Abstract
Murine immunoglobulin G (IgG) plays an important role in mediating protective immune responses to malaria. We still know relatively little about which IgG subclasses protect against this disease in mouse models, although IgG2a and IgG2b are considered to be the most potent and dominate in successful passive transfer experiments in rodent malarias. To explore the mechanism(s) by which the different mouse IgG subclasses may mediate a protective effect, we generated mouse IgG1, IgG2a, IgG2b and IgG3 specific for the C-terminal 19-kDa region of Plasmodium falciparum merozoite surface protein 1 (PfMSP119), and to the homologous antigen from Plasmodium yoelii (P. yoelii), both major targets of protective immune responses. This panel of eight IgGs bound antigen with an affinity comparable to that seen for their epitope-matched parental monoclonal antibodies (mAbs) from which they were derived, although for reasons of yield, we were only able to explore the function of mouse IgG1 recognizing PfMSP119 in detail, both in vitro and in vivo. Murine IgG1 was as effective as the parental human IgG from which it was derived at inducing NADPH-mediated oxidative bursts and degranulation from neutrophils. Despite showing efficacy in in vitro functional assays with neutrophils, the mouse IgG1 failed to protect against parasite challenge in vivo. The lack of protection afforded by MSP119-specific IgG1 against parasite challenge in wild type mice suggests that this Ab class does not play a major role in the control of infection with mouse malaria in the Plasmodium berghei transgenic model.
Highlights
Amongst mouse immunoglobulin G (IgG) subclasses, IgG2a and IgG2b are considered to be the most potent activators, and dominate in successful passive transfer experiments in both murine infection, and murine tumour models (Clynes et al, 2000; Nimmerjahn and Ravetch, 2005; Spencer Valero et al, 1998)
PfMSP119 and PyMSP119-specific mouse IgG1, IgG2a, IgG2b and IgG3 were secreted into culture supernatants from stably transfected Chinese hamster ovary (CHO)-K1 or human embryonic kidney (HEK)-293T cells
We focus on the PfMSP119-specific mouse IgG1, IgG2a, IgG2b and IgG3 that were purified from CHO-K1 or HEK-293T culture supernatants by protein-G affinity-chromatography and appeared pure by SDS–PAGE analysis (Fig. 4a)
Summary
Amongst mouse IgG subclasses, IgG2a and IgG2b are considered to be the most potent activators, and dominate in successful passive transfer experiments in both murine infection (including malaria), and murine tumour models (Clynes et al, 2000; Nimmerjahn and Ravetch, 2005; Spencer Valero et al, 1998). Such functional distinctions have been attributed to differences in their capacity to fix complement and/or recruitment of relevant Fc-receptors for IgG (FccRs) (Nimmerjahn and Ravetch, 2005). Present address: Liverpool School of Tropical Medicine, liverpool.ac.uk (R.J. Pleass). 1 Present address: Liverpool School of Tropical Medicine, Pembroke Place, Liverpool.
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