Andrey P. Prodeus

A Critical Role for Complement in Maintenance of Self-Tolerance

The role of complement in the maintenance of self-tolerance has been examined in two models: an immunoglobulin transgenic model of peripheral tolerance and a lupus-like murine model of CD95 (Fas) deficiency. We find that self-reactive B lymphocytes deficient in complement receptors CD21/CD35 or transferred into mice deficient in the complement protein C4 are not anergized by soluble self-antigen. In the second model, deficiency in CD21/CD35 or C4 combined with CD95 deficiency results in high titers of anti-nuclear antibodies leading to severe lupus-like disease. These findings suggest a novel role for the complement system in B cell tolerance and provide insight into the genetic association of complement deficiency with susceptibility to systemic lupus erythematosus.

Impaired mast cell-dependent natural immunity in complement C3-deficient mice

The complement system is widely regarded as essential for normal inflammation, not least because of its ability to activate mast cells. However, recent studies have called into question the importance of complement in several examples of mast cell-dependent inflammatory responses. To investigate the role of complement in mast cell-dependent natural immunity, we examined the responses of complement-deficient mice to caecal ligation and puncture, a model of acute septic peritonitis that is dependent on mast cells and tumour necrosis factor-α (TNF-α). We found that C4- or C3-deficient mice were much more sensitive to caecal ligation and puncture than wild-type (WT) controls (100% versus 20% in 24-h mortality, respectively). C3-deficient mice also exhibited reductions in peritoneal mast cell degranulation, production of TNF-α, neutrophil infiltration and clearance of bacteria. Treating the C3-deficient mice with purified C3 protein enhanced activation of peritoneal mast cells, TNF-α production, neutrophil recruitment, opsonophagocytosis of bacteria and resistance to caecal ligation and puncture, confirming that the defects were complement-dependent. These results provide formal evidence that complement activation is essential for the full expression of innate immunity in this mast cell-dependent model of bacterial infection.

Linkages of innate and adaptive immunity

The innate immune system is activated by pathogens or environmental antigens following their binding by recognition molecules such as mannan-binding lectin, C-reactive protein and the mannose receptor. Natural antibody, which represents a collection of germline-encoded antigen recognition molecules, is also important in recognition of pathogens and activation of the innate immune system via the classical pathway of complement activation. The major source of natural antibody is CD5+ B-1 cells which differ from conventional B cells (B-2 cells) firstly because they are thought to require contact with antigen for expansion and maintenance and secondly because in general they do not appear to undergo somatic hypermutation. We review results which support an important role for complement in maintenance of B-1 cells, the effect being mediated by B cell expression of complement receptors CD21 and CD35. We propose that complement and natural antibody are interdependent: clonal selection and expansion of CD5+ B-1 cells is dependent on contact with antigen coated by the complement component C3d, while efficient recognition of pathogens and activation of complement is dependent in a large part on natural antibody. This hypothesis is supported by the finding that mice deficient in CD21 and CD35 have a reduced number of CD5+ B-1 cells and are missing specificities for certain antigens commonly found in wild-type mice, such as lipopolysaccharide, Escherichia coli surface antigens and neoepitopes expressed on hypoxic intestinal endothelium.