Richard Riley, Ph.D.
Professor of Microbiology & Immunology
Description of Research
Altered B Cell Development in Senescence. Senescent mice show diminished B lymphopoiesis when compared to young mice and typically exhibit decreased numbers of pre-B cells and newly formed B cells within the bone marrow. Dr. Riley’s laboratory has focused upon elucidating the mechanisms responsible for the altered B lymphopoiesis in old age and also the ramifications for antibody repertoire and humoral immunity. In particular, they have found that B lymphopoiesis in old age is partially interrupted at the pro-B to pre-B cell transition, a developmental step which requires both function of the pre-B cell receptor complex and responses to the growth and survival cytokine IL-7. Expression of a critical component of the pre-B cell receptor, the surrogate light chain, is reduced in aged mice and IL-7 responsiveness is diminished. This predisposes the B cell precursors in aged mice to apoptotic cell death. These functions, and others important to B cell development, are governed, in part, via the transcriptional regulator E2A. E2A expression is also compromised in old age; this appears to involve enhanced degradation of E2A proteins. As a consequence of the B cell developmental deficits in old age, the repertoire of antibody specificities is skewed and capacity to develop effective immune responses is hindered.
More recently, we have determined that a distinct subset of mature B cells, called Age-associated B Cells (or ABC), are expanded in the spleen and bone marrow of aged mice. The ABC mediate, via TNFa, apoptosis in B cell precursors and contribute to both a pro-inflammatory bone marrow microenvironment and the loss of B lymphopoiesis in old age. ABC are likely “chronically activated or exhausted” B cells; initial analyses of antibody repertoires suggest that ABC are selected by particular apoptotic cell antigens.
Importantly, the relative sensitivity of B cell precursors to apoptosis induced by ABC and pro-inflammatory cytokines is dictated by the levels of unique molecular complexes of surface proteins with the SLC. In pro-B cells, this complex is made up of a non-classical cadherin, cadherin 17, and the SLC while in pre-B cells, the mu Ig heavy chain together with SLC forms the pre-B cell receptor (preBCR). Altered survival of pro-B and pre-B cells in older adults may be pertinent to the etiology of and treatments for Acute Lymphoblastic Leukemia (ALL). The survival vs. apoptosis in B cell precursors is apparently regulated, in part, by the nature of the SLC containing complex: apoptosis is favored by signaling via the cadherin 17/SLC complex in pro-B cells; survival is favored by preBCR signaling in pre-B cells. These properties may regulate the normal homeostasis of pro-B vs. pre-B cells within the bone marrow, contribute to alterations in B cell precursors in old age, and possibly affect susceptibility to transformation.
- A key transcription factor (E2A) and the SLC, both of which are critical to B lineage cell development, are decreased in aged B cell precursors. This provides a molecular basis for understanding deficient B lymphopoiesis in senescence.
- A unique population of B cells (ABC) is expanded in the bone marrow of old mice, produces TNFa, and induces pro-B cell apoptosis both in vitro and in vivo. This provides a new model for understanding the deficits in B lymphopoiesis seen in old age and the connection with inflammation.
- The cadherin/SLC and preBCR complexes regulate susceptibility of B cell precursors to apoptosis. This provides a conceptual framework to address not only constraints on new B cell production in old age, but also susceptibility of B cell precursors in the elderly to tumor formation.