title: Intravenous immunoglobulin induces a functional silencing program similar to anergy in human B cells.
abstract: BACKGROUND
  Chronic inflammatory and autoimmune diseases are largely due to inappropriate response of hyperactive or autoreactive B cells. These autoreactive B cells can evade central tolerance checkpoints and migrate to the periphery, where they would be silenced by anergy. Such anergic cells are characterized by B-cell receptor (BCR) desensitization and altered downstream signaling.
  
  
  OBJECTIVE
  We sought to determine whether intravenous immunoglobulin (IVIg) induces a nonresponsive state of B cells and to address the similarities of this mechanism to those described in anergy.
  
  
  METHODS
  Human B cells were stimulated with anti-IgM antibody, and effects of IVIg on several parameters, such as calcium release, tyrosine phosphorylation, BCR aggregation, BCR internalization, or transcriptional activity, were studied by using flow cytometry, confocal microscopy, Western blotting, and a quantitative PCR array.
  
  
  RESULTS
  IVIg-treated B cells show defects in activating coreceptor expression, calcium signaling, and BCR aggregation on engagement by antigen. IVIg also induces suppression of phosphoinositide 3-kinase signaling, which plays a central role in determining B-cell fate. All these events ultimately lead to profound modifications in gene expression, resulting in long-term functional but reversible silencing of IVIg-treated B cells.
  
  
  CONCLUSIONS
  Our findings provide insights into the effectiveness of IVIg in treating autoimmune or inflammatory pathologies associated with the loss of B-cell tolerance. Furthermore, these data provide a model to explore the complexity of positive versus negative selection in B cells.
authors.affiliation: EA2216, Immunology and Pathology, Université Européenne de Bretagne, Université de Bretagne Occidentale, Brest, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Séïté
authors.affiliation: EA2216, Immunology and Pathology, Université Européenne de Bretagne, Université de Bretagne Occidentale, Brest, France.
authors.forename: Carole
authors.initials: C
authors.lastname: Goutsmedt
authors.affiliation: EA2216, Immunology and Pathology, Université Européenne de Bretagne, Université de Bretagne Occidentale, Brest, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Youinou
authors.affiliation: EA2216, Immunology and Pathology, Université Européenne de Bretagne, Université de Bretagne Occidentale, Brest, France. Electronic address: pers@univ-brest.fr.
authors.forename: Jacques-Olivier
authors.initials: JO
authors.lastname: Pers
authors.affiliation: EA2216, Immunology and Pathology, Université Européenne de Bretagne, Université de Bretagne Occidentale, Brest, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Hillion
mesh_terms: D000888:Antibodies, Anti-Idiotypic / Q000276:immunology; D001327:Autoimmune Diseases / Q000276:immunology / Q000628:therapy*; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D020013:Calcium Signaling / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D002648:Child; D017635:Clonal Anergy / Q000187:drug effects; D006801:Humans; D007108:Immune Tolerance; D016756:Immunoglobulins, Intravenous / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects; D011940:Receptor Aggregation / Q000187:drug effects; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*
chemical_list: D000888:Antibodies, Anti-Idiotypic; D016756:Immunoglobulins, Intravenous; D007166:Immunosuppressive Agents; D011947:Receptors, Antigen, B-Cell; C044203:anti-IgM
keywords: B cells; B-cell receptor; BCR; CTB; Cholera toxin B; FACS; FITC; Fluorescein isothiocyanate; Fluorescence-activated cell sorting; IVIg; Intravenous immunoglobulin; NF-κB; NFAT; Nuclear factor of activated T cells; Nuclear factor κB; PE; PI3K; PIP3; PTEN; Phosphatase and tensin homolog; Phosphatidylinositol (3,4,5)-trisphosphate; Phosphoinositide 3-kinase; Phosphotyrosine; Phycoerythrin; SA-IVIg; SHIP; SHP; Sialylated intravenous immunoglobulin; Src homology domain 2-containing inositol phosphatase; Src homology domain 2-containing protein tyrosine phosphatase; TRITC; Tetrarhodamine isothiocyanate; anergy; autoimmunity; chronic inflammatory diseases; immune tolerance; p-Tyr