Defects in early B-cell development: comparing the consequences of abnormalities in pre-BCR signaling in the human and the mouse

Immunol Rev. 2000 Dec;178:75-90. doi: 10.1034/j.1600-065x.2000.17809.x.


Patients with genetic defects in B-cell development provide an unusual opportunity to dissect the requirements for normal B-cell maturation. It is striking that all of the known genetic defects that result in a failure of B-cell development involve signaling through the pre-B-cell receptor (pre-BCR). Approximately 85% of affected patients are males with mutations in the X chromosome-encoded cytoplasmic tyrosine kinase Btk. Preliminary experiments using stem cell transplants and retroviral-mediated gene therapy in Btk-deficient mice suggest that it may be relatively easy to correct serum immunoglobulins but harder to correct antibody production to T-cell-independent antigens in this disorder. About 3-6% of patients with defects in B-cell development have deletions or critical base pair substitutions in the mu constant region gene. Patients with defects in Igalpha, lambda5 and B-cell linker protein (BLNK) have also been described. All of these patients have a block at the pro-B to pre-B-cell transition. Defects in Btk, lambda5 and BLNK result in a more severe phenotype in the human compared to the mouse. These findings suggest that requirements for signaling through the pre-BCR are more stringent in the human compared to the mouse. Possible explanations for this observation are discussed.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Agammaglobulinaemia Tyrosine Kinase
  • Agammaglobulinemia / genetics
  • Agammaglobulinemia / immunology
  • Agammaglobulinemia / therapy
  • Animals
  • B-Lymphocytes / cytology*
  • B-Lymphocytes / immunology*
  • Carrier Proteins / genetics
  • Cell Differentiation
  • Female
  • Genes, Immunoglobulin
  • Genetic Therapy
  • Hematopoiesis
  • Humans
  • Male
  • Mice
  • Mutation
  • Phosphoproteins / genetics
  • Protein-Tyrosine Kinases / deficiency
  • Protein-Tyrosine Kinases / genetics
  • Receptors, Antigen, B-Cell / genetics*
  • Signal Transduction
  • Species Specificity
  • X Chromosome / genetics


  • Adaptor Proteins, Signal Transducing
  • B cell linker protein
  • Carrier Proteins
  • Phosphoproteins
  • Receptors, Antigen, B-Cell
  • Protein-Tyrosine Kinases
  • Agammaglobulinaemia Tyrosine Kinase
  • BTK protein, human