The complement system and innate immunity via Toll-like receptors (TLRs) play critical roles in immune defenses against pathogens. These two systems traditionally have been considered to be separate. However, recent studies indicate that the two systems can regulate each other. In retrospect this is not surprising since both play a role in the inflammatory response. Please consider the following experiments:

1. Sepsis was induced in wild type and MyD88 knockout (MyD88^-/-) mice. The levels of complement factor B mRNA were assessed. Approximately 30% less complement Factor B mRNA was present in MyD88^-/- mice than in wild type mice.

2. In follow up studies sepsis was induced in wild type and MyD88 knockout (MyD88^-/-) mice. Western blot analysis was used to determine levels of various complement proteins in sera of experimental animals. Inwild type mice induction of sepsis resulted in an increase in serum levels of complement factor B and ofC3. Ba and C3a fragments also were increased as compared to non-septic mice. In contrast, sera fromMyD88^-/- mice undergoing sepsis had no increase in complement factor B and C3 and additionally, there was less Ba and C3a than in sera from wild type septic mice.

3. When the same experiments as in (2) above were done with TLR2^-/-. TLR4^-/-, or TRIF^-/- mice it was found that the increase in complement factor B mRNA was similar to that found in wild type mice.

4. separate experiments complement factor B knockout (cfB^-/-) mice were generated. Sepsis was induced in wild type and cfB^-/- mice. The wild type septic mice had greater bacteremia (i.e., higher bacterial load) than did the cfB^-/- mice. Furthermore, the wild type septic mice had a mortality rate of 68% while septic cfB^-/- mice had a mortality of 42%.