Defects in early B-cell development: comparing the consequences of abnormalities in pre-BCR signaling in the human and the mouse.
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.
Conley
M E
ME
Department of Immunology, St Jude Children's Research Hospital, Memphis, TN 38101-0318, USA. maryellen.conley@stjude.org
Rohrer
J
J
Rapalus
L
L
Boylin
E C
EC
Minegishi
Y
Y
D048868:Adaptor Proteins, Signal Transducing; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000361:Agammaglobulinemia / Q000235:genetics / Q000276:immunology / Q000628:therapy; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D002352:Carrier Proteins / Q000235:genetics; D002454:Cell Differentiation; D005260:Female; D005803:Genes, Immunoglobulin; D015316:Genetic Therapy; D006410:Hematopoiesis; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation; D010750:Phosphoproteins / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics; D011947:Receptors, Antigen, B-Cell / Q000235:genetics*; D015398:Signal Transduction; D013045:Species Specificity; D014960:X Chromosome / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; C113939:B cell linker protein; D002352:Carrier Proteins; D010750:Phosphoproteins; D011947:Receptors, Antigen, B-Cell; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human