Dextran-conjugated anti-IgD antibodies inhibit T cell-mediated IgE production but augment the synthesis of IgM and IgG.
We previously demonstrated that anti-IgD antibodies conjugated to dextran (alpha delta-dex) were a potent co-stimulus for Ig secretion by resting murine B cells in the presence of cytokines. However, although alpha delta-dex stimulated the secretion of most Ig isotypes it selectively failed to costimulate IgE production even in the presence of high concentrations of IL-4. Earlier reports indicated that unconjugated anti-IgM, which was not an effective costimulus for Ig secretion, in fact inhibited Ig production induced by LPS. We determined the effect of alpha delta-dex, at concentrations that costimulated cytokine-induced Ig secretion, on Ig production by LPS- or T cell-activated B cells, and whether IgE production was affected in a selective manner. We observed that alpha delta-dex inhibited Ig isotype production (IgE > IgG > IgM) by LPS-activated B cells, while further stimulating their proliferation. This effect of alpha delta-dex was mediated directly at the level of the B cell and was accompanied by a comparable inhibition in Ig class switching, as assessed by flow cytometric analysis of membrane Ig isotype-positive cells. The inhibitory effects of alpha delta-dex on LPS-induced Ig secretion and class switching occurred at 1000-fold lower concentrations of anti-IgD than that reported necessary for inhibition by unconjugated anti-IgM. Whereas IL-4 + IL-5 costimulated Ig isotype production by alpha delta-dex-activated cells, the further addition of LPS led to a marked ablation of the Ig secretory response indicating the cross-inhibitory effects of these two modes of B cell activation. By contrast, alpha delta-dex augmented IgM and IgG1 secretion by resting B cells stimulated with either an anti-CD3-activated CD4+ Th2 clone or with activated T cell membranes in combination with IL-4 + IL-5. However, alpha delta-dex potently inhibited T cell-mediated IgE secretion. These findings underscore the existence of, and demonstrate a number of novel interrelationships between, three distinct pathways of B cell differentiation induced by different modes of activation. Further, the observation that pg/ml quantities of alpha delta-dex selectively inhibits T cell-induced IgE production in vitro suggests a novel strategy to down-regulate this Ig isotype in vivo.
Peçanha
L M
LM
Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814.
Yamaguchi
H
H
Lees
A
A
Noelle
R J
RJ
Mond
J J
JJ
Snapper
C M
CM
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology*; D003911:Dextrans / Q000494:pharmacology*; D005260:Female; D007072:Immunoglobulin D / Q000276:immunology*; D007073:Immunoglobulin E / Q000096:biosynthesis; D007074:Immunoglobulin G / Q000096:biosynthesis; D007132:Immunoglobulin Isotypes / Q000096:biosynthesis*; D007075:Immunoglobulin M / Q000096:biosynthesis; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D013601:T-Lymphocytes / Q000276:immunology*
D000276:Adjuvants, Immunologic; D000888:Antibodies, Anti-Idiotypic; D003911:Dextrans; D007072:Immunoglobulin D; D007074:Immunoglobulin G; D007132:Immunoglobulin Isotypes; D007075:Immunoglobulin M; D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides; C039951:anti-IgD; D007073:Immunoglobulin E