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

Abstract

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.

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

“…1 Various studies have investigated the different steps and the transcription factors involved in this phase of B-cell development. 2 The checkpoint at the pre-BCR level is required for the following VJ L rearrangement that allows the assembly of the mature B-cell receptor (BCR) -composed of mHC, light chain, and the Iga/Igb heterodimeric signal-transducing elements -and its expression on the surface of newly formed immature B cells. 3 The correct expression and signaling activity of the BCR are required for normal B-cell development.…”

Pre-B Cell Receptor Assesses the Quality of IgH Chains and Tunes the Pre-B Cell Repertoire by Delivering Differential Signals

“…Once a productive rearrangement occurs at the IgH locus at the pro-B cell stage, H chains are produced and assembled with invariant VpreB/ 5 surrogate light (SL) 3 chains to form the pre-BCR (4,5). A deficiency in pre-BCR formation or signaling results in severe impairment of B cell differentiation in both humans and mice (6). Thus, the formation of the pre-BCR functions as a checkpoint to positively select the pro-B cells that have succeeded in a productive rearrangement of the IgH chain gene (7)(8)(9).…”

Bruton’s agammaglobulinemia in an adult male due to a novel mutation: a case report

“…BTK is critical in the maturation of pre-B cells to mature B cells (2,3). Patients with XLA have significantly reduced levels of mature B lymphocytes (<1% of normal) in their peripheral blood (4).…”