X-Linked Immune Deficiency (xid) of CBA/N Mice

Wicker, Linda S.; Scher, I

doi:10.1007/978-3-642-70986-9_6

Cited by 81 publications

(85 citation statements)

References 68 publications

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“…6A), which are known to be affected by defective Btk function (8,9,34). In contrast, the rescue of the proliferative response to anti-IgM stimulation was modest (Fig.…”

Section: Kinase-independent Adapter Function Of Btk In Mature B Cellsmentioning

confidence: 93%

“…Btk-deficient mice have severely decreased levels of IgM and IgG3 in the serum and do not mount specific Ab responses to T cell-independent type II (TI-II) Ags in vivo, and xid B cells undergo apoptosis instead of proliferation in response to in vitro stimulation (8,9,(31)(32)(33). The K430R-Btk transgene provided a significant correction of the decreased levels of IgM in the serum of Btk-deficient mice, while only a modest increase in IgG3 was observed (Fig.…”

Section: Kinase-independent Adapter Function Of Btk In Mature B Cellsmentioning

confidence: 99%

“…Btk-deficient mice manifest a specific arrest of peripheral B cell development within the immature B cell pool at the progression of IgM high to IgM low AA4 ϩ CD23 ϩ transitional B cells (8 -12). In these mice, the numbers of pre-B cells that are generated in the bone marrow (BM) are normal (8,9,13). Nevertheless, Btk is crucially involved in the regulation of the developmental progression of pre-B cells by limiting the IL-7-driven expansion of large cycling pre-B cells (14,15).…”

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confidence: 99%

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Function of Bruton’s Tyrosine Kinase during B Cell Development Is Partially Independent of Its Catalytic Activity

Middendorp¹,

Dingjan²,

Maas

et al. 2003

The Journal of Immunology

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The Tec family member Bruton’s tyrosine kinase (Btk) is a cytoplasmic protein tyrosine kinase that transduces signals from the pre-B and B cell receptor (BCR). Btk is involved in pre-B cell maturation by regulating IL-7 responsiveness, cell surface phenotype changes, and the activation of λ L chain gene rearrangements. In mature B cells, Btk is essential for BCR-mediated proliferation and survival. Upon BCR stimulation, Btk is transphosphorylated at position Y551, which promotes its catalytic activity and subsequently results in autophosphorylation at position Y223 in the Src homology 3 domain. To address the significance of Y223 autophosphorylation and the requirement of enzymatic activity for Btk function in vivo, we generated transgenic mice that express the autophosphorylation site mutant Y223F and the kinase-inactive mutant K430R, respectively. We found that Y223 autophosphorylation was not required for the regulation of IL-7 responsiveness and cell surface phenotype changes in differentiating pre-B cells, or for peripheral B cell differentiation. However, expression of the Y223F-Btk transgene could not fully rescue the reduction of λ L chain usage in Btk-deficient mice. In contrast, transgenic expression of kinase-inactive K430R-Btk completely reconstituted λ usage in Btk-deficient mice, but the defective modulation of pre-B cell surface markers, peripheral B cell survival, and BCR-mediated NF-κB induction were partially corrected. From these findings, we conclude that: 1) autophosphorylation at position Y223 is not essential for Btk function in vivo, except for regulation of λ L chain usage, and 2) during B cell development, Btk partially acts as an adapter molecule, independent of its catalytic activity.

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“…6A), which are known to be affected by defective Btk function (8,9,34). In contrast, the rescue of the proliferative response to anti-IgM stimulation was modest (Fig.…”

Section: Kinase-independent Adapter Function Of Btk In Mature B Cellsmentioning

confidence: 93%

Section: Kinase-independent Adapter Function Of Btk In Mature B Cellsmentioning

confidence: 99%

mentioning

confidence: 99%

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Function of Bruton’s Tyrosine Kinase during B Cell Development Is Partially Independent of Its Catalytic Activity

Middendorp¹,

Dingjan²,

Maas

et al. 2003

The Journal of Immunology

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“…In comparison with human XLA, the Xid phenotype is less severe because of the redundancy of other Tec kinases, which apparently can compensate for the lack of BTK in murine B cells. [20][21][22][23] Current intravenous Ig treatment for XLA is fairly effective and the quality of life of most patients has significantly improved over the last two decades, but it is not possible to prevent all infections. Despite prompt administration of antibiotics when needed, recurrent infections can cause progressive and irreversible organ damage, particularly of the lung and consequently represent a life-threatening risk.…”

Section: Introductionmentioning

confidence: 99%

Correction of B-cell development in Btk-deficient mice using lentiviral vectors with codon-optimized human BTK

Baert

Pike-Overzet

et al. 2010

Leukemia

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X-linked agammaglobulinemia (XLA) is the most common primary immunodeficiency (PID) in man and caused by mutations in the Bruton's tyrosine kinase (BTK) gene. XLA is characterized by a B-cell differentiation arrest in bone marrow, absence of mature B cells and immunoglobulins (Igs), and recurrent bacterial infections. We used self-inactivating lentiviral vectors expressing codon-optimized human BTK under the control of three different ubiquitous or B cell-specific promoters. BtkÀ/À mice engrafted with transduced cells showed correction of both precursor B-cell and peripheral B-cell development. Lentiviral vectors containing the wildtype BTK sequence did not correct the phenotype. All treated mice with codon-optimized BTK exhibited the recovery of B1 cells in the peritoneal cavity, and of serum IgM and IgG3 levels. Calcium mobilization responses upon B-cell receptor stimulation as well as in vivo responses to T cell-independent antigens were restored. Viral promoters overexpressing BTK 4100-fold above normal resulted in erythro-myeloid proliferations independent of insertional mutagenesis. However, transplantation into secondary BtkÀ/À recipients using cellular promoters resulted in functional restoration of peripheral B cells and IgM levels, without any adverse effects. In conclusion, transduction of human BTK corrects B-cell development and antigen-specific antibody responses in BtkÀ/À mice, thus indicating the feasibility of lentiviral gene therapy for XLA, provided that BTK expression does not vastly exceed normal levels.

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“…These diseases are characterized by defects in B cell development and function. Genetic and biochemical analyses indicate that Btk is a component of the signal transduction pathways utilized by the B cell antigen receptor (BCR), IL-5R, IL-6R, IL-10R, CD38, and FceRI (Wicker and Scher, 1986;Hinshelwood et al, 1995;Saouf et al, 1994;Aoki et al, 1994;de Weers et al, 1994;Koike et al, 1995;Sato et al, 1994;Hitoshi et al, 1993;Matsuda et al, 1995;Santos-Argumedo et al, 1995;Go et al, 1990;Kawakami et al, 1994). Activation of Btk by either receptor crosslinking or a point mutation E41K in the PH domain (Btk*) is dependent on Src family kinases Afar et al, 1996;Saouf et al, 1994;Mahajan et al, 1995) and is correlated with increased tyrosine phosphorylation Li et al, 1995;Mahajan et al, 1995;Hinshelwood et al, 1995;Aoki et al, 1994;de Weers et al, 1994;Saouf et al, 1994;Sato et al, 1994;Kawakami et al, 1994;Matsuda et al, 1995) and translocation to the plasma membrane (Li et al, 1995;Kawakami et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

Constitutive membrane association potentiates activation of Bruton tyrosine kinase

Rawlings

Park

et al. 1997

Oncogene

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Mutations in the nonreceptor tyrosine kinase Btk result in the B cell immunode®ciencies X-linked agammaglobulinemia (XLA) in humans and X-linked immunode®-ciency (xid) in mice. Genetic and biochemical evidence implicates Btk as a key component of several B cell signaling pathways. Activation of Btk by a point mutation (E41K) within the PH domain (Btk*) results in ®broblast transformation and is correlated with increased membrane localization of Btk. When wild type Btk is activated by coexpression with Lyn, the tyrosine phosphorylated pool of Btk is highly enriched in the membrane fraction. To determine whether membrane association is su cient to activate Btk, we targeted Btk to the plasma membrane using a series of fusion proteins including GagBtk, CD16Btk and CD4Btk. Constitutive membrane association greatly enhanced the ability of Btk to transform Rat2 ®broblasts in the presence of high levels of Src activity. All membrane targeted forms of Btk were highly tyrosine phosphorylated. Transformation required membrane localization, Btk kinase activity, transphosphorylation by Src family kinases, and an intact SH2 domain but not the PH or SH3 domains. These data suggest that membrane localization is a critical early step in Btk activation.

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X-Linked Immune Deficiency (xid) of CBA/N Mice

Cited by 81 publications

References 68 publications

Function of Bruton’s Tyrosine Kinase during B Cell Development Is Partially Independent of Its Catalytic Activity

Function of Bruton’s Tyrosine Kinase during B Cell Development Is Partially Independent of Its Catalytic Activity

Correction of B-cell development in Btk-deficient mice using lentiviral vectors with codon-optimized human BTK

Constitutive membrane association potentiates activation of Bruton tyrosine kinase

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