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Intravenous immunoglobulin replacement therapy in common variable immunodeficiency induces B cell depletion through differentiation into apoptosis-prone CD21low B cells

  • PATHOGENESIS AND THERAPY IN AUTOIMMUNE DISEASES
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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 CD21low B cells that are spontaneously expanded in a subset of CVID and in some other immunological disorders. The CD21low 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 CD21low B cells that undergo accelerated apoptosis.

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Acknowledgments

This work was supported by a Grant (C26A12H92L) from the Intramural Research Program of Sapienza University of Rome to M. Fiorilli; M. Visentini was supported by Fondazione Roma, Rome, Italy.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Clinical Medicine, Sapienza University of Rome, Viale dell’Università 37, 00185, Rome, Italy

    Milica Mitrevski, Ramona Marrapodi, Alessandro Camponeschi, Cristina Lazzeri, Laura Todi, Massimo Fiorilli & Marcella Visentini

  2. Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy

    Isabella Quinti

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  1. Milica Mitrevski
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  2. Ramona Marrapodi
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  3. Alessandro Camponeschi
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  7. Massimo Fiorilli
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Correspondence to Marcella Visentini.

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Mitrevski, M., Marrapodi, R., Camponeschi, A. et al. Intravenous immunoglobulin replacement therapy in common variable immunodeficiency induces B cell depletion through differentiation into apoptosis-prone CD21low B cells. Immunol Res 60, 330–338 (2014). https://doi.org/10.1007/s12026-014-8599-8

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