In the past funding period, we focused on the production of new, immature B-cells in aged mice by assessing kinetics of production, number of cells produced/day, and population turnover in the bone marrow and spleen. We found that B-lineage precursors decline with age, but newly-made B cells are generated in the bone marrow of aged animals at about the same rate as that observed in young animals. In spite of ongoing formation of new B-cells in the aged, few of these newly-made B-cells become part of the transitional or mature B-cell pools in the spleens. Kinetic studies indicate that splenic B-cells turn over very slowly and are long-lived in aged mice. We and others have concluded that B-cell homeostasis differs in aged mice from the well described homeostatic patterns of young mice. Furthermore, our results imply that a major defect is the inability of immature B-cells to join the peripheral B cell compartments. Adoptive transfer studies show that even young immature B-cells cannot home effectively to an aged spleen, suggesting a deficiency in the aged tissue microenvironment. In contrast, immature B-cells from aged mice are equally able to home to spleen compared to those from young mice. The tissue architecture of aged spleen and lymph nodes is disrupted in appearance and chemokine production is reduced, which likely alters lymphocyte migration and homeostasis. Thus, our results emphasize the acute need to know more about how immune homeostasis changes with age. Two general premises are addressed in this renewal application: (1) We hypothesize that B-cell homeostasis changes because the marrow and splenic microenvironments are altered during aging. (2) We propose that alterations in the microenvironments are modulated by changes in the types of B-cells populating the marrow and secondary tissues.
Aim I will define the deficiencies of the aged lymphoid microenvironment that affect B-cell homeostasis and the homing and retention of newly-made B-cells.
Aim II addresses the hypothesis that the long-lived, mature B-cells found in the spleens of aged mice are insufficient to maintain chemokine production and normal lymphoid compartmentalization.
Aim III proposes that mature and effector B-cell populations (plasma cells), which are retained in bone marrow in increasing numbers with age, actually alter the ability of marrow stromal cells to function in B-lymphopoiesis. We believe that changes in B-cell homeostasis may predict poor immune function in the aged. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
2R01AG013874-05A2
Application #
7104697
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Fuldner, Rebecca A
Project Start
1997-09-30
Project End
2010-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
5
Fiscal Year
2006
Total Cost
$284,540
Indirect Cost
Name
Loyola University Chicago
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
791277940
City
Maywood
State
IL
Country
United States
Zip Code
60153
Zook, Erin C; Zhang, Shubin; Gerstein, Rachel M et al. (2013) Enhancing T lineage production in aged mice: a novel function of Foxn1 in the bone marrow niche. J Immunol 191:5583-93
Birjandi, Shirin Z; Ippolito, Jill A; Ramadorai, Anand K et al. (2011) Alterations in marginal zone macrophages and marginal zone B cells in old mice. J Immunol 186:3441-51
Zook, Erin C; Krishack, Paulette A; Zhang, Shubin et al. (2011) Overexpression of Foxn1 attenuates age-associated thymic involution and prevents the expansion of peripheral CD4 memory T cells. Blood 118:5723-31
Wols, Heather A Minges; Johnson, Kara M; Ippolito, Jill A et al. (2010) Migration of immature and mature B cells in the aged microenvironment. Immunology 129:278-90
Minges Wols, Heather A; Witte, Pamela L (2008) Plasma cell purification from murine bone marrow using a two-step isolation approach. J Immunol Methods 329:219-24
Minges Wols, Heather A; Ippolito, Jill A; Yu, Zheng et al. (2007) The effects of microenvironment and internal programming on plasma cell survival. Int Immunol 19:837-46
Pifer, Jeannette; Stephan, Robert P; Lill-Elghanian, Deborah A et al. (2003) Role of stromal cells and their products in protecting young and aged B-lineage precursors from dexamethasone-induced apoptosis. Mech Ageing Dev 124:207-18
Minges Wols, Heather A; Underhill, Gregory H; Kansas, Geoffrey S et al. (2002) The role of bone marrow-derived stromal cells in the maintenance of plasma cell longevity. J Immunol 169:4213-21
Gray Parkin, Kirstin; Stephan, Robert P; Apilado, Ron-Gran et al. (2002) Expression of CD28 by bone marrow stromal cells and its involvement in B lymphopoiesis. J Immunol 169:2292-302
Underhill, Gregory H; Minges Wols, Heather A; Fornek, Jamie L et al. (2002) IgG plasma cells display a unique spectrum of leukocyte adhesion and homing molecules. Blood 99:2905-12

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