IMPAIRED MAST CELL-DEPENDENT NATURAL IMMUNITY IN COMPLEMENT C3-DEFICIENT MICE

The complement system is widely regarded as essential for normal infla mmation, not least because of its ability to activate mast cells(1-5). However, recent studies have called into question the importance of c omplement in several examples of mast cell-dependent inflammatory resp onses(6-9). To investigate the role of complement in mast cell-depende nt natural immunity, we examined the responses of complement-deficient mice(10,11) to caecal ligation and puncture(12), model of acute septi c peritonitis(12,13) that is dependent on mast cells and tumour necros is factor-alpha (TNF-alpha). We found that C4- or C3-deficient mice(10 ,11) '' were much more sensitive to caecal ligation and puncture than wild-type (WT) controls (100% versus 20% in 24-h mortality, respective ly). C3-deficient mice also exhibited reductions in peritoneal mast ce ll degranulation, production of TNF-alpha, neutrophil infiltration and clearance of bacteria. Treating the C3-deficient mice with purified C 3 protein enhanced activation of peritoneal mast cells, TNF-alpha prod uction, neutrophil recruitment, opsonophagocytosis of bacteria and res istance to caecal ligation and puncture, confirming that the defects w ere complement-dependent. These results provide formal evidence that c omplement activation is essential for the full expression of innate im munity in this mast cell-dependent model of bacterial infection.