As a result of advances in the development of monoclonal antibodies to leukocyte cell surface antigens and flow cytometry, it is possible to resolve various stages of murine and human B-cell development from the hematopoietic stem cell (HSC) to newly produced, surface IgM expressing B cells.
Murine B-Cell Development
As the progeny of murine HSCs differentiate, they generate multipotent progenitors (MPPs). MPPs include four phenotypically separable subsets; MPP1s are short-term HSCs, MPP2s and MPP3s are myeloerythroid biased, and MPP4s primarily generate lymphoid progeny. MPP4s are presumably the precursors of most lineage-negative (Lin−) CD117(c-kit)low Sca-1low CD127+ (interleukin-7 receptor α) common lymphoid progenitors (CLPs). Lin− indicates that the cells lack expression of determinants present on mature myeloid, erythroid, and lymphoid lineage cells. CLPs then mature through pre-pro-B, pro-B, pre-B-, and B-cell stages of development that can be phenotypically resolved based on their expression of various cell surface and cytoplasmic determinants (Fig. 1). The stages of development depicted in Fig. 1 are based on the scheme originally defined by Hardy.
Fig1. HEMATOPOIESIS WITH AN EMPHASIS ON B-CELL DEVELOPMENT. Human and mouse B-cell differentiation and selected cell surface and cytoplasmic determinants used to distinguish various stages of development are shown. Newly produced B cells migrate to the spleen and mature through transitional cell stages into marginal zone or follicular B cells. CLP, Common lymphoid progenitor; CMP, common myeloid progenitor; FO, follicular B cells; HSC, hematopoietic stem cell; MPP, multipotential progenitor; MZ, marginal zone B cells; T1, transitional 1 B cells; T2, transitional 2 B cells.
Human B-Cell Development
The human MPP compartment is not as well defined as in the mouse, but various downstream stages of development which parallel those in the mouse can be phenotypically identified. For example, CLPs sequentially generate pro-B, pre-B, and B cells each of which expresses distinct combinations of cell surface determinants. Fig. 1 shows that human pre-B and newly produced B cells express CD20. It is relevant to note this determinant because antibodies that recognize it (rituximab) are in widespread clinical use for the treatment of lymphoma and, increasingly, autoimmune diseases.
Developing and mature B-lineage cells express additional cell surface determinants that include CD21, CD22, CD24, CD38, and CD40, several of which are linked to critical intracellular signaling pathways.
