pERKing up the BLIMP in plasma cell differentiation.
ABSTRACT The intracellular pathways that induce the differentiation of naïve B cells into antibody-secreting plasma cells remain poorly defined. A new study now provides surprising evidence that the activation of extracellular signal-regulated kinase (ERK) is pivotal for inducing the transcriptional repressor B lymphocyte-induced maturation protein 1 (Blimp-1), which is required for plasma cell differentiation. Consequently, ERK-deficient B cells were unable to generate plasma cells effectively. This is an unexpected result, because previous work has shown that ERK signaling functions chiefly to induce cell division, whereas plasma cells are considered to be nondividing, terminally differentiated cells. This finding not only reveals an important signaling pathway that underlies antibody-mediated immunity but also raises important questions about the varying roles that ERK, and perhaps other kinases, may play in different biological contexts.
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ABSTRACT: Mature B cell differentiation involves a well-established transcription factor cascade. However, the temporal dynamics of cell signaling pathways regulating transcription factor network and coordinating cell proliferation and differentiation remain poorly defined. To gain insight into the molecular processes and extrinsic cues required for B cell differentiation, we set up a controlled primary culture system to differentiate human naive B cells into plasma cells (PCs). We identified T cell-produced IL-2 to be critically involved in ERK1/2-triggered PC differentiation. IL-2 drove activated B cell differentiation toward PC independently of its proliferation and survival functions. Indeed, IL-2 potentiated ERK activation and subsequent BACH2 and IRF8 downregulation, sustaining BLIMP1 expression, the master regulator for PC differentiation. Inhibition of the MAPK-ERK pathway, unlike STAT5 signaling, impaired IL-2-induced PC differentiation and rescued the expression profile of BACH2 and IRF8. These results identify IL-2 as a crucial early input in mature B cell fate commitment.The Journal of Immunology 05/2012; 189(1):161-73. · 5.36 Impact Factor
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ABSTRACT: Fever is a common symptom of illness in children, and although not harmful in itself, fever and its associated symptoms are often treated with antipyretic drugs. A number of national and other guidelines now recommend against their routine use; a conclusion that was initially supported by a study showing that the prophylactic use of paracetamol might reduce antibody response to some vaccine antigens, although data from booster vaccinations are more equivocal. Although in vivo data on the cause of this inhibition are scarce, in vitro data suggests that the cause may be due to inhibition of the mitogen activated protein kinase/extracellular regulated protein kinase pathways, and a subsequent reduction in the process of plasma cell differentiation at the beginning of the antibody response. This suggests that in high-risk patients these drugs could be avoided in the early part of an infection when plasma-cell differentiation is occurring. More data are needed to define this period; until then existing data support the recommendation against the routine use of these drugs.Medical Hypotheses 06/2014; · 1.15 Impact Factor