title: Isotype switching by human B cells is division-associated and regulated by cytokines.
abstract: Isotype switching by murine B cells follows a pattern whereby the proportion of cells undergoing switching increases with division number and is regulated by cytokines. Here we explored whether human B cells behaved in a similar manner. The effect of IL-4, IL-10, and IL-13, alone or in combination, on Ig isotype switching by highly purified naive human CD40 ligand (CD40L)-activated B cells was measured against division number over various harvest times. Switching to IgG was induced by IL-4 and, to a lesser extent, IL-13 and IL-10. The combination of IL-10 with IL-4, but not IL-13, induced a higher percentage of cells to undergo switching. Isotype switching to IgG by human CD40L-activated naive B cells was found to be linked to the division history of the cells: IgG(+) cells appeared in cultures of B cells stimulated with CD40L and IL-4 after approximately the third cell division, with the majority expressing IgG1, thus revealing a predictable pattern of IgG isotype switching. These results reveal a useful quantitative framework for monitoring the effects of cytokines on proliferation and isotype switching that should prove valuable for screening Ig immunodeficiencies and polymorphisms in the population for a better understanding of the regulation of human humoral immune responses.
authors.affiliation: Immune Regulation Group, Centenary Institute for Cancer Medicine and Cell Biology, Locked Bag #6, Newtown, New South Wales 2042, Australia. s.tangye@centrenary.usyd.edu.au
authors.forename: Stuart G
authors.initials: SG
authors.lastname: Tangye
authors.forename: Anthea
authors.initials: A
authors.lastname: Ferguson
authors.forename: Danielle T
authors.initials: DT
authors.lastname: Avery
authors.forename: Cindy S
authors.initials: CS
authors.lastname: Ma
authors.forename: Philip D
authors.initials: PD
authors.lastname: Hodgkin
mesh_terms: D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D023201:CD40 Ligand / Q000494:pharmacology; D002455:Cell Division / Q000276:immunology; D002469:Cell Separation; D002478:Cells, Cultured; D016207:Cytokines / Q000502:physiology*; D015536:Down-Regulation / Q000276:immunology; D005312:Fetal Blood / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D006801:Humans; D017578:Immunoglobulin Class Switching; D007072:Immunoglobulin D / Q000096:biosynthesis; D007074:Immunoglobulin G / Q000096:biosynthesis; D007075:Immunoglobulin M / Q000096:biosynthesis; D007136:Immunoglobulins / Q000096:biosynthesis; D016753:Interleukin-10 / Q000502:physiology; D018793:Interleukin-13 / Q000502:physiology; D015847:Interleukin-4 / Q000502:physiology; D007399:Interphase / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013997:Time Factors
chemical_list: D016207:Cytokines; D007072:Immunoglobulin D; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007136:Immunoglobulins; D018793:Interleukin-13; D016753:Interleukin-10; D023201:CD40 Ligand; D015847:Interleukin-4