Genetic defect in human X-linked agammaglobulinemia impedes a maturationalevolution of pro-B cells into a later stage of pre-B cells in the B-cell differentiation pathway

Surrogate light chains (lambda 5/VpreB) are selectively expressed in early precursors of B cells. B-cell defects in X-linked agammaglobulinemia (XLA) are caused by mutations in the gene for Bruton's tyrosine kinase, To elucid ate the nature of early B-lineage cells In bone marrow (BM), samples from 1 3 XLA patients and 24 healthy controls of different ages were comparatively analyzed using an antihuman VpreB monoclonal antibody. Expression of surro gate light (SL) and mu-heavy chains were examined after cell membrane perme abilization because they are mainly expressed in the cytoplasm of early B-l ineage cells. A flow cytometric analysis of normal BM identified 5 discrete cell types of B cells: mu(-)SL(++) (pro-B [B-cell progenitor]), mu(low)SL( ++) (pre-B1a), mu(low)SL(+) (pre-B1b), mu(low)SL(-)(pre-BP), and mu(high)SL (-) (B). The large cells, presumably in cycling states, were enriched in pr e-B1a cells. The frequencies of B-lineage cells in BM were higher in young children, and declined with advancing age. In contrast, XLA showed a profou nd reduction in BM B-lineage cells. In XLA BM, an expansion of pro-B cells with some small pre-Bla calls was marked, but other cells were negligible. These observations illustrate a B-cell maturation defect in XLA as well as a normal human B-cell differentiation pathway. The results suggest that the genetic defect in XLA may impede the evolution of pro-B cells beyond the e arlier pre-B stage into the later stage of pre-a cells in B-cell developmen t. (C) 2000 by The American Society of Hematology.