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• W2025496979 abstract "Common variable immunodeficiency (CVID) is a heterogeneous disorder characterized by B-cell dysfunction and, in a subgroup, by expansion of CD21(low) B cells. The CD21(low) B cells display defects in early B-cell receptor (BCR) signaling resembling those of anergic B cells.We sought to investigate whether B cells from patients with CVID, like anergic B cells, have defects in extracellular signal-regulated kinase (ERK) phosphorylation and in endocytic trafficking of the BCR.Using flow cytometry, we evaluated phosphorylated ERK (pERK) expression and internalization of cross-linked BCR in B-cell subsets. The localization of internalized BCR to lysosome-associated membrane protein 1-positive late endosomes was evaluated with confocal microscopy.Constitutive pERK levels were increased in naive and IgM(+) memory B cells of patients with CVID compared with those of healthy donors, whereas the pERK increment induced by BCR cross-linking was relatively reduced. Intravenous immunoglobulin administration enhanced these anomalies, but they appeared to be intrinsic to B cells from patients with CVID. Cross-linking-induced BCR endocytosis was decreased in the IgM(+) memory B cells, especially in those with a CD21(low) phenotype, but not in the naive B cells of patients with CVID with CD21(low) expansion. Internalized BCR localized normally to late endosomes. Pharmacologic inhibition of ERK phosphorylation suppressed BCR endocytosis in B cells of healthy patients and those with CVID.The B cells of patients with CVID with CD21(low) B-cell expansion resemble anergic B cells based on high constitutive pERK expression. The IgM(+) memory B cells of these patients, especially those that are CD21(low), have a defect in BCR endocytosis seemingly caused by dysregulated ERK signaling." @default.
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• W2025496979 date "2014-08-01" @default.
• W2025496979 modified "2023-09-27" @default.
• W2025496979 title "Dysregulated extracellular signal-regulated kinase signaling associated with impaired B-cell receptor endocytosis in patients with common variable immunodeficiency" @default.
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• W2025496979 doi "https://doi.org/10.1016/j.jaci.2014.03.017" @default.
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