Bruton's Tyrosine Kinase Is Essential for Human B Cell Tolerance

Ng, Yen-Shing; Wardemann, Hedda; Chelnis, James; Cunningham‐Rundles, Charlotte; Meffre, Eric

doi:10.1084/jem.20040920

Cited by 133 publications

(176 citation statements)

References 51 publications

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“…1B) implicate Btk signaling in the termination of V(D)J recombination activity upon productive Ig L chain rearrangement in immature B cells. This would be consistent with the finding that peripheral B cells from X-linked agammaglobulinemia patients, who have mutations in the Btk gene, show a distinct Ab repertoire consistent with extensive secondary V(D)J recombination (49).…”

Section: Discussionsupporting

confidence: 90%

Bruton’s Tyrosine Kinase and SLP-65 Regulate Pre-B Cell Differentiation and the Induction of Ig Light Chain Gene Rearrangement

Kersseboom

Zijlstra

et al. 2006

The Journal of Immunology

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Bruton’s tyrosine kinase (Btk) and the adapter protein SLP-65 (Src homology 2 domain-containing leukocyte-specific phosphoprotein of 65 kDa) transmit precursor BCR (pre-BCR) signals that are essential for efficient developmental progression of large cycling into small resting pre-B cells. We show that Btk- and SLP-65-deficient pre-B cells have a specific defect in Ig λ L chain germline transcription. In Btk/SLP-65 double-deficient pre-B cells, both κ and λ germline transcripts are severely reduced. Although these observations point to an important role for Btk and SLP-65 in the initiation of L chain gene rearrangement, the possibility remained that these signaling molecules are only required for termination of pre-B cell proliferation or for pre-B cell survival, whereby differentiation and L chain rearrangement is subsequently initiated in a Btk/SLP-65-independent fashion. Because transgenic expression of the antiapoptotic protein Bcl-2 did not rescue the developmental arrest of Btk/SLP-65 double-deficient pre-B cells, we conclude that defective L chain opening in Btk/SLP-65-deficient small resting pre-B cells is not due to their reduced survival. Next, we analyzed transgenic mice expressing the constitutively active Btk mutant E41K. The expression of E41K-Btk in Ig H chain-negative pro-B cells induced 1) surface marker changes that signify cellular differentiation, including down-regulation of surrogate L chain and up-regulation of CD2, CD25, and MHC class II; and 2) premature rearrangement and expression of κ and λ light chains. These findings demonstrate that Btk and SLP-65 transmit signals that induce cellular maturation and Ig L chain rearrangement independently of their role in termination of pre-B cell expansion.

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Section: Discussionsupporting

confidence: 90%

Bruton’s Tyrosine Kinase and SLP-65 Regulate Pre-B Cell Differentiation and the Induction of Ig Light Chain Gene Rearrangement

Kersseboom

Zijlstra

et al. 2006

The Journal of Immunology

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“…1) and the inhibition of PI3K with inhibitors (29) result in a phenotype compatible with a role for basal signaling in suppressing Rag induction. Of interest, a recent report showed that a high percentage of B cells that "squeak" through development in human X-linked agammaglobulinemia, a disorder characterized by mutations in btk, have a peripheral B cell repertoire enriched for autoimmune BCRs (68). The authors propose that inefficient signaling through the BCR may favor the development of autoreactive B cells, which is consistent with the model proposed here.…”

Section: Discussionsupporting

confidence: 78%

B Cell Receptor Basal Signaling Regulates Antigen-Induced Ig Light Chain Rearrangements

Schram

Tze

Ramsey

et al. 2008

The Journal of Immunology

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BCR editing in the bone marrow contributes to B cell tolerance by orchestrating secondary Ig rearrangements in self-reactive B cells. We have recently shown that loss of the BCR or a pharmacologic blockade of BCR proximal signaling pathways results in a global “back-differentiation” response in which immature B cells down-regulate genes important for the mature B cell program and up-regulate genes characteristic of earlier stages of B cell development. These observations led us to test the hypothesis that self-Ag-induced down-regulation of the BCR, and not self-Ag-induced positive signals, lead to Rag induction and hence receptor editing. Supporting this hypothesis, we found that immature B cells from xid (x-linked immunodeficiency) mice induce re-expression of a Rag2-GFP bacterial artificial chromosome reporter as well as wild-type immature B cells following Ag incubation. Incubation of immature B cells with self-Ag leads to a striking reversal in differentiation to the pro-/pre-B stage of development, consistent with the idea that back-differentiation results in the reinduction of genes required for L chain rearrangement and receptor editing. Importantly, Rag induction, the back-differentiation response to Ag, and editing in immature and pre-B cells are inhibited by a combination of phorbol ester and calcium ionophore, agents that bypass proximal signaling pathways and mimic BCR signaling. Thus, mimicking positive BCR signals actually inhibits receptor editing. These findings support a model whereby Ag-induced receptor editing is inhibited by BCR basal signaling on developing B cells; BCR down-regulation removes this basal signal, thereby initiating receptor editing.

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“…BCR-mediated signaling and Toll-like receptor-mediated signaling in precursor B cells are important for the removal of autoreactive B-cell receptors, as patients with genetic defects in BTK or MyD88 have been shown to have increased number of B cells carrying autoreactive BCRs. 26,27 Because the CD19 complex is important for signaling by the BCR, it might have a similar role in the removal of B cells carrying autoreactive B-cell receptors. In our cohort of 30 carriers of a CD19 gene mutation, we did not find increased autoimmunity or increased levels of ANAs.…”

Section: Discussionmentioning

confidence: 99%

B-cell maturation and antibody responses in individuals carrying a mutated CD19 allele

et al. 2010

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Homozygous CD19 mutations lead to an antibody deficiency due to disruption of the CD19 complex and consequent impaired signaling by the B-cell antigen receptor. We studied the effects of heterozygous CD19 mutations on peripheral B-cell development and antibody responses in a large family with multiple consanguineous marriages. Sequence analysis of 96 family members revealed 30 carriers of the CD19 mutation. Lymphocyte subset counts were not significantly different between carriers and noncarriers in three different age groups (0-10 years; 11-18 years; adults). B cells of carriers had reduced CD19 and CD21 median expression levels, and had reduced proportions of transitional (0-10 years) and CD5 þ B cells (adults). CD19 carriers did not show clinical signs of immunodeficiency; they were well capable to produce normal serum Ig levels and had normal responses to primary and booster vaccinations. The frequency of mutated Vk alleles was not affected. Heterozygous loss of CD19 causes some changes in the naive B-cell compartment, but overall in vivo B-cell maturation or humoral immunity is not affected. Many antibody deficiencies are not monogenetic, but likely caused by a combination of multiple genetic variations. Therefore, functional analyses of immune cell function should be carried out to show whether heterozygous mutations contribute to disease.

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Bruton's Tyrosine Kinase Is Essential for Human B Cell Tolerance

Cited by 133 publications

References 51 publications

Bruton’s Tyrosine Kinase and SLP-65 Regulate Pre-B Cell Differentiation and the Induction of Ig Light Chain Gene Rearrangement

Bruton’s Tyrosine Kinase and SLP-65 Regulate Pre-B Cell Differentiation and the Induction of Ig Light Chain Gene Rearrangement

B Cell Receptor Basal Signaling Regulates Antigen-Induced Ig Light Chain Rearrangements

B-cell maturation and antibody responses in individuals carrying a mutated CD19 allele

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