1. Constitutive activation of Bruton's tyrosine kinase induces the formation of autoreactive IgM plasma cells.
- Author
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Kersseboom R, Kil L, Flierman R, van der Zee M, Dingjan GM, Middendorp S, Maas A, and Hendriks RW
- Subjects
- Agammaglobulinaemia Tyrosine Kinase, Animals, Antibodies, Antinuclear genetics, Antibodies, Antinuclear metabolism, Antigen-Antibody Complex metabolism, B-Lymphocyte Subsets immunology, B-Lymphocyte Subsets pathology, Calcium Signaling genetics, Cell Differentiation genetics, Cell Differentiation immunology, Cell Proliferation, Enzyme Activation genetics, Enzyme Activation immunology, Immune Tolerance genetics, Immunoglobulin M blood, Immunoglobulin M genetics, Lymphocyte Activation genetics, Mice, Mice, Transgenic, Mutant Proteins genetics, Plasma Cells immunology, Plasma Cells pathology, Protein-Tyrosine Kinases genetics, Protein-Tyrosine Kinases immunology, Receptors, Antigen, B-Cell genetics, Receptors, Antigen, B-Cell immunology, Receptors, Antigen, B-Cell metabolism, Transgenes genetics, Antibodies, Antinuclear biosynthesis, B-Lymphocyte Subsets metabolism, Immunoglobulin M biosynthesis, Plasma Cells metabolism, Protein-Tyrosine Kinases metabolism
- Abstract
B-cell receptor (BCR)-mediated signals provide the basis for B-cell differentiation in the BM and subsequently into follicular, marginal zone, or B-1 B-cell subsets. We have previously shown that B-cell-specific expression of the constitutive active E41K mutant of the BCR-associated molecule Bruton's tyrosine kinase (Btk) leads to an almost complete deletion of immature B cells in the BM. Here, we report that low-level expression of the E41K or E41K-Y223F Btk mutants was associated with reduced follicular B-cell numbers and significantly increased proportions of B-1 cells in the spleen. Crosses with 3-83 mu delta and VH81X BCR Tg mice showed that constitutive active Btk expression did not change follicular, marginal zone, or B-1 B-cell fate choice, but resulted in selective expansion or survival of B-1 cells. Residual B cells were hyperresponsive and manifested sustained Ca(2+) mobilization. They were spontaneously driven into germinal center-independent plasma cell differentiation, as evidenced by increased numbers of IgM(+) plasma cells in spleen and BM and significantly elevated serum IgM. Because anti-nucleosome autoantibodies and glomerular IgM deposition were present, we conclude that constitutive Btk activation causes defective B-cell tolerance, emphasizing that Btk signals are essential for appropriate regulation of B-cell activation.
- Published
- 2010
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