Abstract
Interleukin-21 (IL-21) is an important promoter for differentiation of human B cells into immunoglobulin (Ig)-secreting cells. The objective of this study was to evaluate an IL-21-based approach to induce immunoglobulin production in B cells from patients with common variable immunodeficiency (CVID) or selective IgA deficiency (IgAD). We show that a combination of IL-21, IL-4, and anti-CD40 stimulation induces class-switch recombination to IgG and IgA and differentiation of Ig-secreting cells, consisting of both surface IgG(+) (sIgG(+)) and sIgA(+) B cells and CD138(+) plasma cells, in patients with CVID or IgAD. Stimulation with IL-21 was far more effective than stimulation with IL-4 or IL-10. Moreover, spontaneous apoptosis of CD19(+) B cells from patients with CVID or IgAD was prevented by a combination of IL-21, IL-4, and anti-CD40 stimulation. Analysis of IL-21 and IL-21 receptor (IL-21R) mRNA expression upon anti-CD3 stimulation of T cells, however, showed no evidence for defective IL-21 expression in CVID patients and sequencing of the coding regions of the IL21 gene did not reveal any mutations, suggesting a regulatory defect. Thus, our work provides an initial basis for a potential therapeutic role of IL-21 to reconstitute immunoglobulin production in CVID and IgAD.
MeSH terms
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Apoptosis / drug effects
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B-Lymphocytes / drug effects
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B-Lymphocytes / immunology
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B-Lymphocytes / pathology
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Case-Control Studies
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Cell Differentiation / drug effects
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Common Variable Immunodeficiency / drug therapy*
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Common Variable Immunodeficiency / genetics
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Common Variable Immunodeficiency / immunology*
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Drug Synergism
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Gene Expression
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Humans
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IgA Deficiency / drug therapy*
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IgA Deficiency / genetics
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IgA Deficiency / immunology*
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Immunoglobulin A / biosynthesis
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Immunoglobulin Class Switching / drug effects
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Immunoglobulin G / biosynthesis
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Immunoglobulins / biosynthesis*
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In Vitro Techniques
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Interleukin-10 / pharmacology
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Interleukin-2 / administration & dosage
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Interleukin-2 / pharmacology
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Interleukin-21 Receptor alpha Subunit / genetics
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Interleukin-4 / administration & dosage
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Interleukin-4 / pharmacology
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Interleukins / administration & dosage
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Interleukins / genetics
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Interleukins / pharmacology*
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Recombinant Proteins / administration & dosage
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Recombinant Proteins / pharmacology
Substances
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IL10 protein, human
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IL2 protein, human
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IL21R protein, human
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IL4 protein, human
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Immunoglobulin A
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Immunoglobulin G
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Immunoglobulins
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Interleukin-2
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Interleukin-21 Receptor alpha Subunit
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Interleukins
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RNA, Messenger
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Recombinant Proteins
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Interleukin-10
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Interleukin-4
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interleukin-21