Complement C3 deficiency exacerbates development of cardiovascular lesions in the LCWE-induced Kawasaki Disease Vasculitis

Abstract

Abstract Background Kawasaki disease (KD) is an acute febrile systemic vasculitis of childhood, mostly affecting the coronary arteries. A central feature of acute KD is the activation of the innate and adaptive immune systems. Serum complement component C3 is significantly increased in children during the acute stages of KD, and a polymorphism of a C type lectin, mannose binding lectin (MBL), has been associated with KD vasculitis and coronary artery lesions. However, the role of the complement pathway in KD vasculitis remains unclear. Objective Determine if the complement system contributes to KD pathogenesis in the Lactobacillus casei cell wall extract (LCWE)-mediated murine model of KD vasculitis. Methods and Results Serum levels of various complement proteins were elevated in LCWE-injected mice. We observed that the LCWE extract, rich in rhamnose and a TLR2 ligand, was able to bind both C3 and MBL in-vitro. Genetic deletion of C3 exacerbated LCWE-induced aortitis, coronary arteritis and abdominal aorta dilation and aneurysm. Furthermore, in-vivo blockade of C5 with a C5aR1 antagonist (PMX205) also increased these cardiovascular lesions in LCWE mice. Conclusions Blocking key components of the complement system, such as C3 and C5aR, significantly enhanced cardiovascular lesions in the LCWE-induced KD vasculitis mouse model. Thus, C3 or downstream activation fragments may play a protective role in the development of KD cardiovascular lesions. Whether this protection is due to complement mediated increased clearance of immune complexes or common carbohydrate pathogen molecules will need to be determined and may help our current understanding of the immunopathologic mechanisms of KD vasculitis. (Supported by NIH grant AI072726 to MA)