To B or Not to B? Glucocorticoid Impact on B Lymphocyte Fate and Function

Abstract

Lymphocytes have been used to study the action of glucocorticoids for more than a half-century. Although it had been recognized that adrenal steroids administered in vivo could cause atrophy of the thymus and lymph nodes of the rat (1), Dr Allan Munck and his colleagues were the first to show that a specific biochemical change (reduction in glucose use) could be elicited by glucocorticoids acting on thymocytes and that these effects seem to be mediated through hormone interaction with highly specific intracellular binding sites (2–5). These receptors were also recognized to mediate the apoptotic response of lymphoid cells of some species, and murine lymphoma cell lines that exhibited resistance to these lytic effects of glucocorticoids were used as a tool to explore the structure-function relationships of the glucocorticoid receptor (GR) (6–9). The power of this approach drove many important discoveries in the field of steroid hormone action. In what has seemed at times like a parallel universe, glucocorticoids were being applied in the clinical setting for the control of both normal and abnormal immune system function long before we knew anything about how they worked (10). These hormonal compounds were used to treat patients with immune system neoplasms and autoimmune, allergic, or inflammatory diseases as well as those undergoing organ transplantation, even though the mechanisms by which these various clinical effects were mediated remained largely obscure. We have now begun to recognize that the glucocorticoid actions on the immune system likely extend beyond apoptotic responses and suppression of cytokine gene expression in thymus-derived lymphocytes (11). This recognition has led to the expectation that other specific cellular and molecular targets of glucocorticoids can be identified in the immune system and, hopefully, exploited for therapeutic application in the clinical setting. In this issue of Endocrinology, Gruver-Yates et al (12) present an exploration of the expression of the GR across the developmental pathway of (bone marrow derived) Blymphocytes, the antibody-producing cells of the humoral immune system. The authors use flow cytometric techniques to meticulously characterize GR expression in immature B cell subsets extracted from bone marrow and from peripheral lymphoid organs, and they demonstrate functionality of these receptors by assessing the apoptotic responses of these cells to glucocorticoids administered in vitro and in vivo. Their results are of particular interest in that they identify B-lymphocytes at all stages of development as potential targets of glucocorticoid action. Although endocrinologists seem to have heretofore largely ignored the B lymphocyte as a glucocorticoid target, immunologists (for at least a time) showed considerable interest in the idea. In vivo experiments in humans receiving supraphysiological doses of exogenous glucocorticoids [100 or 400 mg of hydrocortisone (13) or 60 mg of prednisone (14)] resulted in transient reductions in the number of circulating lymphocytes after 4–6 hours. These effects reverted to normal by 24 hours. The most pronounced reductions occurred in T cells, but circulating B cell numbers were also reduced by nearly 50% (14). The ability of the remaining circulating lymphocytes to respond to phytohemagglutinin (a T cell mitogen) was unaltered, but responses to pokeweed mitogen (a B cell mitogen) were reduced by the highest dose of hydrocortisone (13). Because previous studies had demonstrated resistance of human lymphoid cells to glucocorticoid-mediated lysis (15), the investigators interpreted their findings in