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 7

In vivo reconstitution of PMNs at the tissue site restores experimental BP in C4–/– mice.

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In vivo reconstitution of PMNs at the tissue site restores experimental ...
C4–/– mice were injected i.d. with pathogenic anti-mBP180 R530 IgG alone or in conjunction with IL-8 (50 ng/injection) or PMNs (5 × 105 cells) and were examined 12 hours after IgG injection. MPO activity assay showed significantly higher levels of PMN recruitment in the lesional skin of WT mice injected with pathogenic IgG, C4–/– mice coinjected with IL-8, and C4–/– mice coinjected with PMNs compared with C4–/– mice injected with pathogenic IgG alone as well as the nonlesional skin of WT and C4–/– mice injected with control IgG. 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 C4–/– mice injected with pathogenic IgG alone; Student’s t test for paired samples.