Defective B cell development and function in Btk-deficient mice

Khan, Wasif N.; Alt, Frederick W.; Gerstein, Rachel M.; Malynn, Barbara A.; Larsson, Inger; Rathbun, Gary; Davidson, Laurie A.; Müller, Sussane; Kantor, Aaron B.; Herzenberg, Leonora A.; Rosen, Fred S.; Sideras, Paschalis

doi:10.1016/1074-7613(95)90114-0

Cited by 669 publications

(650 citation statements)

References 84 publications

Supporting

Mentioning

607

Contrasting

Unclassified

Order By: Relevance

“…1C). As previously described [23,24], Btk-deficient mice had a specific defect in B220 high mature recirculating cells in the BM and exhibited relatively increased IgM high IgD low transitional B-cell fractions with impaired maturation into IgM low IgD high mature follicular B cells in the spleen. We have previously reported that high expression of E41K-Btk (E-Btk-3) resulted in an almost complete arrest of B-cell development at the B220 low IgM low immature B-cell stage in the BM [28].…”

supporting

confidence: 57%

“…Whereas in humans Btk mutations cause a severe arrest of B-cell development at the pre-B-cell stage leading to X-linked agammaglobulinemia, in the mouse there is only a mild pre-B-cell defect, differentiation of transitional into mature peripheral B cells is impaired and B-1 cells are lacking [23][24][25]. The pleckstrin homology domain mutant E41K-Btk displayed robust transformation potential in a soft-agar assay, increased membrane localization and phosphorylation in quiescent cells, independent of PI3K activity [26].…”

mentioning

confidence: 99%

See 1 more Smart Citation

Constitutive activation of Bruton's tyrosine kinase induces the formation of autoreactive IgM plasma cells

et al. 2010

View full text Add to dashboard Cite

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 3-83md 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 21 mobilization. They were spontaneously driven into germinal center-independent plasma cell differentiation, as evidenced by increased numbers of IgM 1 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. IntroductionSignals transmitted by the B-cell receptor (BCR) control the antigen response of B cells and are 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-a, 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 selfantigen, direct maturation of naive immature B cells from the follicular into the B-1 or MZ B-cell fate [6,7]. Eur. J. Immunol. 2010. 40: 2643-2654 DOI 10.1002 Leukocyte signaling 2643In mature B cells, BCR engagement induces phosphorylation of Ig-a and Ig-b 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 Cg2 (Plcg2). Activation of Plcg2 by Btk results in the generation of the Ca 21 -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 Plcg2 or the excitatory co-receptor CD19 result in a hyporesponsive phenotype, mainly characterize...

show abstract

supporting

confidence: 57%

mentioning

confidence: 99%

Constitutive activation of Bruton's tyrosine kinase induces the formation of autoreactive IgM plasma cells

et al. 2010

View full text Add to dashboard Cite

show abstract

“…PLCg2 À/À and BTK À/À -deficient mice have been previously described [24,43]. All animal studies were approved by the Washington University animal studies committee.…”

Section: Micementioning

confidence: 99%

Requirement of phospholipase C‐γ2 (PLCγ2) for Dectin‐1‐induced antigen presentation and induction of T_H1/T_H17 polarization

et al. 2009

Self Cite

View full text Add to dashboard Cite

DC recognize microbial components through an array of receptors known as PRR. PRR initiate intracellular signals, which engender DC with the capacity to stimulate T-cell responses. Dectin-1 is a PRR that recognizes b-glucan, a major constituent of many fungi's outer cell wall. Here we show that Dectin-1 activates DC through phospholipase (PLC)c2 signaling. PLCc2-deficient DC were unable to expand antigen-specific T cells and induce T H 1 and T H 17 differentiation in response to b-glucan. Mechanistically, PLCc2-deficiency impaired the capacity of DC to secrete polarizing cytokines following exposure to b-glucan. Dectin-1 required PLCc2 to activate MAPK, AP-1 and NF-jB, which induce cytokine gene expression. Moreover, PLCc2 controlled Dectin-1-mediated NFAT activation and induction of NFAT-dependent genes such as IL-2, cyclooxigenase-2 and Egr transcription factors. We conclude that PLCc2 is a crucial signaling mediator that modifies DC gene expression program to activate DC responses to b-glucan-containing pathogens.Key words: DC . Dectin-1 . PLCg . Signaling Supporting Information available online Introduction DC play a key role in gathering information from the surrounding environment and initiating appropriate immune responses when needed [1,2]. Because they bridge innate and adaptive immunity, DC are equipped with a multitude of intracellular and cell surface receptors that sense microbial components and trigger host responses to invading pathogens. These receptors, collectively known as PRR, include TLR [3], C-type lectins such as Dectin-1 [4], scavenger receptors [5], the nucleotide-binding oligomerization domain (NOD) proteins NOD1 and NOD2, the NOD-like receptors and the RIG-like receptors [6].Dectin-1 recognizes b-glucan, a major constituent of many fungi's outer cell wall [4,7] and triggers intracellular signals through a cytoplasmic tyrosine motif resembling the ITAM. Upon ligand binding, this motif is phosphorylated by src family kinases [8] and recruits the tyrosine kinase Syk [9], which initiates a signaling cascade leading to NF-kB [10], NFAT [11] and MAPK [12] activation. Along with Bcl-10 and MALT1, CARD9 is a crucial mediator in the ITAM-signaling pathway that links recognition of b-glucan by Dectin-1 to NF-kB and MAPK activation [13,14]. Overall, the Syk-CARD9 pathway is essential for [20,21]. Syk, together with the tyrosine kinases BTK and Src, activate PLCg through tyrosine phosphorylation [22]. Another downstream ITAM mediator, PI-3K, activates PLCg by generating phosphatidylinositol 3,4,5 trisphosphate, which binds the pleckstrin homology domain of PLCg, promoting PLCg recruitment to the cell membrane. Thus, the ability of Dectin-1 to initiate an ITAM-Syk-signaling pathway [9] provides a rationale for studying the role of PLCg in Dectin-1-mediated antimicrobial responses in DC.PLCg includes two isoforms, PLCg1 and PLCg2, which hydrolyze membrane phosphatidylinositol 4,5-biphosphate into inositol 1,4,5-trisphosphate and diacylglicerol (DAG) [20]. Inositol 1,4,5-trisphosphate triggers the ...

show abstract

“…Btk -/- [10], BLNK -/- [13], and PLCc2 -/- [17] mice on a mixed C57BL/6 Â 129 background were mated to generate Btk -/-PLCc2 -/-, BLNK -/-Btk -/-, and BLNK -/-PLCc2 -/-mice. Mice were genotyped by PCR and sacrificed if they developed signs of illness such as scruffy fur, hunched posture, lack of movement, hind limb paralysis, or visible tumors.…”

Section: Micementioning

confidence: 99%

“…A similar disease results from mutation of the human BLNK gene [9]. Mice lacking Btk [10][11][12], BLNK [13][14][15][16], or PLCc2 [17,18] have a milder phenotype with the predominant defect at the T2 to mature transition in the periphery. Btk -/-mice have a reduced frequency of Igk-expressing cells due to a role for Btk in Igk rearrangement in pre-B cells [19].…”

Section: Introductionmentioning

confidence: 99%

Btk and phospholipase Cγ2 can function independently during B cell development

et al. 2007

View full text Add to dashboard Cite

The pre-BCR and the BCR regulate B cell development via a signalosome nucleated by the adaptor protein B cell linker protein (BLNK). Formation of this complex facilitates activation of phospholipase C (PLC) c2 by Bruton's tyrosine kinase (Btk). To determine whether Btk and PLCc2 also have separate functions, we generated Btk -/-PLCc2 -/-mice. They demonstrated a block in development at the pre-B stage and increased pre-BCR surface expression. This phenotype was more severe than that of Btk -/-or PLCc2 -/-mice. Although both Btk and PLCc2 were required for proliferation of splenic B cells in response to BCR cross-linking, they contributed differently to anti-IgM-induced phosphorylation of ERK. Btk -/-and PLCc2 -/-mice each had a reduced frequency of Igk-expressing B cells and impaired migration of pre-B cells towards stromal cellderived factor 1. However, the increase in pre-B cell malignancy that occurs in BLNK -/-mice in the absence of Btk was not observed in the absence of PLCc2. Thus, Btk and PLCc2 act both in concert and independently throughout B cell development. IntroductionSignals from the B cell antigen receptor (BCR) regulate multiple stages of B lymphopoiesis [1]. In pre-B cells, the pre-BCR signals for proliferation, allelic exclusion of the IgH locus, down-regulation of VpreB and k5 expression, and light chain rearrangement. The pre-BCR is predominantly intracellular and is believed to signal in a ligand-independent manner. The BCR is first expressed on the surface of immature B cells. Antigen encounter at this stage results in negative selection via deletion, anergy, or receptor editing. A tonic BCR signal is required for differentiation beyond the T2 stage in the periphery and survival of mature B cells. Mature B cells proliferate and differentiate upon stimulation with foreign antigen in the appropriate context. BCR and pre-BCR signaling is mediated by a signalosome composed of Syk, Bruton's tyrosine kinase (Btk), B cell linker protein (BLNK; also known as SLP65 and BASH), and phospholipase C (PLC) c2 [2-4]. Receptor cross-linking activates Syk, which phosphorylates the adaptor protein BLNK. Btk and PLCc2 bind to phosphorylated BLNK via their SH2 domains. Btk then phosphorylates and activates PLCc2, resulting in changes in intracellular Ca 2+ and the activation of protein kinase Cb. Btk can also mediate BCR-stimulated Ca 2+ flux [5] and B cell development [6] independently of its catalytic activity. Btk acts as an adaptor to recruit and activate phosphatidylinositol 4-phosphate 5-kinase (PIP5K) [5], which produces the substrate for PLCc2. Thus, Btk signals through PLCc2 directly, by phosphorylation, and indirectly, by increasing substrate availability.Loss of Btk function causes the human immunodeficiency X-linked agammaglobulinemia (XLA) [7,8], which is characterized by a block in B cell development at the pre-B stage. A similar disease results from

show abstract

Defective B cell development and function in Btk-deficient mice

Cited by 669 publications

References 84 publications

Constitutive activation of Bruton's tyrosine kinase induces the formation of autoreactive IgM plasma cells

Constitutive activation of Bruton's tyrosine kinase induces the formation of autoreactive IgM plasma cells

Requirement of phospholipase C‐γ2 (PLCγ2) for Dectin‐1‐induced antigen presentation and induction of T_H1/T_H17 polarization

Btk and phospholipase Cγ2 can function independently during B cell development

Contact Info

Product

Resources

About

Defective B cell development and function in Btk-deficient mice

Cited by 669 publications

References 84 publications

Constitutive activation of Bruton's tyrosine kinase induces the formation of autoreactive IgM plasma cells

Constitutive activation of Bruton's tyrosine kinase induces the formation of autoreactive IgM plasma cells

Requirement of phospholipase C‐γ2 (PLCγ2) for Dectin‐1‐induced antigen presentation and induction of TH1/TH17 polarization

Btk and phospholipase Cγ2 can function independently during B cell development

Contact Info

Product

Resources

About

Requirement of phospholipase C‐γ2 (PLCγ2) for Dectin‐1‐induced antigen presentation and induction of T_H1/T_H17 polarization