Interleukin 13 induces interleukin 4-independent IgG4 and IgE synthesis and CD23 expression by human B cells.

The present results indicate that B cells isolated from chronic lymphocytic leukemia (B-CLL) from 11 of 14 patients are capable of specifically producing IgE upon costimulation with IL-4 and hydrocortisone (HC). IgE is detected by intracytoplasmic fluorescence staining and by RIA. Clinical, hematological, and immunological parameters (including Rai stage, WBC, Lc, sIg kappa/lambda, CD5, and CD23 expression) cannot distinguish the IgE responder from the nonresponder patients. IL-4 alone is a potent inducer of human IgE synthesis by normal PBMC and we show here that its effect is strikingly enhanced by HC. The IgE produced by B-CLLs are monoclonal since they display the same L chain type as the freshly isolated CD5+ B-CLLs. We, therefore, conclude that the combination of IL-4 and HC can abrogate the maturation arrest of CD5+ B-CLLs by inducing their differentiation into IgE-producing cells. The present data provide a unique model to study the isotype switching to IgE and the regulation of human IgE synthesis by monoclonal human B cells.

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Disodium cromoglycate inhibits S mu-->S epsilon deletional switch recombination and IgE synthesis in human B cells.

Journal of Experimental Medicine ◽

10.1084/jem.180.2.663 ◽

1994 ◽

Vol 180 (2) ◽

pp. 663-671 ◽

Cited By ~ 47

Author(s):

R K Loh ◽

H H Jabara ◽

R S Geha

Keyword(s):

T Cells ◽

B Cells ◽

B Cell ◽

Allergic Disease ◽

Interleukin 4 ◽

Pokeweed Mitogen ◽

Disodium Cromoglycate ◽

Isotype Switching ◽

Human B Cells ◽

Ige Synthesis

IgE synthesis requires interleukin 4 (IL-4) and a T-B cell interaction that involves the B cell antigen CD40 and its ligand expressed on activated T cells. IL-4 induces epsilon germline transcription whereas ligation of CD40 results in deletional S mu-->S epsilon switch recombination, expression of mature epsilon transcripts, and IgE synthesis and secretion. We demonstrate that disodium cromoglycate (DSCG), a drug commonly used for the prophylactic treatment of allergic disease, inhibits T cell-driven IgE synthesis by human B cells at concentrations readily achievable in the course of inhaled therapy for asthma. Inhibition of IgE synthesis by DSCG was not the result of drug toxicity because DSCG did not affect the viability of T and B cells or their proliferation to mitogens. DSCG did not interfere with CD40 ligand expression by T cells but clearly targeted the B cells because it inhibited IgE synthesis induced by anti-CD40 and IL-4 in populations of highly purified B cells. DSCG had no effect on the induction of epsilon germline transcripts by IL-4 but strongly inhibited CD40 mediated S mu-->S epsilon deletional switch recombination in IL-4-treated B cells as assayed by nested primer PCR. The effect of DSCG was not specific for CD40-mediated induction of IgE isotype switching because DSCG inhibited IgE synthesis as well as S mu-->S epsilon deletional switch recombination induced by hydrocortisone and IL-4 in B cells. Moreover, the effect of DSCG was not specific for IgE isotype switching because DSCG inhibited the synthesis of IgG4 by B cells sorted for lack of surface expression of IgG4 and stimulated with anti-CD40 and IL-4. DSCG caused only minimal inhibition (< 15%) of spontaneous IgE synthesis by lymphocytes from patients with the hyper-IgE syndrome and did not affect pokeweed mitogen-induced IgG and IgA synthesis by lymphocytes suggesting that it has little effect on B cells that have already undergone isotype switching. These results indicate that DSCG inhibits switching to IgE in B cells and suggest a novel potential mechanism for the prevention of allergic disease by DSCG.

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Signal Transduction Pathway of Interleukin-4 and Interleukin-13 in Human B Cells Derived from X-linked Severe Combined Immunodeficiency Patients

Journal of Biological Chemistry ◽

10.1074/jbc.271.2.619 ◽

1996 ◽

Vol 271 (2) ◽

pp. 619-622 ◽

Cited By ~ 68

Author(s):

Kenji Izuhara ◽

Toshio Heike ◽

Takeshi Otsuka ◽

Kunihiro Yamaoka ◽

Mitsuhumi Mayumi ◽

...

Keyword(s):

Signal Transduction ◽

B Cells ◽

Severe Combined Immunodeficiency ◽

Signal Transduction Pathway ◽

Interleukin 4 ◽

Transduction Pathway ◽

Combined Immunodeficiency ◽

Interleukin 13 ◽

Human B Cells

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Role of interleukin-4 and interleukin-13 in synthesis of IgE and expression of CD23 by human B cells

Allergy ◽

10.1111/j.1398-9995.1994.tb00122.x ◽

1994 ◽

Vol 49 (8) ◽

pp. 576-586 ◽

Cited By ~ 60

Author(s):

J. Punnonen ◽

G. Aversa ◽

B. G. Cocks ◽

J. E. Vries

Keyword(s):

B Cells ◽

Interleukin 4 ◽

Interleukin 13 ◽

Human B Cells

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CD40 and IgE: synergism between anti-CD40 monoclonal antibody and interleukin 4 in the induction of IgE synthesis by highly purified human B cells.

Journal of Experimental Medicine ◽

10.1084/jem.172.6.1861 ◽

1990 ◽

Vol 172 (6) ◽

pp. 1861-1864 ◽

Cited By ~ 310

Author(s):

H H Jabara ◽

S M Fu ◽

R S Geha ◽

D Vercelli

Keyword(s):

Monoclonal Antibody ◽

B Cells ◽

B Cell ◽

Interleukin 4 ◽

B Cell Differentiation ◽

Human B Cells ◽

Molecular Events ◽

Ige Synthesis ◽

Ige Response

A novel pathway of IgE-B cell differentiation has been identified. Engagement of the B cell antigen CD40 by F(ab')2 fragments of monoclonal antibody (mAb) 626.1 in the presence of recombinant interleukin 4 (rIL-4) induced intense IgE synthesis, but modest IgG synthesis, by highly purified human B cells. Surface IgE- B cells isolated by cell sorting were induced to produce IgE by mAb 626.1 and IL-4. Thus, IgE synthesis is unlikely to result from expansion of a B cell population precommitted to IgE in vivo. A neutralizing anti-IL-6 antibody strongly, but not completely, inhibited the IgE response. This indicates that autocrine production of IL-6 plays an important amplification role in IgE synthesis triggered by anti-CD40 mAb and IL-4. Although the exact role played by CD40 in IgE responses in vivo remains to be established, this T cell-independent system represents a useful model to characterize the biochemical and molecular events leading to IgE synthesis in human B cells.

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Membranes of activated CD4+ T cells expressing T cell receptor (TcR) αβ or TcR γδ induce IgE synthesis by human B cells in the presence of interleukin-4

European Journal of Immunology ◽

10.1002/eji.1830220505 ◽

1992 ◽

Vol 22 (5) ◽

pp. 1133-1141 ◽

Cited By ~ 29

Author(s):

Hugues Gascan ◽

Gregorio G. Aversa ◽

Jean-Françlois Gauchat ◽

Peter Van Vlasselaer ◽

Maria-Grazia Roncarolo ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

T Cell Receptor ◽

Cd4 T Cells ◽

Cell Receptor ◽

Interleukin 4 ◽

Human B Cells ◽

Ige Synthesis

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Molecular analysis of the induction of immunoglobulin E synthesis in human B cells by interleukin 4 and engagement of CD40 antigen.

Journal of Experimental Medicine ◽

10.1084/jem.175.1.289 ◽

1992 ◽

Vol 175 (1) ◽

pp. 289-292 ◽

Cited By ~ 103

Author(s):

S K Shapira ◽

D Vercelli ◽

H H Jabara ◽

S M Fu ◽

R S Geha

Keyword(s):

B Cells ◽

Hot Spots ◽

Epstein Barr Virus ◽

Immunoglobulin E ◽

Interleukin 4 ◽

Barr Virus ◽

Human B Cells ◽

Molecular Events ◽

Ige Synthesis ◽

Epstein Barr

The molecular events leading to immunoglobulin E (IgE) synthesis in human sIgE- B cells stimulated with interleukin 4 (IL-4) and anti-CD40 monoclonal antibody (mAb) 626.1 were analyzed. Anti-CD40 mAb increased the levels of IL-4-induced germline C epsilon transcripts and induced the production of mature C epsilon mRNA. These effects were dependent on the presence of IL-4. Nested primer PCR revealed deletional switch recombination occurring only in B cell stimulated with both IL-4 and anti-CD40 mAb. DNA sequence analysis of switch fragments showed direct S mu/S epsilon joining, without the deletions or duplications within S mu often found in B cells stimulated with IL-4 and Epstein-Barr virus. Analysis of the switch junction map sites showed "hot spots" for recombination within S mu, but not within S epsilon. These findings indicate that IL-4 provides a signal to B cells to induce germline C epsilon transcription and concurrent CD40 engagement induces S mu/S epsilon deletional switch recombination, production of mature C epsilon mRNA, and IgE synthesis.

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