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


RESULTS
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.


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.
Jabara
H H
HH
Division of Immunology, Children's Hospital, Boston, MA 02115, USA.
Vercelli
D
D
Schneider
L C
LC
Williams
D P
DP
Genbauffe
F S
FS
Poisson
L R
LR
Waters
C A
CA
Geha
R S
RS
D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D004167:Diphtheria Toxin / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D017578:Immunoglobulin Class Switching; D007073:Immunoglobulin E / Q000096:biosynthesis; D015847:Interleukin-4 / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D018123:Receptors, Interleukin / Q000378:metabolism*; D019948:Receptors, Interleukin-4; D011993:Recombinant Fusion Proteins; D013601:T-Lymphocytes / Q000502:physiology; D013997:Time Factors
C093203:DAB(389)-interleukin 4; D004167:Diphtheria Toxin; D011500:Protein Synthesis Inhibitors; D018123:Receptors, Interleukin; D019948:Receptors, Interleukin-4; D011993:Recombinant Fusion Proteins; D015847:Interleukin-4; D007073:Immunoglobulin E