A HUMAN NON-XLA IMMUNODEFICIENCY DISEASE CHARACTERIZED BY BLOCKAGE OFB-CELL DEVELOPMENT AT AN EARLY PROB CELL STAGE

We report a detailed analysis of a B cell defect affecting a patient g irl born from first cousin parents, characterized by a severe non-X-li nked agammaglobulinemia with a total absence of CD19(+) cells in the p eriphery. In the bone marrow, CD19 expression was also highly impaired , resulting in the absence of both B and preB compartments. By contras t, CD34(+)CD10(+), CD34(+)Psi L(+), and some CD19(+)CD10(+) mostly CD3 4(+) early proB cells were present, although diminished. Semiquantitat ive RT-PCR analysis performed on mononuclear bone marrow cells indicat ed that lambda-like, VpreB, Rag-1, Rag-2, and TdT transcripts expresse d during proB cell stages were found at normal levels whereas E2A, CD1 0, Syk, Pax-5, CD19, Ig alpha, Ig beta, V-H-C-mu, and V-kappa-C-kappa transcripts characteristic of later stages were severely depressed. Th is phenotype resembles that of Pax-5 knock-out mice, but since the cod ing sequence of the patient Pax-5 cDNA was shown to be normal, the def ect might rather result from an altered regulation of this gene. All t hese data indicate that the patient suffers from a new genetic defect that results in an arrest of differentiation within the proB cell comp artment, i.e., earlier than X-linked agammaglobulinemia, before the on set of Ig gene rearrangements.