A NON-XLA PRIMARY DEFICIENCY CAUSES THE EARLIEST KNOWN DEFECT OF B-CELL DIFFERENTIATION IN HUMANS - A COMPARISON WITH AN XLA CASE

We report a detailed comparison of B cell defects in two patients, one XLA and one non-XLA. Both had severe agammaglobulinemia with a total absence of CD19(+) cells in the periphery. In the non-XLA case, CD19 e xpression was also highly impaired in the bone marrow, resulting in th e absence of both B and preB compartments. Early proB cells were prese nt since CD34(+)CD10(+) and some CD19(+)CD10(+) mostly CD34(+) were id entified, although diminished. By contrast, in the XLA patient the CD3 4(+)CD19(+) proB cells were increased whereas the CD34(-)CD19(+) preB cell population was low. Semi-quantitative RT-PCR analysis performed o n mononuclear bone marrow cells from the non-XLA patient indicated tha t lambda-like, VpreB, Rag-1, Rag-2 and TdT transcripts expressed durin g proB cell stages were found at normal levels whereas E2A, CD10, Syk, Pax-5, CD19, Ig alpha, Ig beta, V-H-C mu and V-K-C-K transcripts char acteristic of later stages were severely depressed. By contrast in the XLA patient most of these transcripts were observed in normal amounts . The phenotype of the non-XLA patient resembles that of Pax-5 or Ig b eta knock-out mice, but since the coding sequence of both cDNAs were s hown to be normal, the blockage might rather result from an altered re gulation of one of these genes or from defect of other genes. All thes e data indicate that the non-XLA patient suffers from a new genetic de fect that results in an arrest of differentiation within the proB cell compartment, before the onset of Ig gene rearrangements. From all aga mmaglobulinemias reported so far, including XLA cases and those result ing from C mu gene defects, the non-XLA patient exhibits the earliest blockage in the B cell differentiation pathway. (C) 1997 Elsevier Scie nce B.V.