title: Defective calcium signaling and disrupted CD20-B-cell receptor dissociation in patients with common variable immunodeficiency disorders.
abstract: BACKGROUND
  B cells of patients with common variable immunodeficiency (CVID) disorders display impairment in production of immunoglobulin class-switched antibodies, which is possibly contributed to by defects in early B-cell activation. On resting B cells, B-cell receptors (BCRs) are organized in oligomers that are signaling inactive. Their triggering by cognate antigen causes the lateral reorganization of BCRs and associated proteins into signalosomes, resulting in BCR-activated calcium entry. In resting cells the B-cell surface antigen CD20 is associated with the BCR but dissociates on signalosome formation.
  
  
  OBJECTIVE
  We sought to determine whether CD20 dissociation from the BCR during early B-cell activation might contribute to the development of CVID disorders.
  
  
  METHODS
  We evaluated BCR signalosome formation, internalization, and signaling in primary B cells of pediatric patients with CVID disorders and healthy control subjects.
  
  
  RESULTS
  In many pediatric patients with CVID disorders, B cells exhibit significant deficits in BCR triggering-mediated calcium entry in the cytosol, which correlates with impaired plasmablast differentiation in vitro. These alterations did not originate from upregulation of CD22 or defects in calcium channels and did not involve gene mutations in phospholipase Cγ2 or Bruton tyrosine kinase. Instead, B cells from patients with CVID disorders exhibited reduced BCR dissociation from CD20. BCR or CD20 cross-linking induced less BCR internalization, and antibody-mediated CD20 triggering elicited less BCR downstream signaling, as measured based on secondary fluxes.
  
  
  CONCLUSIONS
  We propose that CD20 dissociation from the BCR signalosome is pivotal to BCR-mediated calcium mobilization in the cytosol. Defects in CD20/BCR signalosome conformation might predispose to the spectrum of CVID disorders.
authors: Department of Pediatric Immunology and Infectious Diseases, University Medical Center Utrecht and Wilhelmina Children's Hospital, Utrecht, The Netherlands.
authors: Annick A J M
authors: AA
authors: van de Ven
authors: Ewoud B
authors: EB
authors: Compeer
authors: Andries C
authors: AC
authors: Bloem
authors: Lisette
authors: L
authors: van de Corput
authors: Marielle
authors: M
authors: van Gijn
authors: Joris M
authors: JM
authors: van Montfrans
authors: Marianne
authors: M
authors: Boes
mesh_terms: D000293:Adolescent; D018951:Antigens, CD20 / Q000276:immunology / Q000378:metabolism*; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D020013:Calcium Signaling; D002454:Cell Differentiation; D002469:Cell Separation; D002648:Child; D002675:Child, Preschool; D017074:Common Variable Immunodeficiency / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008213:Lymphocyte Activation; D008297:Male; D011485:Protein Binding; D011940:Receptor Aggregation; D011947:Receptors, Antigen, B-Cell / Q000276:immunology / Q000378:metabolism*
chemical_list: D018951:Antigens, CD20; D011947:Receptors, Antigen, B-Cell