Mouse genetic background is a major determinant of isotype-related differences for antibody-mediated protective efficacy against Cryptococcus neoformans.
The protective efficacy of mAbs to Cryptococcus neoformans glucuronoxylomannan depends on Ab isotype. Previous studies in A/JCr and C57BL/6J mice showed relative protective efficacy of IgG1, IgG2a >> IgG3. However, we now report that in C57BL/6J x 129/Sv mice, IgG3 is protective while IgG1 is not protective, with neither isotype being protective in 129/Sv mice. IgG1, IgG2a, and IgG3 had different effects on IFN-gamma expression in infected C57BL/6J x 129/Sv mice. IgG1-treated C57BL/6J x 129/Sv mice had significantly more pulmonary eosinophilia than IgG2a- and IgG3-treated C57BL/6J x 129/Sv mice. C. neoformans infection and Ab administration had different effects on FcgammaRI, FcgammaRII, and FcgammaRIII expression in C57BL/6J, 129/Sv, and C57BL/6J x 129/Sv mice. Our results indicate that the relative efficacy of Ab isotype function against C. neoformans is a function of the genetic background of the host and that IgG3-mediated protection in C57BL/6J x 129/Sv mice was associated with lower levels of IFN-gamma and fewer pulmonary eosinophils. The dependence of isotype efficacy on host genetics underscores a previously unsuspected complex relationship between the cellular and humoral arms of the adaptive immune response.
Rivera
Johanna
J
Department of Microbiology and Immunology, Division of Infectious Diseases, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Casadevall
Arturo
A
D000818:Animals; D000908:Antibodies, Fungal / Q000008:administration & dosage / Q000502:physiology* / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000502:physiology / Q000627:therapeutic use; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D003433:Crosses, Genetic; D003453:Cryptococcosis / Q000235:genetics* / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D003455:Cryptococcus neoformans / Q000276:immunology; D005260:Female; D020022:Genetic Predisposition to Disease; D007073:Immunoglobulin E / Q000097:blood; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000502:physiology / Q000627:therapeutic use; D007132:Immunoglobulin Isotypes / Q000008:administration & dosage / Q000235:genetics / Q000502:physiology*; D008168:Lung / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D017452:Receptors, IgG / Q000096:biosynthesis; D016019:Survival Analysis
D000908:Antibodies, Fungal; D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D007132:Immunoglobulin Isotypes; D017452:Receptors, IgG; D007073:Immunoglobulin E