Abstract
Immunoglobulin class switch recombination (CSR) to IgE is a tightly regulated process central to atopic disease. To profile the B-cell transcriptional responses underlying the activation of the germinal centre activities leading to the generation of IgE, naïve human B-cells were stimulated with IL-4 and anti-CD40. Gene expression and alternative splicing were profiled over 12 days using the Affymetrix Human Exon 1.0 ST Array. A total of 1,399 genes, forming 13 temporal profiles were differentially expressed. CCL22 and CCL17 were dramatically induced but followed a temporal trajectory distinct from classical mediators of isotype switching. AICDA, NFIL3, IRF4, XBP1 and BATF3 shared a profile with several genes involved in innate immunity, but with no recognised role in CSR. A transcription factor BHLHE40 was identified at the core of this profile. B-cell activation was also accompanied by variation in exon retention affecting >200 genes including CCL17. The data indicate a circadian component and central roles for the Th2 chemokines CCL22 and CCL17 in the activation of CSR.
Highlights
Immunoglobulin class switch recombination (CSR) to IgE is a tightly regulated process central to atopic disease
CCL22 and CCL17 are both ligands for the chemokine receptor CCR47 and all three of these targets fall within the top twenty genes differentially expressed during the activation of immunoglobulin class switching in human activated B cells (Table 1, Fig. 1)
Immunoglobulin class switching occurs in mature B cells in response to antigen stimulation and co-stimulatory signals received from T helper cells
Summary
Immunoglobulin class switch recombination (CSR) to IgE is a tightly regulated process central to atopic disease. For a B cell to successfully undergo CSR, a number of cellular processes including, proliferation, control of apoptosis, DNA recombination and cell differentiation must be coordinated These processes usually occur in the germinal centres of secondary lymphoid organs or local tissues following antigen encounter in the presence of T cell help. Naïve B cells were stimulated in vitro with IL-4 and anti-CD40 signals that mimic the T cell help received in the germinal centre, inducing a strong activation of NF-kB leading to a proliferative burst and CSR to IgE and IgG3 This co-stimulation signal was applied here to provide a controlled window on the molecular pathways that regulate these germinal centre processes underlying IgE production in human B cells[4]
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