Severe B cell deficiency and disrupted splenic architecture in transgenic mice expressing the E41K mutated form of Bruton's tyrosine kinase.
To identify B-cell signaling pathways activated by Bruton's tyrosine kinase (Btk) in vivo, we generated transgenic mice in which Btk expression is driven by the MHC class II Ea gene locus control region. Btk overexpression did not have significant adverse effects on B cell function, and essentially corrected the X-linked immunodeficiency (xid) phenotype in Btk- mice. In contrast, expression of a constitutively activated form of Btk carrying the E41K gain-of-function mutation resulted in a B cell defect that was more severe than xid. The mice showed a marked reduction of the B cell compartment in spleen, lymph nodes, peripheral blood and peritoneal cavity. The levels in the serum of most immunoglobulin subclasses decreased with age, and B cell responses to both T cell-independent type II and T cell-dependent antigens were essentially absent. Expression of the E41K Btk mutant enhanced blast formation of splenic B cells in vitro in response to anti-IgM stimulation. Furthermore, the mice manifested a disorganization of B cell areas and marginal zones in the spleen. Our findings demonstrate that expression of constitutively activated Btk blocks the development of follicular recirculating B cells.
Dingjan
G M
GM
Department of Cell Biology and Genetics, Faculty of Medicine, Erasmus University Rotterdam, Dr Molewaterplein 50, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands.
Maas
A
A
Nawijn
M C
MC
Smit
L
L
Voerman
J S
JS
Grosveld
F
F
Hendriks
R W
RW
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D000941:Antigens; D000955:Antigens, T-Independent; D001402:B-Lymphocytes / Q000276:immunology*; D001853:Bone Marrow / Q000276:immunology; D005802:Genes, MHC Class II / Q000235:genetics; D008040:Genetic Linkage; D007132:Immunoglobulin Isotypes / Q000097:blood; D007153:Immunologic Deficiency Syndromes / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D019901:Locus Control Region; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D010529:Peritoneal Cavity; D017354:Point Mutation; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D015398:Signal Transduction / Q000276:immunology*; D013154:Spleen / Q000276:immunology* / Q000473:pathology; D014960:X Chromosome / Q000235:genetics
D000941:Antigens; D000955:Antigens, T-Independent; D007132:Immunoglobulin Isotypes; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625951:Btk protein, mouse