Crosses with 3-83μδ and VH81X BCR Tg mice showed that constitutiv

Crosses with 3-83μδ 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 Ca2+ 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 LY2157299 ic50 essential for appropriate regulation of B-cell activation. Signals transmitted by the B-cell receptor (BCR) control the antigen response of B cells and are PD-0332991 cell line also essential regulators of survival, tolerance and differentiation (reviewed in 1, 2). Inducible and stage-specific targeting experiments demonstrated that mature B cells undergo apoptosis upon in vivo BCR ablation or mutation of one of its signaling units, Ig-α, and consequently disappear from the circulation 3, 4. A critical survival signal is provided by PI3K 5, but how this signaling is initiated in resting mature B cells is not fully understood. BCR signal strength is also a key factor in deciding between the three

functionally distinct mature B-cell compartments of follicular, marginal zone (MZ) and B-1 B cells. Increases in BCR signaling strength, induced by low-dose self-antigen, direct maturation of naive immature B cells from the follicular into the GABA Receptor B-1 or MZ B-cell fate 6, 7. In mature B cells, BCR engagement induces phosphorylation of Ig-α and Ig-β and the formation of a lipid raft-associated calcium-signaling module. In this complex Syk phosphorylates the adapter molecule Slp65, thereby providing docking sites for Bruton’s tyrosine kinase

(Btk) and phospholipase Cγ2 (Plcγ2). Activation of Plcγ2 by Btk results in the generation of the Ca2+-releasing factors inositol-1,4,5-trisphosphate and diacylglycerol (reviewed in 8, 9). During these events various co-receptors modulate BCR signaling either positively or negatively 10. Deficiencies of BCR signaling molecules, such as Btk, Slp65 or Plcγ2 or the excitatory co-receptor CD19 result in a hyporesponsive phenotype, mainly characterized by defects in the maturation of splenic follicular B cells, impaired MZ B-cell survival, absence of CD5+ B-1 B cells and impaired T–cell independent antibody responses 11. Conversely, a complex B-cell phenotype characterized by reduced numbers of follicular B cells, elevated numbers of B-1 B cells and to some extent MZ B cells, B-cell hyper-responsiveness and auto-antibody formation is found in genetic changes that increase BCR signaling.

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