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Control of the B cell-intrinsic tolerance programs by ubiquitin ligases Cbl and Cbl-b.

B cell receptor (BCR) signaling plays a critical role in B cell tolerance and activation. Here, we show that mice with B cell-specific ablation of both Cbl and Cbl-b (Cbl-/-Cblb-/-) manifested systemic lupus erythematosus (SLE)-like autoimmune disease. The Cbl double deficiency resulted in a substantial increase in marginal zone (MZ) and B1 B cells. The mutant B cells were not hyperresponsive in terms of proliferation and antibody production upon BCR stimulation; however, B cell anergy to protein antigen appeared to be impaired. Concomitantly, BCR-proximal signaling, including tyrosine phosphorylation of Syk tyrosine kinase, Phospholipase C-gamma2 (PLC-gamma2), and Rho-family GTP-GDP exchange factor Vav, and Ca2+ mobilization were enhanced, whereas tyrosine phosphorylation of adaptor protein BLNK was substantially attenuated in the mutant B cells. These results suggested that the loss of coordination between these pathways was responsible for the impaired B cell tolerance induction. Thus, Cbl proteins control B cell-intrinsic checkpoint of immune tolerance, possibly through coordinating multiple BCR-proximal signaling pathways during anergy induction.

Pubmed ID: 17493844


  • Kitaura Y
  • Jang IK
  • Wang Y
  • Han YC
  • Inazu T
  • Cadera EJ
  • Schlissel M
  • Hardy RR
  • Gu H



Publication Data

May 24, 2007

Associated Grants

  • Agency: NIAID NIH HHS, Id: AI 062931
  • Agency: NHLBI NIH HHS, Id: HL 48702
  • Agency: NIAID NIH HHS, Id: R01 AI062931
  • Agency: NIAID NIH HHS, Id: R01 AI062931-01A2
  • Agency: NIAID NIH HHS, Id: R01 AI062931-02
  • Agency: Intramural NIH HHS, Id:

Mesh Terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Antibodies
  • Antigens
  • B-Lymphocytes
  • Cell Differentiation
  • Cells, Cultured
  • Down-Regulation
  • Immune Tolerance
  • Immunoglobulins
  • Intracellular Signaling Peptides and Proteins
  • Lupus Erythematosus, Systemic
  • Mice
  • Mice, Knockout
  • Protein Binding
  • Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins c-cbl
  • Signal Transduction
  • Ubiquitin