Role of the classical pathway of complement activation in experimentally induced polymicrobial peritonitis

The complement system and the natural antibody repertoire provide a critica l first-line defense against infection. The binding of natural antibodies t o microbial surfaces opsonizes invading microorganisms and activates comple ment via the classical pathway. Both defense systems cooperate within the i nnate immune response. We studied the role of the complement system in the host defense against experimental polymicrobial peritonitis using mice lack ing either C1q or factor B and C2. The Clq-deficient mice lacked the classi cal pathway of complement activation. The factor B- and C2-deficient mice w ere known to lack the classical and alternative pathways, and we demonstrat e here that these mice also lacked the lectin pathway of complement activat ion. Using inoculum doses adjusted to cause 42% mortality in the wild-type strain, none of the mice deficient in the three activation routes of comple ment (factor B and C2 deficient) survived (mortality of 100%). Mortality in mice deficient only in the classical pathway of complement activation (Clq deficient) was 83%. Application of further dilutions of the polymicrobial inoculum showed a dose-dependent decrease of mortality in wild-type control s, whereas no changes in mortality were observed in the two gene-targeted s trains. These results demonstrate that the classical activation pathway is required for an effective antimicrobial immune defense in polymicrobial per itonitis and that, in the infection model used, the remaining antibody-inde pendent complement activation routes (alternative and lectin pathways) prov ide a supporting line of defense to gain residual protection in classical p athway deficiency.