Btk levels set the threshold for B-cell activation and negative selection of autoreactive B cells in mice.
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Btk levels set the threshold for B-cell activation and negative selection of autoreactive B cells in mice. / Kil, Laurens P; Bruijn, de; Marjolein, J W; van Nimwegen, Menno; Corneth, Odilia B J; Hamburg, van; Thaiss, Friedrich; Dingjan, Gemma M; Thaiss, Friedrich; Rimmelzwaan, Guus F; Elewaut, Dirk; Delsing, Dianne; Loo, van; Fokko, Pieter; Hendriks, Rudi W.
In: BLOOD, Vol. 119, No. 16, 16, 2012, p. 3744-3756.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Btk levels set the threshold for B-cell activation and negative selection of autoreactive B cells in mice.
AU - Kil, Laurens P
AU - Bruijn, de
AU - Marjolein, J W
AU - van Nimwegen, Menno
AU - Corneth, Odilia B J
AU - Hamburg, van
AU - Thaiss, Friedrich
AU - Dingjan, Gemma M
AU - Thaiss, Friedrich
AU - Rimmelzwaan, Guus F
AU - Elewaut, Dirk
AU - Delsing, Dianne
AU - Loo, van
AU - Fokko, Pieter
AU - Hendriks, Rudi W
PY - 2012
Y1 - 2012
N2 - On antigen binding by the B-cell receptor (BCR), B cells up-regulate protein expression of the key downstream signaling molecule Bruton tyrosine kinase (Btk), but the effects of Btk up-regulation on B-cell function are unknown. Here, we show that transgenic mice overexpressing Btk specifically in B cells spontaneously formed germinal centers and manifested increased plasma cell numbers, leading to antinuclear autoantibody production and systemic lupus erythematosus (SLE)-like autoimmune pathology affecting kidneys, lungs, and salivary glands. Autoimmunity was fully dependent on Btk kinase activity, because Btk inhibitor treatment (PCI-32765) could normalize B-cell activation and differentiation, and because autoantibodies were absent in Btk transgenic mice overexpressing a kinase inactive Btk mutant. B cells overexpressing wild-type Btk were selectively hyperresponsive to BCR stimulation and showed enhanced Ca(2+) influx, nuclear factor (NF)-?B activation, resistance to Fas-mediated apoptosis, and defective elimination of selfreactive B cells in vivo. These findings unravel a crucial role for Btk in setting the threshold for B-cell activation and counterselection of autoreactive B cells, making Btk an attractive therapeutic target in systemic autoimmune disease such as SLE. The finding of in vivo pathology associated with Btk overexpression may have important implications for the development of gene therapy strategies for X-linked agammaglobulinemia, the immunodeficiency associated with mutations in BTK.
AB - On antigen binding by the B-cell receptor (BCR), B cells up-regulate protein expression of the key downstream signaling molecule Bruton tyrosine kinase (Btk), but the effects of Btk up-regulation on B-cell function are unknown. Here, we show that transgenic mice overexpressing Btk specifically in B cells spontaneously formed germinal centers and manifested increased plasma cell numbers, leading to antinuclear autoantibody production and systemic lupus erythematosus (SLE)-like autoimmune pathology affecting kidneys, lungs, and salivary glands. Autoimmunity was fully dependent on Btk kinase activity, because Btk inhibitor treatment (PCI-32765) could normalize B-cell activation and differentiation, and because autoantibodies were absent in Btk transgenic mice overexpressing a kinase inactive Btk mutant. B cells overexpressing wild-type Btk were selectively hyperresponsive to BCR stimulation and showed enhanced Ca(2+) influx, nuclear factor (NF)-?B activation, resistance to Fas-mediated apoptosis, and defective elimination of selfreactive B cells in vivo. These findings unravel a crucial role for Btk in setting the threshold for B-cell activation and counterselection of autoreactive B cells, making Btk an attractive therapeutic target in systemic autoimmune disease such as SLE. The finding of in vivo pathology associated with Btk overexpression may have important implications for the development of gene therapy strategies for X-linked agammaglobulinemia, the immunodeficiency associated with mutations in BTK.
KW - Animals
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Transgenic
KW - Mice, 129 Strain
KW - Pyrimidines/pharmacology
KW - Myeloid Cells/cytology/immunology
KW - Germinal Center/cytology/immunology
KW - Autoimmunity/immunology
KW - B-Lymphocytes/cytology/immunology
KW - Cell Lineage/immunology
KW - Gene Expression/immunology
KW - Lupus Erythematosus, Systemic/immunology/pathology
KW - Lymphocyte Activation/immunology
KW - Plasma Cells/cytology/immunology
KW - Protein-Tyrosine Kinases/antagonists & inhibitors/genetics/immunology
KW - Pyrazoles/pharmacology
KW - Animals
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Transgenic
KW - Mice, 129 Strain
KW - Pyrimidines/pharmacology
KW - Myeloid Cells/cytology/immunology
KW - Germinal Center/cytology/immunology
KW - Autoimmunity/immunology
KW - B-Lymphocytes/cytology/immunology
KW - Cell Lineage/immunology
KW - Gene Expression/immunology
KW - Lupus Erythematosus, Systemic/immunology/pathology
KW - Lymphocyte Activation/immunology
KW - Plasma Cells/cytology/immunology
KW - Protein-Tyrosine Kinases/antagonists & inhibitors/genetics/immunology
KW - Pyrazoles/pharmacology
M3 - SCORING: Journal article
VL - 119
SP - 3744
EP - 3756
JO - BLOOD
JF - BLOOD
SN - 0006-4971
IS - 16
M1 - 16
ER -
