Role of different pathways of the complement cascade in experimental bullous pemphigoid.
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.
Nelson
Kelly C
KC
Department of Dermatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Zhao
Minglang
M
Schroeder
Pamela R
PR
Li
Ning
N
Wetsel
Rick A
RA
Diaz
Luis A
LA
Liu
Zhi
Z
D000818:Animals; D001324:Autoantigens / Q000276:immunology; D001768:Blister / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002467:Cell Nucleus / Q000235:genetics / Q000473:pathology; D002633:Chemotaxis / Q000187:drug effects; D015922:Complement C1q / Q000276:immunology / Q000378:metabolism*; D003181:Complement C4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011415:Complement Factor B / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D007271:Injections, Intradermal; D016209:Interleukin-8 / Q000008:administration & dosage / Q000494:pharmacology; D008407:Mast Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D024041:Non-Fibrillar Collagens; D010391:Pemphigoid, Bullous / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction; D000097805:Collagen Type XVII
D001324:Autoantigens; D015922:Complement C1q; D003181:Complement C4; D011415:Complement Factor B; D016209:Interleukin-8; D024041:Non-Fibrillar Collagens; D000097805:Collagen Type XVII