Aberrant B Cell Development and Immune Response in Mice with a Compromised BCR Complex

Torres, Raul M.; Flaswinkel, Heinrich; Reth, Michael; Rajewsky, Klaus

doi:10.1126/science.272.5269.1804

Cited by 272 publications

(220 citation statements)

References 56 publications

(11 reference statements)

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“…Several in vivo studies have shown that expression and signaling of the pre-BCR and BCR are prerequisite to complete the development of B lymphocytes (15,16,18,19,32,33,(57)(58)(59)(60). We find that Ig-␣-deficient mice have a block in B cell development that is similar to mice lacking Ig-␤ or m expression.…”

Section: Discussionsupporting

confidence: 52%

“…Mice bearing mutations in or deletions of the cytoplasmic portion of both Ig-␣ and Ig-␤ also show complete block at the pro-B cell stage of B cell development (17,18). However, the same mutations in either Ig-␣ or Ig-␤ cause a partial block at the pre-B cell stage and a more severe arrest at the immature B cell stage, demonstrating that Ig-␣ and Ig-␤ have redundant signaling functions, at least during pre-BCR signaling (17)(18)(19).…”

Section: B Cell Progenitors Are Arrested In Maturation But Have Intacmentioning

confidence: 99%

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B Cell Progenitors Are Arrested in Maturation but Have Intact VDJ Recombination in the Absence of Ig-α and Ig-β

Pelanda

Braun

Hobeika

et al. 2002

The Journal of Immunology

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100

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Ig-α and Ig-β mediate surface expression and signaling of diverse B cell receptor complexes on precursor, immature, and mature B cells. Their expression begins before that of the Ig chains in early progenitor B cells. In this study, we describe the generation of Ig-α-deficient mice and their comparative analysis to mice deficient for Ig-β, the membrane-IgM, and recombination-activating gene 2 to determine the requirement of Ig-α and Ig-β in survival and differentiation of pro-B cells. We find that in the absence of Ig-α, B cell development does not progress beyond the progenitor stage, similar to what is observed in humans lacking this molecule. However, neither in Ig-α- nor in Ig-β-deficient mice are pro-B cells impaired in V(D)J recombination, in the expression of intracellular Ig μ-chains, or in surviving in the bone marrow microenvironment. Finally, Ig-α and Ig-β are not redundant in their putative function, as pro-B cells from Ig-α and Ig-β double-deficient mice are similar to those from single-deficient animals in every aspect analyzed.

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Section: Discussionsupporting

confidence: 52%

Section: B Cell Progenitors Are Arrested In Maturation But Have Intacmentioning

confidence: 99%

B Cell Progenitors Are Arrested in Maturation but Have Intact VDJ Recombination in the Absence of Ig-α and Ig-β

Pelanda

Braun

Hobeika

et al. 2002

The Journal of Immunology

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100

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“…Finally, knockout models of the last two components of the pre-BCR complex, CD79a and CD79b, 14,15 provide evidence for their requirement in B-cell differentiation in the bone marrow, in particular in the V-DJ rearrangement process. Recently, two patients were found to have homozygous defects in Iga: 16,17 comparison with mHCdeficient patients reveals, in both cases, a block at the early stages of B-cell development and similarly impaired V-DJ rearrangements.…”

Section: Introductionmentioning

confidence: 98%

Molecular analysis of the pre-BCR complex in a large cohort of patients affected by autosomal-recessive agammaglobulinemia

et al. 2007

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Autosomal-recessive agammaglobulinemia is a rare and heterogeneous disorder, characterized by early-onset infections, profound hypogammaglobulinemia of all immunoglobulin isotypes and absence of circulating B lymphocytes. To investigate the molecular basis of the disease, 23 patients with early-onset disease and no mutations in Bruton tyrosine kinase, the gene responsible for X-linked agammaglobulinemia, were selected and analyzed by direct sequencing of candidate genes. Two novel mutations in the m heavy chain (mHC) gene (IGHM) were identified in three patients belonging to two unrelated families. A fourth patient carries a previously described G4A nucleotide substitution at the À1 position of an alternative splice site in IGHM; here, we demonstrate that this mutation is indeed responsible for aberrant splicing. Comparison of bone marrow cytofluorimetric profiles in two patients carrying different mutations in the IGHM gene suggests a genotype-phenotype correlation with the stage at which B-cell development is blocked. Several new single nucleotide polymorphisms (SNPs) both in the mHC and in the l5-like/VpreB-coding genes were identified. Two unrelated patients carry compound heterozygous variations in the VpreB1 gene that may be involved in disease ethiology.

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“…The cytoplasmic tails of Igα and Igβ each contain an immunoreceptor tyrosine‐based activation motif (ITAM) with two conserved tyrosines that are crucial for the development and maintenance of mature B cells (Reth, 1989; Torres et al , 1996; Kraus et al , 2001, 2004; Reichlin et al , 2001). Upon antigen ligation and opening of the BCR, the spleen tyrosine kinase (Syk) phosphorylates and interacts with the ITAM tyrosines of Igα and Igβ (Rolli et al , 2002).…”

Section: Introductionmentioning

confidence: 99%

Continuous signaling of CD 79b and CD 19 is required for the fitness of Burkitt lymphoma B cells

Kläsener

Iype

et al. 2018

The EMBO Journal

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Expression of the B‐cell antigen receptor (BCR) is essential not only for the development but also for the maintenance of mature B cells. Similarly, many B‐cell lymphomas, including Burkitt lymphoma (BL), require continuous BCR signaling for their tumor growth. This growth is driven by immunoreceptor tyrosine‐based activation motif (ITAM) and PI3 kinase (PI3K) signaling. Here, we employ CRISPR/Cas9 to delete BCR and B‐cell co‐receptor genes in the human BL cell line Ramos. We find that Ramos B cells require the expression of the BCR signaling component Igβ (CD79b), and the co‐receptor CD19, for their fitness and competitive growth in culture. Furthermore, we show that in the absence of any other BCR component, Igβ can be expressed on the B‐cell surface, where it is found in close proximity to CD19 and signals in an ITAM‐dependent manner. These data suggest that Igβ and CD19 are part of an alternative B‐cell signaling module that use continuous ITAM/PI3K signaling to promote the survival of B lymphoma and normal B cells.

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Aberrant B Cell Development and Immune Response in Mice with a Compromised BCR Complex

Cited by 272 publications

References 56 publications

B Cell Progenitors Are Arrested in Maturation but Have Intact VDJ Recombination in the Absence of Ig-α and Ig-β

B Cell Progenitors Are Arrested in Maturation but Have Intact VDJ Recombination in the Absence of Ig-α and Ig-β

Molecular analysis of the pre-BCR complex in a large cohort of patients affected by autosomal-recessive agammaglobulinemia

Continuous signaling of CD 79b and CD 19 is required for the fitness of Burkitt lymphoma B cells

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