title: 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.
abstract: 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.
authors.affiliation: The CBR Institute for Biomedical Research, Boston, Massachusetts 02115, USA.
authors.forename: Zaheed
authors.initials: Z
authors.lastname: Husain
authors.forename: Nichol
authors.initials: N
authors.lastname: Holodick
authors.forename: Caitlin
authors.initials: C
authors.lastname: Day
authors.forename: Irma
authors.initials: I
authors.lastname: Szymanski
authors.forename: Chester A
authors.initials: CA
authors.lastname: Alper
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D018941:Antigens, CD19 / Q000276:immunology; D018951:Antigens, CD20 / Q000276:immunology*; D017209:Apoptosis / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology / Q000494:pharmacology*; D020170:Caspase 1 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D017098:IgA Deficiency / Q000276:immunology / Q000628:therapy; D007070:Immunoglobulin A / Q000096:biosynthesis / Q000276:immunology*; D007375:Interleukin-1 / Q000276:immunology / Q000378:metabolism; D016753:Interleukin-10 / Q000276:immunology / Q000494:pharmacology*; D020382:Interleukin-18 / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D041681:NIH 3T3 Cells; D020411:Oligonucleotide Array Sequence Analysis; D009842:Oligopeptides / Q000494:pharmacology; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology
chemical_list: D018941:Antigens, CD19; D018951:Antigens, CD20; D007070:Immunoglobulin A; D007375:Interleukin-1; D020382:Interleukin-18; D009842:Oligopeptides; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; C096429:L 709049; D023201:CD40 Ligand; D020170:Caspase 1