Biomedical subjects

Susan Harless Smith

Publications and source records attributed to Susan Harless Smith.

6 recordsLinked to original sources

PubMed2004

Perspectives on the nature of BCR-mediated survival signals.

In the June 11 issue of Cell, Kraus et al. (2004) show, through conditional mutagenesis, that mature B cells have a drastically reduced life span in the absence of normal B cell antigen receptor (BCR) surface expression or tonic signal transduction. These studies support a role for signal transduction downstream of the BCR, rather than continued surface expression per se for the maintenance and survival of mature B cells in the periphery. Further, these studies exclude transient INF(gamma)-induced activation as a prerequisite to apoptosis in receptor-less cells.

B-Lymphocytes↗

PubMed2003

Critical roles for Rac1 and Rac2 GTPases in B cell development and signaling.

The Rac1 guanosine triphosphatase (GTPase) has been implicated in multiple cellular functions, including actin dynamics, proliferation, apoptosis, adhesion, and migration resulting from signaling by multiple receptors, including the B cell antigen receptor (BCR). We used conditional gene targeting to generate mice with specific Rac1 deficiency in the B cell lineage. In the absence of both Rac1 and the highly related Rac2, B cell development was almost completely blocked. Both GTPases were required to transduce BCR signals leading to proliferation, survival and up-regulation of BAFF-R, a receptor for BAFF, a key survival molecule required for B cell development and maintenance.

Animals↗

PubMed2003

Cutting edge: B cell receptor signals regulate BLyS receptor levels in mature B cells and their immediate progenitors.

This study examines how B lymphocyte stimulator (BLyS) receptor expression and responsiveness are influenced by B cell receptor (BcR) signaling. Our results show that resting and BcR-stimulated B cells are dependent on BLyS for survival and that B cells remain BLyS responsive during BcR-induced activation. Further, BcR ligation up-regulates expression of the BLySR B cell maturation defect/BLySR3 (Bcmd/BR3), but not other known BLySRs. Finally, the coupling of BcR signaling with Bcmd/BR3 expression is limited to late transitional and mature B cells. Together, these findings establish the coupling of BcR signaling with Bcmd/BR3 expression as a fundamental aspect of follicular B cell selection, survival, and activation.

Animals↗

PubMed2003

Peripheral B cell selection and homeostasis.

The size and makeup of mature B cell compartments are controlled by the proportion of immature B cells that complete differentiation, coupled with the average lifespan of mature B cells. Thus, determining the selective and homeostatic factors controlling these parameters is key to understanding how the B cell repertoire is established and maintained. Our previous work defined the developmental stages spanning immature B cell formation in the marrow and final maturation in the periphery. More recently, we have focused on the molecular basis for survival and differentiation within these developmental subsets, with emphasis on the role of BLyS and BLyS receptors. Through developmental and kinetic studies in normal and mutant mice, we have found that BLyS controls peripheral B cell numbers in two ways: by varying the proportion of cells that complete transitional B cell development and by serving as the primary determinant of mature follicular B cell lifespan. Ongoing studies are aimed at determining the mechanism of BLyS activity in these subsets, as well as how BLyS responsiveness is integrated with BcR signaling. Additionally, we have begun studies on how these selective and homeostatic processes change with age. Our results indicate that the size and dynamics of most B cell subsets shift with age, suggesting age-associated alterations in both intrinsic and microenvironmental factors that govern these processes.

Aging↗

PubMed2003

BLyS: the pivotal determinant of peripheral B cell selection and lifespan.

The mechanisms that maintain a steady state pool of B cells that is adequately diverse yet devoid of autoreactivity remain poorly understood. B cells are generated throughout life from pluripotent stem cells and transit a series of phenotypically and functionally defined subsets prior to final maturation in the periphery. Kinetic analyses of these subsets have revealed that considerable cell losses occur during late stages of B cell differentiation, such that only a fraction of newly formed B cells survive to join the mature peripheral pool. These losses reflect the aggregate of negative selection against autoreactive clonotypes and the positive selection of specificities. Because B cell genesis in the marrow is not coupled to peripheral numbers and most mature B cells are quiescent, homeostatic control of the peripheral pool relies largely upon the proportion of B cells that complete maturation and the lifespan of mature B cells. The newly discovered TNF family member, BLyS( trade mark 2), plays a critical role in the maturation, selection and survival of B cells. In these capacities, BLyS acts primarily through the Bcmd/BR3 receptor, affording B cell survival at least in part through the regulation of Bcl-2 family members via NF kappa-B mediated mechanisms. Recent evidence suggests that Bcmd/BR3 receptor expression is controlled by B cell antigen receptor signaling, forging a mechanistic link between specificity based selection and BLyS mediated survival. Our rapidly expanding understanding of BLyS and its receptors may eventually afford novel pharmacologic strategies aimed at the direct manipulation of peripheral B cell selection and homeostasis.

Animals↗

PubMed2003

Integrating B cell homeostasis and selection with BLyS.

The mechanisms that maintain a pool of B cells that is adequately diverse yet devoid of pathogenic autoreactivity remain poorly understood. B cells complete maturation after migrating to the periphery, where they transit several intermediate developmental stages prior to recruitment into the long-lived primary pool. Since B lineage commitment is not coupled to peripheral B cell numbers and most mature peripheral B cells are quiescent, the sizes of mature peripheral compartments are primarily determined by the proportion of immature B cells that survive transit through later developmental stages, coupled with the longevity of mature B cells themselves. Compelling evidence indicates that the B cell antigen receptor (BcR) plays an essential role in all of these processes, but further findings indicate a similar role for the recently described tumor necrosis factor family member B lymphocyte stimulator (BLyS). Signaling through the BLyS receptor, Bcmd/BR3, controls B cell numbers in two ways: by varying the proportion of cells that complete transitional B cell development, and by serving as the primary determinant of mature B cell longevity. The striking congruence of BcR- and BLyS-mediated effects on B cell selection and survival suggests these pathways may be related. The recent discovery that BcR signaling is selectively coupled to Bcmd/BR3 expression links BcR- and BLyS-mediated activities in transitional and mature B cells, suggesting specificity-based selection and survival may be mechanistically similar processes.

Animals↗