Early Events in Mammalian B-Cell Differentiation

Oklahoma Medical Research Foundation, Oklahoma City OK

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Abstract

Large numbers of B lymphocytes are produced within bone marrow throughout life, constantly replenishing the humoral immune system. It is important to understand how this process is controlled and experiments with mice suggest that two categories of steroid hormones have important roles. Hormone withdrawal through castration, mutation or adrenalectomy increases lymphopoietic activity while experimental treatment with estrogen or glucocorticoids selectively suppresses lymphocyte formation in marrow. There is unfortunately little information about long- range consequences for humans who are deliberately or environmentally exposed to many related compounds. Until recently, it has been difficult to identify the cellular targets of these hormones and perform meaningful studies of molecular mechanisms. However, there have been steady improvements in resolution and sorting of rare subsets of marrow precursors, as well as defined conditions for their propagation in culture. The result is that we now have much better insight into early differentiation pathways through which stem cells give rise to precursors of B, T and NK cells. Several findings suggest that these lineages diverge from myeloid and erythroid progenitors at, or just before, a hormone sensitive stage. Ongoing studies will clarify when such lineage fate decisions are made and reveal how hormones selectively influence them. While steroid hormones can regulate stromal cells within bone marrow, it is now clear that rare early lymphocyte precursors are also direct targets. Ongoing studies will investigate what hormone receptors are utilized and molecular consequences of receptor ligation. Surprisingly, the immune system develops during embryonic life although estrogen levels are high and sufficient to suppress lymphocyte formation in maternal bone marrow. This may now be explained by developmentally dependent control of sex steroid receptors. The first appearance of these receptors on neonatal hematopoietic cells will be carefully documented and environmental control of this process investigated. The studies are providing basic information about lymphocyte production that should ultimately help understand, manage and cure immunodeficiency, autoimmune and malignant diseases.