Immunoglobulin G Monoclonal Antibodies toCryptococcus neoformansProtect Mice Deficient in Complement Component C3

Abstract

Passive administration of monoclonal antibodies (MAbs) to the capsular polysaccharide of Cryptococcus neoformans can alter the course of infection in mice. In a murine model of cryptococcal infection, immunoglobulin G1 (IgG1), IgG2a, and IgG2b switch variants of the anti-capsular 3E5 MAb prolong the survival of lethally infected mice, whereas the 3E5 IgG3 MAb does not protect and in some cases enhances infection, shortening the life spans of infected mice. We examined the role of complement component C3 in Ab-mediated protection by determining the efficacy of the four mouse IgG subclasses against C. neoformans in mice genetically deficient in factor C3 as well as mice acutely depleted of C3. Similar to other complement-deficient animal models, C3؊/؊ mice and mice depleted of C3 by cobra venom factor were more susceptible to C. neoformans infection than control mice, providing further evidence that complement is important in the host defense against the fungus. In the absence of C3, all IgG isotypes prolonged the lives of mice infected with C. neoformans, indicating that protection by IgG does not require the complement pathways. Furthermore, we observed protection with IgG3 in the complement-deficient mice, suggesting that complement is involved in the lack of protection observed with IgG3 in other mouse models.

Mouse Genetic Background Is a Major Determinant of Isotype-Related Differences for Antibody-Mediated Protective Efficacy againstCryptococcus neoformans

“…Mechanisms by which Ab can affect a cell-mediated response include enhanced Ag presentation, changes in cytokine expression as a result of FcR activation, and increased expression of costimulatory molecules (35). Additional evidence for the dependence of IgG3 efficacy on other components of the immune system came from studies in complement-deficient mice, which showed that the disease-enhancing effect of IgG3 in C57BL/6J mice is dependent on the presence of C3 (36).…”

Producción de anticuerpos IgG1 anti-glucuronoxilomanana en ratones resistentes a la criptococosis

“…We show that BALB/c and CBA/J mice, defined as moderately and highly resistant to C. neoformans infection (4), produce higher amounts of total IgG (mainly of the IgG 1 isotype) than the susceptible C57BL/6 mice. Protection mediated by exogenous IgG 1 anti-GXM specific mAbs has been shown in several studies (6,10); in contrast to non-protective IgG 3 mAbs directed to the same epitope (10), IgG1 antibodies have been previously reported as protective in experiments of passive transfer in the mouse model (23)(24)(25). In these studies, it was observed that the three strains of infected animals produced both IgG 2a and IgG 2b but at relatively lower levels, and there were no significant differences between strains (23)(24)(25).…”

“…Protection mediated by exogenous IgG 1 anti-GXM specific mAbs has been shown in several studies (6,10); in contrast to non-protective IgG 3 mAbs directed to the same epitope (10), IgG1 antibodies have been previously reported as protective in experiments of passive transfer in the mouse model (23)(24)(25). In these studies, it was observed that the three strains of infected animals produced both IgG 2a and IgG 2b but at relatively lower levels, and there were no significant differences between strains (23)(24)(25). Taken together, these results suggest that IgG 2a and IgG 2b do not play an important role in murine resistance or susceptibility to cryptococcosis in vivo.…”

The protective role of immunoglobulins in fungal infections and inflammation

“…(Fig. 1) The complement component C3 was found to be dispensable for the protection by these IgGs [67]. In addition, mouse background also shown to influence the protection given by IgG subclass antibodies [68] thus underscoring the complex relationship between the cellular and humoral components of the immune system.…”