High immunoglobulin G2 (IgG2) and low IgG4 levels are associated with human resistance to Plasmodium falciparum malaria

There is accumulating evidence for a role of immunoglobulin G (IgG) in prot ection against malarial infection and disease. Only IgG1 and IgG3 are consi dered cytophilic and protective against P. falciparum, whereas IgG2 and IgG 4 were thought to be neither and even to block protective mechanisms. Howev er, no clear pattern of association between isotypes and protection has so far emerged. We analyzed the isotypic distribution of the IgG response to c onserved epitopes and P. falciparum blood-stage extract in 283 malaria-expo sed individuals whose occurrence of infection and malaria attack had been m onitored for about 1 year. Logistic regression analyses showed that, at the end of the season of transmission, high levels of IgG2 to RESA and to MSP2 epitopes were associated with low risk of infection. Indeed, IgG2 is able to bind Fc gamma RIIA in individuals possessing the H131 allele, and we sho wed that 70% of the study subjects had this allele. Also, high specific IgG 4 levels were associated with an enhanced risk of infection and with a high risk of malaria attack Moreover, specific IgG2 and IgG3 levels, as well as the IgG2/IgG4 and IgG3/IgG4 ratios, increased with the age of subjects, in parallel with the protection against infection and disease. IgG4 likely co mpetes with cytophilic antibodies for antigen recognition and may therefore block cytotoxicity mediated by antibody-activated effector cells. In concl usion, these results favor a protective role of IgG3 and IgG2, which may ac tivate effector cells through Fc gamma RIIA, and provide evidence for a blo cking role of IgG4 in malarial infection and disease.