The Fc portion of antibody to yellow fever virus NS1 is a determinant of protection against YF encephalitis in mice.
The mechanism by which antibodies to the flavivirus nonvirion protein NS1 protect mice against encephalitis is unknown but their binding to cell surface NS1 raises the possibility of involvement of an Fc piece-directed immune function. To investigate this, we prepared the F(ab')2 moiety of a protective IgG2a monoclonal antibody (Mab) against yellow fever virus (YF) NS1 and isolated IgG2a- and IgG2b-secreting isotype switch variants from a hybridoma that secretes a nonprotective IgG1 anti-YF NS1 Mab. Each Mab, complexed to NS1, bound to macrophage Fc receptor (FcR) but only the IgG2a and IgG2b Mabs sensitized YF-infected cells to complement-mediated cytolysis. Passively transferred IgG2a Mabs, but not F(ab')2, IgG1, or IgG2b Mabs, interfered with replication of YF in mouse brain. IgG2a Mabs protected mice against YF encephalitis but passive transfer of a mixture of variant IgG2a and parent IgG1 Mabs, or of unrelated IgG2a and IgG1 Mabs directed at the same NS1 epitope, resulted in markedly reduced protection, findings that may bear on flavivirus vaccine design. IgG2a Mab interfered with CNS YF replication in, and protected, C3-depleted mice, but not mice treated with high-dose cyclophosphamide to eliminate antibody-dependent killer cell activity. Taken together, these results indicate that epitope specificity alone may be inadequate to account for protection by anti-NS1 antibody and are consistent with involvement of an FcR-dependent protective mechanism that is governed by antibody isotype.
Department of Medicine, Rochester General Hospital, New York 14621.
J J
JJ
Schlesinger
M
M
Foltzer
S
S
Chapman
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000914:Antibodies, Viral / Q000276:immunology*; D000956:Antigens, Viral / Q000276:immunology*; D001921:Brain / Q000382:microbiology; D003176:Complement C3 / Q000276:immunology; D003520:Cyclophosphamide / Q000494:pharmacology; D004660:Encephalitis / Q000276:immunology* / Q000382:microbiology; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D007141:Immunoglobulin Fc Fragments / Q000276:immunology*; D007074:Immunoglobulin G / Q000276:immunology; D007132:Immunoglobulin Isotypes / Q000276:immunology; D051379:Mice; D017361:Viral Nonstructural Proteins / Q000276:immunology*; D014765:Viral Vaccines / Q000276:immunology*; D014779:Virus Replication; D015005:Yellow fever virus / Q000276:immunology*
D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; D000956:Antigens, Viral; D003176:Complement C3; D007140:Immunoglobulin Fab Fragments; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D007132:Immunoglobulin Isotypes; D017361:Viral Nonstructural Proteins; D014765:Viral Vaccines; D003520:Cyclophosphamide