Involvement of the Lectin Pathway of Complement Activation in Antimicrobial Immune Defense during Experimental Septic Peritonitis

Abstract

A critical first line of defense against infection is constituted by the binding of natural antibodies to microbial surfaces, activating the complement system via the classical complement activation pathway. In this function, the classical activation pathway is supported and amplified by two antibody-independent complement activation routes, i.e., the lectin pathway and the alternative pathway. We studied the contribution of the different complement activation pathways in the host defense against experimental polymicrobial peritonitis induced by cecal ligation and puncture by using mice deficient in either C1q or factors B and C2. The C1q-deficient mice lack the classical complement activation pathway. While infection-induced mortality of wild-type mice was 27%, mortality of C1q-deficient mice was increased to 60%. Mice with a deficiency of both factors B and C2 lack complement activation via the classical, the alternative, and the lectin pathways and exhibit a mortality of 92%, indicating a significant contribution of the lectin and alternative pathways of complement activation to survival. For 14 days after infection, mannan-binding lectin (MBL)-dependent activation of C4 was compromised. Serum MBL-A and MBL-C levels were significantly reduced for 1 week, possibly due to consumption. mRNA expression profiles did not lend support for either of the two MBL genes to respond as typical acute-phase genes. Our results demonstrate a long-lasting depletion of MBL-A and MBL-C from serum during microbial infection and underline the importance of both the lectin and the alternative pathways for antimicrobial immune defense.

Complement Factor B Is the Downstream Effector of TLRs and Plays an Important Role in a Mouse Model of Severe Sepsis

“…In a non-severe model of polymicrobial peritonitis, mice deficient in C1q (lack classical pathway) or deficient in cfB and C2 (lack all three pathways) have an increased mortality rate compared to WT mice, indicating a critical contribution of the three complement pathways to host defense (56). However, under severe septic and hyper-inflammatory conditions, they may be improperly controlled and may contribute to tissue injury and organ failure (57).…”

Properdin Plays a Protective Role in Polymicrobial Septic Peritonitis

“…These are generated after activation of the alternative pathway of complement via deposition of C3b to target surfaces by so-called spontaneous tickover of fluid phase C3 or by activation of classical or lectin pathways (via recognition of immune complexes or carbohydrate moieties on microorganisms, respectively). C1q-deficient mice (deficient of the recognition molecule of the classical pathway) and mice with a dual deficiency of factor B and C2 (affecting activities for lectin, classical and alternative pathways) (all on Sv/129 background) have previously been studied in sublethal CLP (12). The study concluded that intact lectin and alternative pathways are important for survival of sublethal CLP; however, it did not allow quantification of the separate contribution of the alternative pathway amplification to this effect.…”

Ficolins do not alter host immune responses to lipopolysaccharide-induced inflammation in vivo

“…A later study found that serum MBL-A and MBL-C levels were reduced for 1 week after CLP, while the mRNA levels where unchanged, indicating consumption rather than decreased protein expression 41 . Another study found that ficolin-B mRNA expression was higher in neutrophils isolated from mice subjected to CLP compared to naive mice 42 .…”