Interleukin-4 receptor expression by human B cells : functional analysis with a human interleukin-4 toxin, DAB389IL-4

• Published in: Journal of allergy and clinical immunology Vol. 95; no. 4; pp. 893 - 900
• Main Authors: JABARA, H. H, VERCELLI, D, SCHNEIDER, L. C, WILLIAMS, D. P, GENBAUFFE, F. S, POISSON, L. R, WATERS, C. A, GEHA, R. S
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier 01.04.1995
• Subjects: B-Lymphocytes - drug effects; B-Lymphocytes - metabolism; Biological and medical sciences; Diphtheria Toxin - administration & dosage; Diphtheria Toxin - pharmacology; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Humans; Immunobiology; Immunoglobulin Class Switching; Immunoglobulin E - biosynthesis; Interleukin-4 - administration & dosage; Interleukin-4 - metabolism; Interleukin-4 - pharmacology; Lymphoid cells: ontogeny, maturation, markers, receptors, circulation and recirculation; Protein Synthesis Inhibitors - pharmacology; Receptors, Interleukin - metabolism; Receptors, Interleukin-4; Recombinant Fusion Proteins; T-Lymphocytes - physiology; Time Factors; Human; Immunoglobulins; Leukocyte; Antibody; IgE; Cytokine; Molecular hybrid; Biosynthesis; B-Lymphocyte; Diphtheria; Infection; Toxin; Interleukin 4; Membrane receptor; Bacteriosis
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/S0091-6749(95)70134-6

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. In diphtheria toxin IL-4 (DAB389IL-4) the receptor-binding domain of diphtheria toxin has been replaced with human IL-4. DAB389IL-4 cytotoxicity depends on IL-4R binding and internalization. Addition of DAB389IL-4 inhibited IgE synthesis induced by IL-4+ anti-CD40 monoclonal antibody or hydrocortisone. IgE inhibition resulted from DAB389IL-4 B-cell cytotoxicity because DAB389IL-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 DAB389IL-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 DAB389IL-4. Thus the loss of functional IL-4R immunoglobulin-secreting B cells is independent of isotype switching. 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.