Studies of group B streptococcal infection in mice deficient in complement component C3 or C4 demonstrate an essential role for complement in both innate and acquired immunity.

Abstract

Group B streptococci (GBS) cause sepsis and meningitis in neonates and serious infections in adults with underlying chronic illnesses. Specific antibodies have been shown to be an important factor in protective immunity for neonates, but the role of serum complement is less well defined. To elucidate the function of the complement system in immunity to this pathogen, we have used the approach of gene targeting in embryonic stem cells to generate mice totally deficient in complement component C3. Comparison of C3-deficient mice with mice deficient in complement component C4 demonstrated that the 50% lethal dose for GBS infection was reduced by "50-fold and 25-fold, respectively, compared to control mice. GBS were effectively killed in vitro by human blood leukocytes in the presence of specific antibody and C4-deficient serum but not C3-deficient serum. The defective opsonization by C3-deficient serum in vitro was corroborated by in vivo studies in which passive immunization of pregnant dams with specific antibodies conferred protection from GBS challenge to normal and C4-deficient pups but not C3-deficient pups. These results indicate that the alternative pathway is sufficient to mediate effective opsonophagocytosis and protective immunity to GBS in the presence of specific antibody. In contrast, the increased susceptibility to infection of nonimmune mice deficient in either C3 or C4 implies that the classical pathway plays an essential role in host defense against GBS infection in the absence of specific immunity.

Genetic Evidence for Involvement of Classical Complement Pathway in Induction of Experimental Autoimmune Myasthenia Gravis

“…Thus, even with a deficiency in C4, the adaptive host defense against pathogens may be expected to remain unaffected and the complement system may be expected to continue to clear viruses, apoptotic cells, and tumor cells. However, the classical complement pathway is also known to be involved in both host defense against infection and disposal of immune complexes (34,35), which suggests that its inhibition may result in increased susceptibility to lethal infection (35) and autoimmune disease. Interestingly, C4-deficient mice (but not C3-deficient mice) can effectively mediate opsonization, phagocytosis, and protective immunity to streptococci in the presence of passively transferred specific Abs (35), implicating that in the deficiency of the classical complement pathway, the immune system may be sufficient for an effective immune response to pathogens (35).…”

Complement C1q and C3 Are Critical for the Innate Immune Response to Streptococcus pneumoniae in the Central Nervous System

“…Gene-targeted mice lacking expression of C1q were generated by Botto et al (28), as described previously, and then backcrossed for 10 generations onto a C57BL/6 background. The C3-deficient mouse strain was originally produced by Wessels et al (29), obtained from The Jackson Laboratory (strain B6.129S4-C3 tm1Crr /J), and also bred back against the C57BL/6 background for 10 generations. wt C57BL/6 mice were purchased from Charles River Laboratories.…”

Influence of C3 Deficiency on Atherosclerosis

“…3 Mice deficient in C3 have diminished protective inflammatory responses to infections, a profound defect in their antibody response to T-dependent antigens, diminished germinal center formation, and a failure in isotype switching. 4,5 Individuals with atherosclerotic disease produce antibodies specific to atheroma antigens, such as oxidized low-density lipoproteins (LDLs) 6 and heat shock protein 60/65. 7 Antibody responses to oxidation-specific epitopes of oxidized LDL may modulate atherosclerotic disease.…”