Constitutive activation of Bruton's tyrosine kinase induces the formation of autoreactive IgM plasma cells.
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.
Kersseboom
Rogier
R
Department of Immunology, Erasmus MC Rotterdam, Rotterdam, The Netherlands.
Kil
Laurens
L
Flierman
Roelof
R
van der Zee
Marten
M
Dingjan
Gemma M
GM
Middendorp
Sabine
S
Maas
Alex
A
Hendriks
Rudi W
RW
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D000936:Antigen-Antibody Complex / Q000378:metabolism; D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D020013:Calcium Signaling / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D007108:Immune Tolerance / Q000235:genetics; D007075:Immunoglobulin M / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000235:genetics; D010950:Plasma Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D019076:Transgenes / Q000235:genetics
D000974:Antibodies, Antinuclear; D000936:Antigen-Antibody Complex; D007075:Immunoglobulin M; D050505:Mutant Proteins; D011947:Receptors, Antigen, B-Cell; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625951:Btk protein, mouse