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Title: Cytokine control of human immunoglobulin class and IgG subclass production
Author: Kotowicz, Karolena
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 1994
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Cytokines are important regulators of Ig class production. In mice, IL4, IFNγ and TGFβ control IgE and IgG1, IgG2a and IgG3, and IgA and IgG2b respectively. In humans, IL4 regulates IgE and IgG4, and TGFβ regulates IgA production, but cytokines which regulate the other human IgG subclasses are unknown. A system was developed for the polyclonal activation of human B cells using Epstein Barr Virus (EBV). The kinetics of this system were optimised for the addition of cytokines. ELISA assays were developed for the measurement of human IgA, IgM, IgE, IgG, IgG1, IgG2, IgG3 and IgG4 in cell culture supernatants. The effects of selected cytokines and antibodies to functional B cell surface antigens were studied. IL2 and IL6 were BCDFs increasing all Ig classes and IgG subclasses with the exception of IgE. Low concentrations of TGFβ increased IgA but high concentrations inhibited B cell proliferation and Ig class production. IL5, IFN? and IFN? were found to have no effect. IL4 showed dual BCDF activity. Low doses of IL4 (1-5 U/ml) induced IgM, IgA, IgG1, IgG2 and IgG3 production by up to ten fold above control levels while high doses of IL4 (100 U/ml or greater) specifically increased IgE and IgG4. Low doses of IL4 also induced IgG and IgA production by mIgM- and mIgM+ B cells. These results were consistent with heavy chain class switching and BCDF activity by IL4. Anti-CD40 mAbs increased B cell proliferation and Ig production. Addition of low dose IL4 (5 U/ml) suppressed anti-CD40 induced proliferation and enhanced Ig production whereas high dose IL4 (100 U/ml) inhibited anti-CD40 induced Ig production and enhanced proliferation. Anti-CD23 antibodies inhibited EBV and IL4 induced IgA, IgM and IgG secretion as well as IL4 induced IgE secretion. These results show that IL4 has a dual role in the regulation of human Ig production. These functions may be mediated through two IL4Rs and signalling through these receptors can differentially control the effects of CD40 ligation. In addition, ligation of CD23 can inhibit the effects transduced through both receptors and prevent IL4 dependent IgE and low dose IL4 dependent IgM, IgA and IgG production.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available