IntroductionIn the bone marrow (BM), B-cell differentiation leads to generation of a broad repertoire of antibody-bearing cells in an antigenindependent manner. After ordered rearrangement of the heavy and light chain loci, immature B cells are the first B-cell subset to express a B-cell receptor (BCR), composed of a surface immunoglobulin M (IgM) and the Ig␣/Ig signaling complex (reviewed in Meffre et al 1 ). This process yields a number of potentially self-reactive clones, which can be eliminated by apoptosis (clonal deletion), modified by secondary rearrangements (receptor editing), or rendered hyporesponsive (anergy). [2][3][4][5] In the mouse, 2 ϫ 10 7 immature B cells are generated every day, of which around 90% undergo negative selection. 6 Before migrating to the periphery, immature B cells develop into IgM hi IgD lo CD21 Ϫ CD23 Ϫ type 1 (T1) transitional B cells. 7 They differentiate in the spleen into IgM hi IgD ϩ CD21 ϩ CD23 ϩ type 2 (T2) transitional B cells and then into either IgM hi IgD Ϫ CD21 ϩ CD23 Ϫ marginal zone or IgM lo IgD hi CD21 ϩ CD23 ϩ follicular mature B cells. 8 Both transitional B-cell subsets appear to be short lived (3 to 4 days) 6 and nondividing in vivo, 9 although recent studies show that T2's proliferate and up-regulate survival signals, whereas T1's die after in vitro BCR engagement. 10 Moreover, T1's express CD95 but not the antiapoptotic molecule bcl-2, 7 further suggesting that T1 might be the target of the B-cell-negative selection occurring in the periphery. 11 Such transitional B-cell subsets have not yet been defined in humans. Current characterization of human peripheral blood (PB) B cells is based on the expression of the tumor necrosis factor family member CD27, which distinguishes unmutated IgM ϩ IgD ϩ CD27 Ϫ naive cells (approximately 60% in adults) from somatically hypermutated CD27 ϩ memory cells (40%, of which approximately 40% are IgM ϩ IgD ϩ ). 12 Naive B cells may be the target of negative selection, since heavy chain variable region (V H ) usage as well as the V H complementarity determining region 3 (CDR3) length changes in peripheral mature B cells. [13][14][15] The analysis of primary immune deficiencies is a powerful tool for the study of normal human B-cell differentiation. Immunodeficiency, centromeric region instability, and facial anomalies (ICF) disease is a rare autosomal recessive syndrome, characterized by chromosomal instability and humoral immune deficiency. Patients present recurrent respiratory infections and diarrhea as consequence of hypogammaglobulinemia or agammaglobulinemia, sometimes associated with defective cell-mediated immunity. 16 Developmental defects such as delayed developmental milestones, facial dismorphy (eg, roundness, hypertelorism, macroglossia), and mental retardation have also been observed. Cytogenetic abnormalities include elongation of centromeric or juxtacentromeric heterochromatin of chromosomes 1, 9, and 16, leading to formation of multiradiate figures involving mainly chromosomes 1 and 16. 17 ICF patients show ma...
