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Increased Apoptosis of CD20+ IgA+ B Cells is the Basis for IgA Deficiency: The Molecular Mechanism for Correction In Vitro by IL-10 and CD40L

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IgA deficiency is the most common primary immunodeficiency in humans. Comparative analysis of gene expression in PBMC from IgA-deficient (IgAd) and normal donors using functional multiplex panels showed overexpression of the Caspase-1 (CASP-1) gene. Cells from all the IgAd donors (n=7) expressed 4–10-fold caspase-1 mRNA over normal controls (n=5). CD19+ B cells from all IgAd donors produced IgA in cultures following IL-10 and CD40L with Staphylococcus aureus (Cowan) (SAC) or tetanus toxoid (TT) treatments. In CD19+ B cells from IgAd donors, reconstitution of IgA secretion was associated with protection of the CD20+ B cell population that underwent apoptosis in the absence of IL-10, CD40L, and TT (triple treatment). Caspase-1 gene expression was decreased in the reconstituted cells. Furthermore, treatment with a caspase-1 inhibitor also independently protected against B cell apoptosis in vitro. An apoptosis-specific cDNA array showed differential expression of 4 out of 96 genes and a shift towards survival-related gene expression from the apoptotic to the protected B cells after triple treatment. There was an increase in the expression of the IAP-2 (inhibitor of apoptosis) gene in the reconstituted cells. Upregulation of the IAP-2 gene protects B cells from deletion and allows for IgA secretion in this system. The inability to detect secreted IgA in IgAd patients could result from the loss of IgA-committed B cells that express high levels of caspase-1.

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ACKNOWLEDGMENTS

We sincerely thank Drs Keith Crawford, Devendra Dubey, Charles Larsen and Judy Lieberman for their review of the manuscript and numerous discussions and suggestions. This work was supported by grant HL-29583 from the National Heart, Lung and Blood Institute of the National Institutes of Health.

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Authors and Affiliations

  1. The CBR Institute for Biomedical Research, Boston, Massachusetts, USA

    Zaheed Husain, Nichol Holodick, Caitlin Day & Chester A. Alper

  2. University of Massachusetts Medical Center, Worcester, Massachusetts, USA

    Irma Szymanski

  3. Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA

    Zaheed Husain

  4. Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA

    Chester A. Alper

  5. The CBR Institute for Biomedical Research, 800 Huntington Ave, Boston, Massachusetts, 02115, USA

    Chester A. Alper

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  1. Zaheed Husain
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Correspondence to Chester A. Alper.

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Husain, Z., Holodick, N., Day, C. et al. Increased Apoptosis of CD20+ IgA+ B Cells is the Basis for IgA Deficiency: The Molecular Mechanism for Correction In Vitro by IL-10 and CD40L. J Clin Immunol 26, 113–125 (2006). https://doi.org/10.1007/s10875-006-9001-y

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