Interleukin-4 receptor expression by human B cells: Functional analysis with a human interleukin-4 toxin, DAB 389IL-4

Abstract

Background: Studies of human IgE-secreting B cells have proven difficult because of the small size of this population. We have used an interleukin-4 (IL-4) fusion toxin to detect functionally IL-4 receptor (IL-4R) expression on B cells involved in IgE synthesis. Methods: In diphtheria toxin IL-4 (DAB 389IL-4) the receptor-binding domain of diphtheria toxin has been replaced with human IL-4. DAB 389IL-4 cytotoxicity depends on IL-4R binding and internalization. Results: Addition of DAB 389IL-4 inhibited IgE synthesis induced by IL-4 + anti-CD40 monoclonal antibody or hydrocortisone. IgE inhibition resulted from DAB 389IL-4 B-cell cytotoxicity because DAB 389IL-4 inhibited IL-4–independent B-cell proliferation. Thus induction of human IgE synthesis involves IL-4R + cells. In contrast, terminally differentiated, IgE-producing B cells no longer express functional IL-4R because DAB 389IL-4 only modestly inhibited ongoing IgE synthesis by B cells from patients with hyper-IgE states and only minimally affected IL-4–induced IgE synthesis in normal B cells when the toxin was added at day 7. Pokeweed mitogen–induced IgM synthesis was sensitive to early but not to late addition of DAB 389IL-4. Thus the loss of functional IL-4R immunoglobulin-secreting B cells is independent of isotype switching. Conclusions: IgE-secreting B cells no longer express functional IL-4R. Therapies for allergic disease that target the IL-4R would not affect IgE-secreting B cells but may block the recruitment of B cells into the IgE-secreting pool. For optimal benefits this approach may be combined with therapies that target IL-4R -, IgE-secreting B cells. (J A LLERGY C LIN I MMUNOL 1995;95:893-900.)