Interleukin-21 restores immunoglobulin production ex vivo in patients with common variable immunodeficiency and selective IgA deficiency.
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.
Borte
Stephan
S
Department of Clinical Immunology and Transfusion Medicine, University of Leipzig, D-04103 Leipzig, Germany. stephan.borte@medizin.uni-leipzig.de
Pan-Hammarström
Qiang
Q
Liu
Chonghai
C
Sack
Ulrich
U
Borte
Michael
M
Wagner
Ulf
U
Graf
Dagmar
D
Hammarström
Lennart
L
D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D016022:Case-Control Studies; D002454:Cell Differentiation / Q000187:drug effects; D017074:Common Variable Immunodeficiency / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology*; D004357:Drug Synergism; D015870:Gene Expression; D006801:Humans; D017098:IgA Deficiency / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology*; D007070:Immunoglobulin A / Q000096:biosynthesis; D017578:Immunoglobulin Class Switching / Q000187:drug effects; D007074:Immunoglobulin G / Q000096:biosynthesis; D007136:Immunoglobulins / Q000096:biosynthesis*; D066298:In Vitro Techniques; D016753:Interleukin-10 / Q000494:pharmacology; D007376:Interleukin-2 / Q000008:administration & dosage / Q000494:pharmacology; D053738:Interleukin-21 Receptor alpha Subunit / Q000235:genetics; D015847:Interleukin-4 / Q000008:administration & dosage / Q000494:pharmacology; D007378:Interleukins / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D000098546:Interleukin-21
C508609:IL10 protein, human; C508594:IL2 protein, human; C508117:IL21R protein, human; C508598:IL4 protein, human; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D007136:Immunoglobulins; D007376:Interleukin-2; D053738:Interleukin-21 Receptor alpha Subunit; D007378:Interleukins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D016753:Interleukin-10; D015847:Interleukin-4; D000098546:Interleukin-21