Central Role of Complement in Passive Protection by Human IgG1 and IgG2 Anti-pneumococcal Antibodies in Mice

Abstract

Streptococcus pneumoniae is an important cause of morbitity and mortality worldwide. Capsule-specific IgG1 and IgG2 Abs are induced upon vaccination with polysaccharide-based vaccines that mediate host protection. We compared the protective capacity of human recombinant serogroup 6-specific IgG1 and IgG2 Abs in mice deficient for either leukocyte FcR or complement factors. Human IgG1 was found to interact with mouse leukocyte FcR in vitro, whereas human IgG2 did not. Both subclasses induced complement activation, resulting in C3c deposition on pneumococcal surfaces. Passive immunization of C57BL/6 mice with either subclass before intranasal challenge with serotype 6A induced similar degrees of protection. FcgammaRI- and III-deficient mice, as well as the combined FcgammaRI, II, and III knockout mice, were protected by passive immunization, indicating FcR not to be essential for protection. C1q or C2/factor B knockout mice, however, were not protected by passive immunization. Passively immunized C2/factor B(-/-) mice displayed higher bacteremic load than C1q(-/-) mice, supporting an important protective role of the alternative complement pathway. Spleens from wild-type and C1q(-/-) mice showed hyperemia and thrombotic vessel occlusion, as a result of septicemic shock. Notably, thrombus formation was absent in spleens of C2/factor B(-/-) mice, suggesting that the alternative complement pathway contributes to shock-induced intravascular coagulation. These studies demonstrate complement to play a central role in Ab-mediated protection against pneumococcal infection in vivo, as well as in bacteremia-associated thrombotic complications.

Affinity of human IgG subclasses to mouse Fc gamma receptors

“…[37][38][39] Similarly, hIgG3 has been found highly efficient in protecting against pneumococcal infections in vivo, also through complement. 40,41 hIgG2 has a comparable binding pattern for the mouse Fc receptors as mIgG1, but with an estimated 5-to 50-fold lower affinity than mIgG1. This is in agreement with the results found by Overdijk et al, who showed hIgG2 to compete moderately with mIgG1 binding for mFcgRIIb and mFcgRIV.…”

“…The variable region of the light chain (anti-D VL) was subcloned into pEE14.4 (Lonza) expression vector containing a kappa light chain. Heavy and light chain vectors to express anti Streptococcus pneumoniae serotype 6A/B IgG1, IgG2 and IgG3 named GDob1 (classed switched variants derived from clone Dob1 44 ) were described by Saeland et al 41 Heavy and light chain vectors to express anti-BetV1 IgG4 directed against major birch allergen from birch pollen (Betula verrucosa) were previously described. 45 To generate anti-Kell mouse IgG subclasses, we used PUMA1 variable domain specific for Kell antigen.…”

The Capsular Serotype ofStreptococcus pneumoniaeIs More Important than the Genetic Background for Resistance to Complement

“…The complement system is an essential element of host defense against pneumococci (3,42). Activation of the complement leads to opsonization of the bacterial surface with C3 activation products C3b and iC3b, which are recognized by complement receptors of phagocytic cells (10,41).…”

The C-type lectin SIGN-R1 mediates uptake of the capsular polysaccharide ofStreptococcus pneumoniaein the marginal zone of mouse spleen

“…A critical role of the spleen is the formation of antibodies by marginal zone B cells (13)(14)(15), particularly complement-fixing antibodies (16)(17)(18)(19)(20). The role of macrophages in the processes of microbial clearance and resistance and antibody formation to S. pneumoniae needs to be considered (21), particularly given recent data that marginal zone macrophages interact and retain B cells in this region (22).…”