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 Blood, 5 November 2009, Vol. 114, No. 19, pp. 4089-4098.
Prepublished online as a Blood First Edition Paper on September 8, 2009; DOI 10.1182/blood-2009-02-207423.

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IMMUNOBIOLOGY

Interleukin-21 restores immunoglobulin production ex vivo in patients with common variable immunodeficiency and selective IgA deficiency

Stephan Borte1, Qiang Pan-Hammarström2, Chonghai Liu2, Ulrich Sack1, Michael Borte3, Ulf Wagner4, Dagmar Graf5, and Lennart Hammarström2

1 Department of Clinical Immunology and Transfusion Medicine, University of Leipzig, Leipzig, Germany; 2 Division of Clinical Immunology and Transfusion Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden; 3 Department of Pediatrics, Municipal Hospital St Georg Leipzig, Leipzig, Germany; 4 Department of Internal Medicine II, University of Leipzig, Leipzig, Germany; and 5 Physician's Practice for Transfusion Medicine and Immunodeficiency, Laboratory Dr Reising-Ackermann, Leipzig, Germany

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.


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