C1q blocking caused a further significant reduction in PMN infiltration in Fb–/– mice relative to C4–/– and WT mice. Levels of PMN infiltration between anti-mC1q–treated WT and C4–/– mice were similar at 12 and 24 hours, but different at 48 hours. Three independent experiments were performed per group. *P < 0.05, ΧP < 0.001 versus WT at the respective time points. #P < 0.05 versus C4–/– at the respective time points.