title: Intravenous immunoglobulin replacement therapy in common variable immunodeficiency induces B cell depletion through differentiation into apoptosis-prone CD21(low) B cells.
abstract: Intravenous immunoglobulin (IVIG), besides its use as replacement therapy in patients with antibody deficiencies, is broadly used as an immunomodulatory agent for the treatment of autoimmune and inflammatory disorders. The mechanisms of action of IVIG include Fc receptor blockade, inhibition of cytokines and growth factors, modulation of macrophages and dendritic cells, enhancement of regulatory T cells, and modulation of B cells through the FcγRIIB receptor and CD22. Recent studies suggest that in vitro exposure of human B cells to IVIG determines functional changes reminiscent of anergy and that IVIG treatment of patients with common variable immunodeficiency (CVID) induces in B cells ERK activation, a feature of anergy. Here, we show that IVIG therapy drives the B cells of patients with CVID to down-regulate CD21 expression and to assume the peculiar phenotype of the anergic-like, apoptosis-prone CD21(low) B cells that are spontaneously expanded in a subset of CVID and in some other immunological disorders. The CD21(low) B cells newly generated after IVIG infusion undergo spontaneous apoptosis upon in vitro culture. Furthermore, IVIG infusion is rapidly followed by a significant, although discrete, decrease in the number of circulating B cells, but not of T cells or of natural killer cells. These findings suggest that IVIG therapy may constrain antibody responses by inducing B cell depletion through differentiation into CD21(low) B cells that undergo accelerated apoptosis.
authors.affiliation: Department of Clinical Medicine, Sapienza University of Rome, Viale dell'Università 37, 00185, Rome, Italy.
authors.forename: Milica
authors.initials: M
authors.lastname: Mitrevski
authors.forename: Ramona
authors.initials: R
authors.lastname: Marrapodi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Camponeschi
authors.forename: Cristina
authors.initials: C
authors.lastname: Lazzeri
authors.forename: Laura
authors.initials: L
authors.lastname: Todi
authors.forename: Isabella
authors.initials: I
authors.lastname: Quinti
authors.forename: Massimo
authors.initials: M
authors.lastname: Fiorilli
authors.forename: Marcella
authors.initials: M
authors.lastname: Visentini
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D017074:Common Variable Immunodeficiency / Q000188:drug therapy* / Q000276:immunology*; D005260:Female; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000494:pharmacology / Q000627:therapeutic use*; D016130:Immunophenotyping; D018655:Lymphocyte Count; D008212:Lymphocyte Depletion; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D017464:Receptors, Complement 3d / Q000378:metabolism
chemical_list: D016756:Immunoglobulins, Intravenous; D017464:Receptors, Complement 3d