Antigen-specific IGG2A production in response to prostaglandin E2, immune complexes, and IFN-gamma.
Immune complexes (IC) can inhibit the differentiation of B lymphocytes into IgM secreting plasma cells in both Ag-specific and polyclonal systems. This report describes the ability of IC and IFN-gamma, or IFN-gamma and PGE2 to regulate the class of Ig produced in an Ag-specific system. In an in vitro model system using fluorescein (FL)-Brucella abortus as Ag, we previously showed that IC composed of an anti-FL antibody and FL-Ag inhibited the ability of FL-specific B cells to develop into IgM plaque-forming cells. In addition, PGE2 sensitized resting B cells to IC, whereas pretreatment with IL-4 alleviated the IC-mediated decrease in the IgM anti-FL response. In this manuscript, we demonstrate that IFN-gamma has antagonistic effects compared to IL-4, and potentiates the IC-induced decrease in the IgM antibody response. Interestingly, we discovered that the virtual ablation of the anti-FL IgM response exhibited by B cells treated with IC and IFN-gamma was accompanied by a dramatic increase in the anti-FL IgG2a response. Furthermore, resting B lymphocytes pulsed with IFN-gamma and PGE2, but not PGF2 alpha, exhibited augmented IgG2a production. This effect was also observed when IFN-gamma-pulsed B cells were stimulated with other agents, such as dibutyryl cAMP and cholera toxin, that elevate intracellular levels of cAMP. In addition, RpcAMP, the R-isomer of a sulfur-modified cAMP and a cAMP antagonist, inhibited anti-FL IgG2a responses. The ability of cAMP elevators such as PGE2 to promote IgG2a production, as well as to increase the frequency of IgG2a secreting cells, was demonstrated in B lymphocytes treated with IFN-gamma and polyclonally activated by LPS. Overall, our results demonstrate that IFN-gamma and PGE2-treated B lymphocytes challenged with antigen or LPS generate elevated levels of IgG2a via a cAMP-dependent pathway. These observations suggest that in vivo, PGE2 secreted by cells such as macrophages potentiates the ability of IFN-gamma to promote an IgG2a response, the predominant murine antiviral Ig.
Stein
S H
SH
Immunobiology Division of the Cancer Center, University of Rochester, School of Medicine and Dentistry, NY 14642.
Phipps
R P
RP
D000818:Animals; D000936:Antigen-Antibody Complex / Q000502:physiology*; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D002772:Cholera Toxin / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology; D015232:Dinoprostone / Q000494:pharmacology*; D019793:Fluorescein; D005452:Fluoresceins; D007074:Immunoglobulin G / Q000096:biosynthesis*; D007075:Immunoglobulin M / Q000096:biosynthesis; D007371:Interferon-gamma / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA
D000936:Antigen-Antibody Complex; D005452:Fluoresceins; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007371:Interferon-gamma; D002772:Cholera Toxin; D000242:Cyclic AMP; D015232:Dinoprostone; D019793:Fluorescein