Early Arrest in B Cell Development in Transgenic Mice That Express the E41K Bruton’s Tyrosine Kinase Mutant Under the Control of the CD19 Promoter Region
| Autor: | Alex Maas, Gemma M. Dingjan, Frank Grosveld, Rudolf W. Hendriks |
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| Rok vydání: | 1999 |
| Předmět: | |
| Zdroj: | The Journal of Immunology. 162:6526-6533 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.162.11.6526 |
| Popis: | Bruton’s tyrosine kinase (Btk) is a nonreceptor protein kinase that is defective in X-linked agammaglobulinemia in humans and in X-linked immunodeficiency in mice. To study the effect of Btk activation in early B cell development in vivo, we have created transgenic mouse strains expressing Btk under the control of the human CD19 promoter region. The transgenic expression of wild-type human Btk corrected all X-linked immunodeficiency features in mice carrying a targeted disruption of the Btk gene. In contrast, expression of an activated form of Btk, the E41K mutant, resulted in an almost complete arrest of B cell development in the immature IgM+IgD− B cell stage in the bone marrow, irrespective of the presence of the endogenous intact Btk gene. Immature B cells were arrested at the progression from IgMlow into IgMhigh cells, which reflects the first immune tolerance checkpoint at which autoreactive B cells become susceptible to apoptosis. As the constitutive activation of Btk is likely to mimic B cell receptor occupancy by autoantigens in the bone marrow, our findings are consistent with a role for Btk as a mediator of B cell receptor-induced apoptotic signals in the immature B cell stage. Whereas the peripheral mature B cell pool was reduced to |
| Databáze: | OpenAIRE |
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