Constitutive activation of Bruton's tyrosine kinase induces the formation of autoreactive IgM plasma cells.
Eur J Immunol
; 40(9): 2643-54, 2010 Sep.
Article
en En
| MEDLINE
| ID: mdl-20623551
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.
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Banco de datos:
MEDLINE
Asunto principal:
Células Plasmáticas
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Proteínas Tirosina Quinasas
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Inmunoglobulina M
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Anticuerpos Antinucleares
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Subgrupos de Linfocitos B
Límite:
Animals
Idioma:
En
Año:
2010
Tipo del documento:
Article