IgE-binding factors (soluble CD23) and IgE regulation.
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Antibodies, Monoclonal↗
Biomedical subjects
G Delespesse
Publications and source records attributed to G Delespesse.
Serum levels of IgE-binding factor (soluble CD23) in diseases associated with elevated IgE.
Several in-vitro experiments suggest that the low affinity receptor for IgE (Fc epsilon RII) and its soluble fragment (IgE-binding factor, IgE-BF) are multi-functional molecules and more particularly that they are capable of regulating the synthesis of human IgE. In an attempt to examine the in-vivo significance of these in-vitro observations, the serum level of IgE-BF was measured in individuals with allergic or parasitic diseases, both associated with an increased production of IgE. IgE-BF was measured by a radioimmunoassay employing two mAbs against Fc epsilon RII (mAbER). We first compared 257 allergic subjects to 172 non-allergic controls matched for age and sex. Statistical analysis of the data, after logarithmic transformation of IgE-BF and IgE values, revealed that despite a great overlap, the allergic subjects had significantly higher levels of IgE-BF. The correlation between IgE and IgE-BF was very weak but significant. Allergic or non-allergic children had significantly higher IgE-BF levels than the corresponding groups of adults; moreover, the inverse correlation between age and IgE-BF levels was significant only in the children and not in the adults. The IgE-BF levels were not influenced by gender, by hyposensitization therapy or by treatment with local steroids. Subjects receiving systemic steroids had lower IgE-BF levels than untreated subjects.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
IgE receptor on human eosinophils (FcERII). Comparison with B cell CD23 and association with an adhesion molecule.
IgE FcR (FcERII) on human eosinophils was characterized and compared with FcERII present on B cells (CD23). Two mAb, BB10 (anti-eosinophil FcERII) and 135 (anti-CD23), bound to the major component of FcERII at 45,000 to 50,000 Mr, both on purified hypodense eosinophils and on a B cell line (WIL-2WT). The specific ligand, human myeloma IgE, was able to bind to the molecules immunoprecipitated by BB10. A cross-reactivity between BB10 and a mAb anti-Leishmania gp63, which is a "fibronectin (Fn)-like" molecule, containing the L-arginine-L-glycyl-L-aspartyl (RGD) cell attachment domain indicated the presence of such a sequence in the common structure present on eosinophil and B cell FcERII. The synthetic tetrapeptide RGDS as well as its inverted sequence (SDGR) reduced the binding of BB10 and anti-Fn mAb to eosinophils and B cells. Flow microfluorometry analysis revealed a variable binding of BB10 and anti-Fn mAb to eosinophils purified from different patients, results compatible with recent findings on the inducibility of FcERIIb. The significant inhibition of IgE-dependent cytotoxicity against parasite targets by preincubation of eosinophils with BB10, anti-Fn and anti-CD23 mAb, with anti-RGDS polyclonal antibodies or with the SDGR peptide suggested the requirement of this cell adhesion sequence for the function of low affinity FcERII. The presence of such a sequence in the C-terminal domain of B cell FcERII raised the possibility of its role in B cell adhesion or B cell growth.
Amino Acid Sequence↗
Effect of interferon-alpha on the expression and release of the CD23 molecule in hairy cell leukemia.
Hairy cells are stimulated to DNA synthesis by low molecular weight B cell growth factor (LMW-BCGF) and this proliferative response is suppressed by interferon (IFN)-alpha, both in vitro and in vivo. The suggestion that the CD23 molecule (Fc epsilon II receptor) might be involved in the signalling pathway of LMW-BCGF prompted us to study the expression of this molecule on hairy cells and its modulation by IFN-alpha. By flow cytometry and direct binding experiments with anti CD23 monoclonal antibodies, the presence of the CD23 antigen was detected in 7 of 12 cases tested, on variable percentages of cells, ranging from low to medium expression. In vitro incubation of hairy cells with IFN-alpha, which elicits a suppression of the proliferative response of these cells to LMW-BCGF, induced a parallel significant reduction of CD23 expression in only three cases. Similarly, a transient in vivo decrease of CD23 expression, concommitant with an inhibition of the LMW-BCGF response, could be detected in only one of three patients injected with IFN-alpha. Soluble sCD23/IgE-binding factor (BF) was quantitated in the serum from six other patients with hyperleukocytic hairy cell leukemia (HCL) undergoing a clinical trial of IFN-alpha therapy. Before treatment, these patients presented higher concentrations of the cleaved soluble form of the CD23 molecule than normal controls. Within a few weeks of IFN-alpha administration, these levels markedly decreased, paralleling a diminution of blood leukemic cells. Of interest, no such diminution was noticed for another patient resistant to IFN-alpha therapy. These results show that the proliferative response of hairy cells to LMW-BCGF is not linked to the expression of the CD23 marker. Besides, when the latter molecule was present, its decrease following IFN-alpha treatment, which could be detected in some cases, was not necessarily required for the suppression of the LMW-BCGF response and is thus not mandatory for the therapeutic efficacy of IFN-alpha. Our results point out that quantitation of serum sCD23/IgE-BF, whether related to a process of autocrine proliferation or not, is a parameter of potential importance for therapy monitoring.
Antigens, Differentiation, B-Lymphocyte↗
Recombinant interleukin 4 suppresses the production of interferon gamma by human mononuclear cells.
rIL-4 inhibits the production of IFN-gamma by PBMC stimulated with mitogens or allogeneic cells. The suppression is observed at the protein and at the mRNA level; it is dose and time dependent, and it is abolished by a neutralizing mAb to IL-4. It is suggested that the balance between the production of IL-4 and IFN-gamma may be significantly influenced by the chronological order of activation of their respective gene.
Blotting, Northern↗
IgE synthesis by chronic lymphocytic leukemia 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.
Antigens, Differentiation↗
Influence of recombinant IL-4, IFN-alpha, and IFN-gamma on the production of human IgE-binding factor (soluble CD23).
This study documents the influence of rIL-4, IFN-gamma, and IFN-alpha on the production of IgE-BF and the expression of lymphocyte receptor for IgE or CD23 Ag (Fc epsilon R II) by human mononuclear cells. IL-4 increases the secretion of IgE-binding factor (BF) by highly purified B lymphocytes, adherent cells, and U937 monoblastic cells. The effect of IL-4 on purified B cells is augmented by costimulating the cells with F(ab')2 anti-IgM. IFN-gamma, IL-2, IL-1-alpha, or IL-1 beta and the low m.w. B cell growth factor have no effect on IgE-BF production by purified B cells even when they are used in combination with anti-IgM. Stimulation of purified T cells with IL-4 or IL-4 plus PMA leads to the production of very small amounts of IgE-BF that might well be derived from the contaminating non-T cells. IFN-gamma increases IgE-BF synthesis by unfractionated PBMC, T cell-depleted PBMC, adherent cells, and U937 cells suggesting that it induces monocytes to release IgE-BF, IFN-gamma suppresses the IL-4-induced Fc epsilon R II expression and IgE-BF production by highly purified B cells but not by PBMC or their T cell-depleted fractions. IFN-alpha inhibits IgE-BF production by IFN-gamma-stimulated PBMC and by IL-4-stimulated cells suggesting that it exerts its effect on B cells and on monocytes. Moreover IFN-alpha suppresses the IL-4-induced expression of Fc epsilon R II on B cells. Both IFN-alpha and IFN-gamma suppress the synthesis of IgE by PBMC in response to IL-4. Taken collectively the results indicate that: 1) IL-4 induces IgE-BF production by both B cells and monocytes, 2) IFN-gamma stimulates IgE-BF synthesis by monocytes but suppresses its production by IL-4-stimulated B cells, and finally 3) IFN-alpha inhibits IgE-BF synthesis in response to either IFN-gamma or IL-4.
Antigens, Differentiation, B-Lymphocyte↗
Mechanisms of formation of IgE-binding factors (soluble CD23)--I. Fc epsilon R II bearing B cells generate IgE-binding factors of different molecular weights.
IgE-binding factors (soluble CD23) are generally considered to have an Mr of 25,000-27,000. The present study first indicates that IgE-BFs with an Mr of 33,000 or 37,000 may also be produced by Fc epsilon R II bearing B cells, depending upon the culture conditions and the nature of the Fc epsilon R II bearing cells. Extending our previous observations that the Mr 25,000-27,000 IgE-BFs are derived from the cleavage of soluble Mr 37,000 precursors, we show here that this cleavage is specifically inhibited by iodoacetamide but not by several other protease inhibitors. The proteolytic enzyme involved in the cleavage of Mr 33,000-37,000 precursors into Mr 25,000-27,000 IgE-BFs is cell-associated and is specifically expressed on Fc epsilon R II bearing cells. As expected, these Mr 33,000 and 37,000 fragments of Fc epsilon R II are capable of binding to IgE. The site at which these molecules are cleaved from Fc epsilon R II was located by determining their amino-terminal sequence. The Mr 37,000 IgE-BFs start at position 81 (glutamine) and the Mr 33,000 IgE-BFs start at position 102 (leucine) of the Fc epsilon R II sequence. Taken collectively, the present study not only contributes to our understanding of the mechanisms of formation of IgE-BFs, but also provides a means to prepare different molecular forms of IgE-BFs which may display different biological activity.
Amino Acid Sequence↗
Human IgE-binding factors.
The production of IgE antibodies is known to be regulated by isotype-specific mechanisms that are not antigen specific. During the last decade several studies have indicated that soluble factors with affinity for IgE (IgE-binding factors, IgE-BFs) may exert such a role by interacting with IgE-bearing B lymphocytes. In the human, some of these IgE-BFs appear to be identical to soluble CD23, a B-cell surface marker thought to be involved in the control of B-cell proliferation or differentiation. In this article, Guy Delespesse and colleagues summarize several new findings regarding the cellular origin, structure and function of IgE-BFs/sCD23.
Antigens, Differentiation, B-Lymphocyte↗
Human Fc epsilon R II and IgE-binding factors.
The low-affinity receptor for IgE (Fc epsilon R II) is mainly expressed on B lymphocytes, although it may also be found on some monocytes, eosinophils, and platelets. The presence of Fc epsilon R II on T cells is still controversial, but our results demonstrate that it is expressed on some HTLV-I-transformed T lymphocytes, and they strongly suggest that it may be found on a small proportion of normal T cells. Fc epsilon R II is a 45-KD glycoprotein containing one N-linked carbohydrate of complex type, O-linked carbohydrates, and sialic acid residues. Fc II is cleaved into soluble fragments with molecular weights of 37, 33, 25, and 12 KD, the first three retain the ability of binding to IgE, i.e., they are IgE-binding factors (IgE-BFs). The enzymes involved in their proteolytic cleavage are cell bound. The cDNA coding for Fc epsilon R II was cloned and functionally expressed. The predicted sequence has no homology with that of murine IgE-BFs which are of T cell origin. However, there is a striking homology with several animal lectins, and since the IgE-binding site is located in the homology region, it is possible that it binds to IgE via the carbohydrates expressed on the Fc region of this immunoglobulin. The expression of Fc epsilon R II on B cells and the release of IgE-BFs are upregulated by interleukin 4 and suppressed by gamma and alpha interferons.(ABSTRACT TRUNCATED AT 250 WORDS)
Antigens, Differentiation, B-Lymphocyte↗
Low-affinity receptor for IgE (FcERII, CD23) and its soluble fragments.
The low-affinity receptor for IgE (FcERII or CD23) is a membrane 45-kD glycoprotein which is cleaved by an autoproteolytic mechanism into soluble 37-, 33- and 25-kD fragments that are capable of binding to IgE (IgE-binding factors, IgE-BFs). FcERIIa (which is expressed only on fresh B cells) differs from FcERIIb (which is expressed on IL4-stimulated B cells, monocytes, eosinophils and T cells) by a few intracytoplasmic amino acids. The only function of FcERII which is clearly demonstrated is the IgE-dependent cytotoxicity of FcERIIb on monocytes and eosinophils. We here review our recent observations indicating that 37-kD IgE-BFs regulate the synthesis of human IgE. Recombinant 37-kD IgE-BFs increase the IL4-induced synthesis of IgE by peripheral blood lymphocytes, as well as the IL4-independent, ongoing synthesis of IgE by either in vivo activated B cells from allergic patients or by in vitro IL4-preactivated B cells.
Antigens, CD↗
Human Fc epsilon RII. Molecular, biological and clinical aspects.
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Amino Acid Sequence↗
Possible role of human lymphocyte receptor for IgE (CD23) or its soluble fragments in the in vitro synthesis of human IgE.
The present study demonstrates that human rIL-4 is capable of inducing the secretion of IgE by PBMC. At a concentration of 200 U/ml, an IgE response was observed in 11/26 cultures of PBMC from normal donors and in 12/15 cultures from allergic individuals. The same rIL-4-stimulated cells released significant amounts of IgE-binding factors (IgE-BF) in their culture supernatant. These IgE-BF were shown for the first time to bind simultaneously to some mAb against Fc epsilon R II (mAbER) and to soluble IgE. The lack of correlation between the rIL-4-induced secretion of IgE-BF and IgE indicates that the production of IgE-BF or the expression of Fc epsilon R II is not the only factor involved in the induction of IgE synthesis by rIL-4. However, the observation that mAbER suppressed the rIL-4-induced IgE synthesis strongly suggests that either Fc epsilon R II or IgE-BF are necessary for an IgE response. Finally, the spontaneous in vitro synthesis of IgE by enriched B cell preparations isolated from atopic donors was suppressed in an isotype-specific manner by the same mAbER or by their F(ab')2 fragments. These observations suggest that the ongoing IgE synthesis by in vivo pre-activated B cells is also regulated by IgE-BF or Fc epsilon R II. It is concluded that Fc epsilon R II or IgE-BF play an essential role both in the induction of IgE synthesis by normal B cells and in the ongoing IgE synthesis by in vivo activated B cells from allergic donors.
Antibodies, Monoclonal↗
IgE receptor on human lymphocytes. IV. Further analysis of its structure and of the role of N-linked carbohydrates.
Previous studies have shown that the low affinity receptor for IgE (Fc epsilon R II) on human B lymphocytes was comprised of three components with apparent Mr of 45, 65 to 95, and 37 kDa. The present results indicate that the 37-kDa component is a soluble degradation fragment of the 45-kDa component and they also suggest that the 65- to 95-kDa component is probably made of aggregates of the above components that are formed after solubilization of the cells. The 45-kDa component appears to be a glycoprotein containing several sialic acid residues, O-linked carbohydrates and one N-linked carbohydrate chain that is of the complex type. Partial digestion of the purified 65- to 95-, 45-, and 37-kDa molecules with alpha-chymotrypsin or protease V8 generates several fragments with identical mobility on SDS-PAGE. The 37 kDa is not N-glycosylated but like the IgE-binding factors present in the culture supernatant of Fc epsilon R-bearing cells, it contains sialic acid and O-linked carbohydrates. On incubation with protease inhibitors, the Mr of IgE-binding factors (BF) is shifted from 25-27 to 37 kDa, indicating that IgE-BF are derived from the proteolytic cleavage of the 37-kDa molecule, previously identified as a membrane component of Fc epsilon R. On incubation with N-glycosylation inhibitors, the production of IgE-BF is significantly increased indicating that N-glycosylation inhibits the degradation of Fc epsilon R into IgE-BF. Inasmuch as the effect of glycosylation inhibitors is not prevented by monensin, it is concluded that all the IgE-BF are derived from surface Fc epsilon R and not from their intracellular precursors.
Antigens, Differentiation, B-Lymphocyte↗
Comparison of mononuclear cell and B-lymphoblastoid histamine-releasing factor and their distinction from an IgE-binding factor.
We have characterized the histamine-releasing factors (HRF) from a B-lymphoblastoid cell line (RPMI 8866), compared it to mononuclear cell-derived HRF, and distinguished these from the IgE-binding factor produced by RPMI 8866. The B-cell-derived HRF fractionates at molecular weights of 90,000, 70,000, and 12-15,000 while mononuclear cell HRF has a major component at 24-26,000. The isoelectric points for B-cell HRF are 6.2-6.3 and 6.6-6.8 in contrast to 6.9 and 7.3 for mononuclear cell-derived HRF. The kinetics of histamine release by either HRF was the same, with half-maximal release in 5-10 min, unlike the rapid release caused by anti-IgE. Since HRF has been reported to be an IgE-binding factor, we screened column fractions for the IgE-binding factor secreted by RPMI 8866; this is known to be a shed low affinity IgE receptor. The chromatographic pattern and isoelectric point of this IgE-binding factor does not correspond to HRF; the purified IgE-binding factor had no significant histamine releasing activity on human basophils, and neither source of HRF was reactive in a radioimmunoassay to the IgE-binding factor. Our data suggest that HRF is quite heterogeneous and varies in physiochemical properties depending upon the cell source. The molecular relatedness (or nonrelatedness) of those HRFs is unclear; however, our data indicate that although HRF or fractions therefrom may bind to IgE as has been reported, it is unrelated to the low affinity IgE receptor.
B-Lymphocytes↗
Structure, function and clinical relevance of the low affinity receptor for IgE.
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Animals↗
Elevation of IgE-binding factors in serum of patients with B cell-derived chronic lymphocytic leukemia.
One hundred nineteen sera from patients with various lymphoproliferative diseases and normal sera were tested by a solid-phase radioimmunoassay (RIA) for their content in IgE-binding factor (IgE-BF), a soluble glycoprotein binding to IgE and derived from low-affinity IgE receptors (Fc epsilon R). Fc epsilon R, recently identified as CD23, are known to be expressed on the surface of B cells at the intermediate stage of differentiation. The results indicate that in all cases of chronic lymphocytic leukemia (CLL) tested (n = 40), IgE-BF levels (45 to 8,656 U/mL) were 3-fold to 500-fold higher than in 24 controls (15.5 +/- 2 U/mL). With a few exceptions, serum IgE-BF levels could differentiate patients with CLL from those with other leukemias or lymphomas. In vitro studies indicated that B lymphocytes isolated from CLL patients produced 8 to 50 times more IgE-BF than did normal B cells (P less than 0.001). IgE-BF level was correlated with the Rai stage of the disease (P = 0.002) and the lymphocyte count (P = 0.041). IgE-BF was purified to homogeneity from one CLL serum sample by a combination of affinity chromatography and reverse-phase high-performance liquid chromatography (HPLC). this IgE-BF proved identical to IgE-BF isolated from the culture supernatant of RPMI 8866 cells, a B lymphoblastoid cell line bearing Fc epsilon R and secreting IgE-BF. Indeed, the two molecules had the same mol wt (25 to 27 kd), the same isoelectric point, and the same tryptic map. We suggest that determination of serum IgE-BF might prove useful for clinical monitoring of CLL.
B-Lymphocytes↗
T-cell-derived IgE-binding factors. I. Cloned and transformed T cells producing IgE-binding factors.
In order to derive T cell clones that can produce factors that specifically regulate the IgE response, Fc epsilon receptor (Fc epsilon R)-positive T cells were isolated from two patients with hyper-IgE states (either the tropical pulmonary eosinophilia syndrome or the hyper-IgE syndrome) and transformed using the human T cell leukemia/lymphoma virus. After infection, these T4-positive, Fc epsilon R-positive T cells manifested a fourfold increase in the surface interleukin 2 receptor, a 10-fold increase in Fc epsilon R, and acquired viral markers not present in the uninfected cells. Cloning soon after transformation allowed for the isolation of 17 distinct T cell clones producing IgE-binding factors. The levels of these binding factors released in supernatant fluid from these clones ranged from 10 to 98 U (negative less than 1 U) using a radioimmunoassay. Furthermore, the presence and kinetics of production of these binding factors also could be demonstrated by metabolic labeling studies. These cells should prove potent immunologic tools for dissecting the various regulatory mechanisms involved in IgE production both in the normal state and in pathologic conditions.
Antigens, Viral↗