This review has summarized the evidence indicating that far more B cells are produced in adult bone marrow than are required to maintain B cell numbers in the periphery. It is shown that most if not all these newly-formed B cells have the potential to become mature peripheral B cells. However, to do this they need to receive an appropriate signal in secondary lymphoid organs. Cells failing to receive such a signal die after a brief period. Two separate situations have been identified which result in recruitment of newly-formed virgin B cells into the peripheral B-cell pool: Following activation by antigen. When the peripheral B-cell pool has been depleted. It is proposed that the first of these signals requires T help and is initiated by antigen presented on interdigitating cells in extrafollicular areas of secondary lymphoid organs. This process seems to be confined to periods immediately following administration of antigen and does not continue in established immune responses to thymus-dependent antigens. It seems probable that continued B cell activation, occurring during long term antibody responses, takes place in the follicles of secondary lymphoid organs and is driven by antigen presented on follicular dendritic cells. Indirect evidence is cited which suggests that somatic mutation in rearranged immunoglobulin V-region genes occurs mainly following B-cell activation in follicles and not during primary B lymphopoiesis. It is suggested that this may involve a hypermutation process which is switched on in activated B cells in germinal centers. Evidence is presented suggesting that plasma cells generated from B cells activated early in immune responses have an average life-span of less than 3 d. However, plasma cells generated in established responses appear to have an average life-span in excess of 20 d. Later sections in the review consider how B-cell recruitment in thymus-independent antibody responses differs markedly from recruitment during thymus-dependent responses. The possible role of splenic marginal zone B cells in some thymus-independent antibody responses is discussed and the evidence indicating that SIgM + ve, IgD-ve marginal zone B cells develop as a distinct population from recirculating SIgM + ve, IgD + ve B cells is summarized.

Antigen-driven selection of virgin and memory B cells.

The first part of this article discusses the isolation and characterization of several monoclonal antibodies to the B lineage-specific surface molecule, B220. B220 was shown to be expressed on precursors of B cells by the demonstration that removal of B220+ cells from B cell-depleted bone marrow removes the ability of bone marrow to regenerate B cells. Although these antibodies recognize a broad range of differentiation stages within the B lineage, they can be used to isolate highly enriched populations of pre-B cells from mouse bone marrow. We also describe the use of antibodies to the surface markers B220 and ThB to define two sequential stages of pre-B cell differentiation. A simplified diagram of our current view of the B lineage differentiation sequence is shown in Figure 4. No attempt has been made to include the various functionally defined B cell subsets on this diagram since we know almost nothing about the expression of these two surface markers on them. This model reflects an assumption that the early part of B cell differentiation is a linear rather than a branching pathway. At present, there is no evidence for a branching pathway, but little evidence against it either. B220 is the first B cell-specific molecule known to be expressed during differentiation and it continues to be expressed on most subsequent B lineage cells. In this regard, it resembles the Thy-1 molecule on thymus-derived lymphocytes and, like Thy-1, B220 should be quite useful for identifying and classifying B lineage cells. One example of this is the use of B220 expression to clearly assign germinal center cells to the B lineage. The example of Thy-1+, RA3-2C2+ cells from mice with the lpr/lpr genotype, however, suggests that some caution should be used when interpreting data, especially with pathological samples. The availability of substantially purified pre-B cell populations has made it possible to follow changes in immunoglobulin gene organization and expression during differentiation. Our current understanding of these events is also shown in Figure 4, correlated with cell surface phenotype. The large pre-B cell population has extensive heavy chain rearrangements and synthesizes significant quantities of mu heavy chain, but does not yet have detectable light chain gene rearrangement. The small pre-B population consists of two cell types, some with kappa gene rearrangement and some without. This suggests that kappa rearrangement occurs within this cell population, which is homogeneous with respect to morphology and surface phenotype. The asynchrony of heavy and light chain gene rearrangement results in an asynchrony at the level of expression of these genes as well, but the purpose of this remains one of many unanswered questions about pre-B cell differentiation. Now that it is possible to identify, isolate, and manipulate pre-B cells as readily as B or T cells, many of these questions may now be addressed.

Surface Antigen Expression and Immunoglobulin Gene Rearrangement During Mouse pre‐B Cell Development

Large lymphoid cells containing small amounts of cytoplasmic IgM (clgM) but undetectable surface immunoglobulin (slg) have recently been recognized as precursors of B lymphocytes. They are a small, rapidly dividing pool of normal marrow lymphoblasts. Since lymphoblasts in most childhood acute lymphoblastic leukemias lack slg and other conventional B-lymphocyte and T-lymphocyte markers, we examined the possibility that some leukemias represent "pre-B"-cell neoplasms. In four of 22 consecutive patients, leukemic cells had the clgM+.slg- phenotype of pre-B cells. These patients' cells shared "common acute-lymphoblastic-leukemia" antigens and "B-cell" alloantigens, but differed in expression of several developmental features characteristic of the B-cell line. Pre-B-cell leukemias were readily responsive to chemotherapy. We conclude that a distinct subpopulation of previously unclassified leukemias reflects oncogenic transformation at the earliest recognizable stage in differentiation along the B-cell axis.

https://www.nejm.org/doi/pdf/10.1056/NEJM197804202981603?listPDF=true

Pre-B-cell leukemia. A new phenotype of childhood lymphoblastic leukemia.

The monoclonal antibody, RA3-2C2, appears to be specific for cells within the B cell lineage. This antibody does not recognize thymocytes, peripheral T cells, or nonlymphoid hematopoietic cells in the spleen or bone marrow. Nor does it recognize the pluripotent hematopoietic stem cells, the spleen colony-forming unit, All sIg+ B cells and most plasma cells are RA3-2C2+. In addition, approximately 20% of nucleated bone marrow cells are RA3-2C2+ but sIg-. This population contains B cell precursors that can give rise to sIg+ cells within 2 d in vitro.

/pdf/a-monoclonal-antibody-that-recognizes-b-cells-and-b-cell-n65khoynip.pdf

A monoclonal antibody that recognizes B cells and B cell precursors in mice.

Analysis of the B-cell progenitor compartment at the level of single cells

With the use of immunofluorescence techniques, cells containing cytoplasmic IgM (cIgM + ), but lacking detectable surface IgM (sIgM + ), have been identified in mouse fetal liver and adult bone marrow as a distinct cell population to sIgM + B lymphocytes. We have shown that there is a considerable difference in the rate of entry of cIgM + and sIgM + cells into DNA synthesis in these locations. Moreover, within the cIgM + population, the largest cells are the main group entering DNA synthesis. Our results are compatible with the notion that a pool of rapidly proliferating, large cIgM + cells is present in fetal liver and adult bone marrow and that these cells give rise to populations of smaller cIgM + cells, which move out of cell cycle, and convert to sIgM + B lymphocytes. However, we recognize that this interpretation is speculative. Finally, we have shown that fetal bone marrow is a site of generation of sIgM + B lymphocytes, but the question as to whether these cells are derived from Ig - precursors within marrow itself remains open.

Studies on the Generation of B Lymphocytes in Fetal Liver and Bone Marrow

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Studies on the Generation of B Lymphocytes in Fetal Liver and Bone Marrow