Early pre-B cells from normal and X-linked agammaglobulinaemia produce C mu without an attached VH region.

Differentiation of B lymphocytes follows an ordered pathway marked by somatic rearrangements of immunoglobulin heavy- and light-chain genes in conjunction with cellular transitions. Although low level constitutive transcription of the mu heavy-chain constant region (C mu) genes may occur in early precursor cells, activation of synthesis and translation of complete mu RNA is thought to accompany somatic rearrangements of DNA. Cytoplasmic mu-chain protein serves as a marker for pre-B cells, the earliest cells committed to differentiation into B lymphocytes, mu-chain gene expression in pre-B cells pre-cedes rearrangement and expression of light-chain genes. We now report that early human pre-B cells, Epstein--Barr virus transformed pre-B cells, and pre-B cell hybrid analogues, produce C mu without the normally associated heavy-chain variable (VH) region. Approximately 5% of normal pre-B cells from adult human bone marrow produce these incomplete mu-chains. Pre-B cells from three patients with X-linked agammaglobulinaemia are exclusively of this immature form, producing C mu without associated VH. This immune deficiency disease represents a block in differentiation secondary to failure to express VH genes.