title: Dysregulated extracellular signal-regulated kinase signaling associated with impaired B-cell receptor endocytosis in patients with common variable immunodeficiency.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Clinical Immunology, Sapienza University of Rome, Rome, Italy.
authors.forename: Marcella
authors.initials: M
authors.lastname: Visentini
authors.affiliation: Department of Clinical Immunology, Sapienza University of Rome, Rome, Italy.
authors.forename: Ramona
authors.initials: R
authors.lastname: Marrapodi
authors.affiliation: Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Conti
authors.affiliation: Department of Clinical Immunology, Sapienza University of Rome, Rome, Italy.
authors.forename: Milica
authors.initials: M
authors.lastname: Mitrevski
authors.affiliation: Department of Clinical Immunology, Sapienza University of Rome, Rome, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Camponeschi
authors.affiliation: Department of Clinical Immunology, Sapienza University of Rome, Rome, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Lazzeri
authors.affiliation: Department of Clinical Immunology, Sapienza University of Rome, Rome, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Carbonari
authors.affiliation: Department of Anatomy, Histology, Forensic Medicine and Orthopedics, Sapienza University of Rome, Rome, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Catizone
authors.affiliation: Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Quinti
authors.affiliation: Department of Clinical Immunology, Sapienza University of Rome, Rome, Italy. Electronic address: massimo.fiorilli@uniroma1.it.
authors.forename: Massimo
authors.initials: M
authors.lastname: Fiorilli
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D017074:Common Variable Immunodeficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D004705:Endocytosis; D011992:Endosomes / Q000276:immunology / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000276:immunology*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007075:Immunoglobulin M / Q000235:genetics / Q000276:immunology; D016756:Immunoglobulins, Intravenous / Q000008:administration & dosage; D007156:Immunologic Memory; D051907:Lysosomal Membrane Proteins / Q000235:genetics / Q000276:immunology; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D021381:Protein Transport; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000276:immunology*; D017464:Receptors, Complement 3d / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D052118:Lysosomal-Associated Membrane Protein 1
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases; D007075:Immunoglobulin M; D016756:Immunoglobulins, Intravenous; D051907:Lysosomal Membrane Proteins; D011947:Receptors, Antigen, B-Cell; D017464:Receptors, Complement 3d; C489116:LAMP1 protein, human; D052118:Lysosomal-Associated Membrane Protein 1
keywords: B-cell receptor; Common variable immunodeficiency; endocytosis; extracellular signal-regulated kinase