The majority of patients with early-onset hypogammaglobulinemia and absent B cells are males with X-linked agammaglobulinemia (29
). These patients have mutations in the hematopoietic-specific cytoplasmic tyrosine kinase Btk (22
). The remaining patients appear to have a heterogeneous group of disorders. We have recently shown that some of these patients have mutations in μ heavy chain (26
) or λ5/14.1 (18
), both of which are components of the pre-BCR complex (31
). To determine whether defects in other components of the pre-BCR might result in immunodeficiency, we screened DNA from affected patients for mutations in VpreB, Igα, and Igβ. We identified a 2-year-old girl with a homozygous splice defect resulting in the truncation of Igα upstream of the transmembrane domain.
Like patients with defects in μ heavy chain (26
), the patient with mutations in Igα had no detectable CD19+
B cells in the peripheral circulation. Analysis of bone marrow from this patient and a patient with an amino acid substitution in μ heavy chain showed that both patients had normal numbers of pro-B cells but an almost complete absence of pre-B cells. There is considerable variation in the number of pro-B cells in normal individuals, and the number tends to decrease with age. This may explain the slightly higher number of pro-B cells in the patient with Igα deficiency compared with the patient with μ heavy chain defects. The amount and diversity of μ heavy chain V-DJ rearrangements in these 2 disorders were equivalent. Both patients had a small number of transcripts utilizing members of the VH1, VH3, and VH4 families.
Mice that are null for Igα have not been described; however, mice with a truncation in Igα that removes the COOH-terminal 40 amino acids of the cytoplasmic domain, including the ITAM motif, have a relatively mild block in the pro-B to pre-B transition (16
). This suggests that the complete failure of B-cell development in the patient with a truncation in Igα before the transmembrane domain is due to the inability of this protein to escort the μ heavy chain and the Igβ component of the signal-transduction module to the cell surface, rather than the loss of the Igα signaling capacity.
In contrast to our findings in the Igα-deficient patient, which show a block at the pro-B to pre-B transition similar to that seen in μ heavy chain deficiency, studies in mice with defects in Igβ are reported to show decreased V-DJ rearrangement when compared with μ-deficient mice (5
). There are several possible explanations for the discordance between human Igα deficiency and murine Igβ deficiency. Under some circumstances, Igβ may reach the cell surface in the absence of Igα (33
). If homodimeric complexes of Igβ (34
), but not Igα, are expressed, it might be possible for Igβ to transmit signals in the absence of Igα, whereas the reverse would not be true. Alternatively, it is possible that there are signal-transduction pathways that are initiated in the cytoplasm by the ITAM-containing domain of Igβ but not Igα. Finally, despite the overall similarity in early B-cell development in mice compared with humans, there may be differences between the 2 species in the cell-surface expression or signaling capacity of Igα/Igβ complexes.
Complexes containing the Igα/Igβ heterodimer can be detected on the surface of murine B-cell precursors before V-DJ rearrangement (3
); however, attempts to document the expression of the same complex on human pro-B cells have not been successful (2
). It should be noted that it has been more difficult to demonstrate the cell-surface expression of all the components of the pre-BCR in human B-cell precursors compared with murine counterparts. In mice, surrogate light chains form complexes with surrogate heavy chains and can be identified on the surface of pro-B cells in the absence of μ heavy chains (37
). There is some controversy about the existence of similar complexes on human pro-B cells. Some groups have evidence suggesting that these complexes are present (38
), but others maintain that these complexes do not occur (41
). Finally, it appears that the intact pre-BCR is expressed more transiently and at lower intensity in human B-cell precursors compared with murine precursors (1
). Although these differences have sometimes been attributed to the reagents or techniques used to demonstrate the various proteins, true differences between the 2 species may exist.
Murine models of immunodeficiency, in which single genes have been rendered nonfunctional, have dramatically increased our understanding of normal lymphocyte development. However, it is clear that that there is not always complete concordance between mice with defects in a particular gene and patients with mutations in the same gene. Detailed evaluation of patients with single gene defects of the immune system can elucidate the pathways in lymphocyte differentiation that are invariant and highly consistent between species and those that show some flexibility and may vary from 1 species to another. In this study, we have done a side-by-side comparison of B-cell differentiation in 2 patients with defects in different components of the pre-BCR. A patient with a functionally null defect in Igα and a patient with a defect in μ heavy chain that would prevent cell-surface expression of the antigen receptor complex had an identical block in B-cell differentiation. This indicates that in the human, Igα is essential for the expression of the pre-BCR, but, does not appear to play a role in B-cell development until it is expressed along with μ heavy chain as part of the pre-BCR.