CD40 stimulation provides an IFN-gamma-independent and IL-4-dependent differentiation signal directly to human B cells for IgE production.
IgE induction from human cells has generally been considered to be T cell dependent and to require at least two signals: IL-4 stimulation and T cell/B cell interaction. In the present study we report a human system of T cell-independent IgE production from highly purified B cells. When human cells were co-stimulated with a mAb directed against CD40 (mAb G28-5), there was induction of IgE secretion from purified blood and tonsil B cells as well as unfractionated lymphocytes. Anti-CD40 alone failed to induce IgE from blood mononuclear cells or purified B cells. The effect of the combination of anti-CD40 and IL-4 on IgE production was very IgE isotype specific as IgG, IgM, and IgA were not increased. Furthermore, anti-CD40 with IL-5 or PWM did not co-stimulate IgG, IgM, or IgA and in fact strongly inhibited PWM-stimulated IgG, IgM and IgA production from blood or tonsil cells. IgE synthesis induced by anti-CD40 plus IL-4 was IFN-gamma independent as is the in vivo production of IgE in humans; the doses of IFN-gamma that profoundly suppressed IgG synthesis induced by IL-4, or IL-4 plus IL-6, had no inhibitory effect on anti-CD40-induced IgE production. Anti-CD23 and anti-IL-6 also could not block anti-CD40 plus IL-4-induced IgE production, but anti-IL-4 totally blocked their effect. IgE production via CD40 was not due to IL-5, IL-6 or nerve growth factor as none of these synergized with IL-4 to induce IgE synthesis by purified B cells. Finally, we observed that CD40 stimulation alone could enhance IgE production from in vivo-driven IgE-producing cells from patients with very high IgE levels; cells that did not increase IgE production in response to IL-4. Taken together, our data suggest that the signals delivered for IgE production by IL-4 and CD40 stimulation may mimic the pathway for IgE production seen in vivo in human allergic disease.
Zhang
K
K
Department of Medicine, UCLA School of Medicine 90024-1680.
Clark
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EA
Saxon
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D015703:Antigens, CD / Q000502:physiology*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000502:physiology*; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D019013:CD40 Antigens; D002454:Cell Differentiation / Q000276:immunology; D004854:Herpesvirus 4, Human; D006801:Humans; D007073:Immunoglobulin E / Q000096:biosynthesis*; D007132:Immunoglobulin Isotypes / Q000096:biosynthesis; D007371:Interferon-gamma / Q000502:physiology; D015847:Interleukin-4 / Q000502:physiology*; D015848:Interleukin-5 / Q000502:physiology; D015850:Interleukin-6 / Q000502:physiology; D009414:Nerve Growth Factors / Q000502:physiology; D011961:Receptors, Fc / Q000502:physiology; D017455:Receptors, IgE; D013601:T-Lymphocytes / Q000276:immunology
D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; D019013:CD40 Antigens; D007132:Immunoglobulin Isotypes; D015848:Interleukin-5; D015850:Interleukin-6; D009414:Nerve Growth Factors; D011961:Receptors, Fc; D017455:Receptors, IgE; D015847:Interleukin-4; D007073:Immunoglobulin E; D007371:Interferon-gamma