Role of the Lectin Pathway of Complement Activation in Septic and Anaphylactic Shock

The complement system constitutes an important part of innate host defence. Complement activation can be initiated via the classical, lectin or alternative pathway. This work focuses on the role of the lectin pathway in mouse models of septic and anaphylactic shock. As a model of septic shock cecal ligation and puncture (CLP) was used. Complement activation is crucial for survival as mouse strains deficient in C I q and factors Band C2 show a higher mortality than complement-sufficient controls. H2-Bƒ/C2-/- mice also demonstrate an impaired bacterial clearance. The involvement of the lectin pathway can be seen in a rapid and long lasting decrease of serum MBL levels. mRNA expression was not altered during the course of infection. Furthermore, MBL deposition was demonstrated on the abscess that forms after peritoneal infection. Activation of the complement system also occurs during anaphylactic shock. It is believed that the classical pathway is responsible for complement activation, as serum C1q levels decrease during shock. This work shows also an involvement of the lectin pathway with serum MBL levels being diminished after antigen challenge. The mechanism leading to this decrease was investigated. To find out whether complement activation is of pathophysiological consequence in anaphylactic shock, several mouse strains with selective deficiencies in complement components, as well as mast-cell deficient mice were tested. Only mast cell deficient mice were protected from anaphylaxis and showed no decrease in serum MBL levels, indicating that cell derived mediators and not the complement system are crucial for the induction of anaphylaxis. Taken together, these results demonstrate a clear need for the complement system in combating bacterial infections during septic shock. In the case of anaphylaxis, however, complement activation is not causative of the symptoms

Role of the lectin pathway of complement activation in septic and anaphylactic shock

The complement system constitutes an important part of innate host defence. Complement activation can be initiated via the classical, lectin or alternative pathway. This work focuses on the role of the lectin pathway in mouse models of septic and anaphylactic shock. As a model of septic shock cecal ligation and puncture (CLP) was used. Complement activation is crucial for survival as mouse strains deficient in C I q and factors Band C2 show a higher mortality than complement-sufficient controls. H2-Bƒ/C2-/- mice also demonstrate an impaired bacterial clearance. The involvement of the lectin pathway can be seen in a rapid and long lasting decrease of serum MBL levels. mRNA expression was not altered during the course of infection. Furthermore, MBL deposition was demonstrated on the abscess that forms after peritoneal infection. Activation of the complement system also occurs during anaphylactic shock. It is believed that the classical pathway is responsible for complement activation, as serum C1q levels decrease during shock. This work shows also an involvement of the lectin pathway with serum MBL levels being diminished after antigen challenge. The mechanism leading to this decrease was investigated. To find out whether complement activation is of pathophysiological consequence in anaphylactic shock, several mouse strains with selective deficiencies in complement components, as well as mast-cell deficient mice were tested. Only mast cell deficient mice were protected from anaphylaxis and showed no decrease in serum MBL levels, indicating that cell derived mediators and not the complement system are crucial for the induction of anaphylaxis. Taken together, these results demonstrate a clear need for the complement system in combating bacterial infections during septic shock. In the case of anaphylaxis, however, complement activation is not causative of the symptoms.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

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

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