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J Immunol. 2006 Oct 15;177(8):5337-46.

ERK signaling is a molecular switch integrating opposing inputs from B cell receptor and T cell cytokines to control TLR4-driven plasma cell differentiation.

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  • 1Australian Cancer Research Foundation Genetics Laboratory and Medical Genome Centre, John Curtin School of Medical Research, Australian Phenomics Facility, Australian National University, Canberra, Australia.

Abstract

Differentiation of B cells into plasma cells represents a critical immunoregulatory checkpoint where neutralizing Abs against infectious agents must be selected whereas self-reactive Abs are suppressed. Bacterial LPS is a uniquely potent bacterial immunogen that can bypass self-tolerance within the T cell repertoire. We show here that during LPS-induced plasma cell differentiation, the ERK intracellular signaling pathway serves as a pivotal switch integrating opposing inputs from Ag via BCR and from the two best characterized B cell differentiation factors made by T cells, IL-2 and IL-5. Continuous Ag receptor signaling through the RAS/MEK/ERK pathway, as occurs in self-reactive B cells, inhibits LPS induction of Blimp-1 and the plasma cell differentiation program. Differentiation resumes after a transient pulse of Ag-ERK signaling, or upon inactivation of ERK by IL-2 and IL-5 through induction of dual-specificity phosphatase 5 (Dusp5). The architecture of this molecular switch provides a framework for understanding the specificity of antibacterial Ab responses and resistance to bacterially induced autoimmune diseases such as Guillain-Barré syndrome.

PMID:
17015719
[PubMed - indexed for MEDLINE]
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