Concerted generation of Ig isotype diversity in human fetal bone marrow.
The human fetal bone marrow B cell compartment of 14- to 21-wk gestational age was examined phenotypically and with respect to Ig H chain commitment and diversity. A dramatic expansion of fetal marrow B cell pools at 16- to 18-wk gestational age characterizes a rapid and concerted chain of differentiation events. Transiently up to 1/4 of nucleated marrow cells are CD20+/CD21+ cells which begin to express surface Ig other than IgM. Limiting dilution analysis of EBV-infected marrow cells delineated a virtually exclusive commitment to IgM production until 15 wk and the absolute and relative number of these cells were small (approximately 5% of comparable adult values). In parallel to the rapid increase in total B cell pools size, cells committed and able to secrete any of the five Ig isotypes are generated by 16-wk gestational age and by 18 wk the frequencies of these cells rapidly reach levels typical for adult peripheral tissue such as blood or lymph node. Fetal L chain diversity always anticipated that observed in adult serum. In addition to rising pool sizes and diverse IgH expression, EBV transformability is a major variable during this period of B cell development with up to 2/3 of B lineage cells transformable, about half of which are pre-B cells. By 21-wk gestational age transformable pre-B cells have disappeared and (as in adult tissue) approximately 10 to 20% of CD20+ cells are transformable. The rapid, concerted expression of full H chain diversity during a narrow period in fetal development is unique to marrow and implies a lymphopoietic process in a privileged site rather than an immunologic differentiation event. During this event, the relative proportions between the different IgH classes expressed, resembled that found in adult tissue, perhaps suggesting that B cell inherent programming rather than only antigenic forces determine heavy chain choice. The staggered expression, early in postnatal life, of IgH regions 3' of the C mu locus may reflect regulatory functions rather than inherent immaturity of the B lineage.
Dosch
H M
HM
Division of Immunology/Rheumatology, Hospital for Sick Children, Toronto, Ontario, Canada.
Lam
P
P
Hui
M F
MF
Hibi
T
T
D000328:Adult; D000916:Antibody Diversity; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D001853:Bone Marrow / Q000276:immunology* / Q000378:metabolism / Q000502:physiology; D002454:Cell Differentiation; D002461:Cell Line, Transformed; D005314:Embryonic and Fetal Development; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D006801:Humans; D007132:Immunoglobulin Isotypes / Q000096:biosynthesis* / Q000145:classification / Q000502:physiology; D010641:Phenotype
D007132:Immunoglobulin Isotypes