BONE-MARROW CELLS IN X-LINKED AGAMMAGLOBULINEMIA EXPRESS PRE-B-SPECIFIC GENES (LAMBDA-LIKE AND V-PRE-B) AND PRESENT IMMUNOGLOBULIN V-D-J GENE USAGE STRONGLY BIASED TO A FETAL-LIKE REPERTOIRE

Expression of Ig and Ig-related genes has been studied in bone marrow cells from two patients with severe form of X-linked agammaglobulinemi a (XLA). Phenotypic analysis revealed the presence of pre-B cells, in the absence of mature B cell markers. The pre-B-specific genes, lambda -like and V pre-B, were normally transcribed. Sequence analysis of 48 distinct V-D-J cDNA clones directly derived from XLA bone marrow cells indicated that they had characteristics of an early fetal pre-B reper toire. All VH families were identified, with a strong bias in the gene usage: a few VH genes were largely overexpressed, either germline or slightly mutated; most genes had been located 3' of the VH locus and w ere also used in fetal liver (8-13 wk of gestation). Short D regions, (resulting from D-D fusion, making usage of all D genes in both orient ations with utilization of the three reading frames), restricted N div ersity, and a fetal JH usage pattern were also observed. Taken togethe r, our data suggest that the XLA defect does not alter V-D-J rearrange ments nor the expression of mu, lambda-like, and V pre-B transcripts a nd most likely results in a poor efficiency of some critical steps of the B cell maturation.