B lymphopoiesis is severely compromised in murine senescence. While there are defects at several distinct stages in the B lymphopoietic pathway in old age, down-regulation at the pro-B to pre-B cell transition likely has a major role in altering the composition of the B cell antibody repertoire. This transition is particularly dependent upon expression of and signaling by the pre-B cell receptor (preBCR), a complex of immunoglobulin 5 heavy chain associated with the surrogate light chains l5 and VpreB. Aged mice have significantly reduced expression of surrogate light chains and poor preBCR function. This results in progressive alteration of the 5 heavy chain repertoire in newly formed B cells in aged mice. However, rather than a random loss of pre-B cells in old age, we propose that the aged pre-B compartment will become skewed in favor of those pre-B cells that undergo positive selection even when surrogate light chain is highly reduced. Moreover, we propose that increases in autoreactivity as well as detrimental changes in the availability of protective antibody responses to pathogens, e.g., S. pneumoniae, are, in part, due to a compromised preBCR checkpoint. To address this hypothesis, we propose 3 integrated Specific Aims.
In Specific Aim 1, we ask "Does compromise of the preBCR checkpoint in old age 'reshape'the Vh repertoire and promote autoreactivity"? Here, the effects of diminished preBCR function on 5 heavy chain usage, and capacity to signal when surrogate light chain is low, will be determined together with impact on autoreactivity.
Specific Aim 2 addresses the fate of autoreactive immature B cells within the bone marrow of aged mice and their contribution to the peripheral B cell pools. Tolerance among immature B cells in aged mice, their capacity to home to the spleen, and, importantly, the expression of protective versus non-protective clonotypes in response to the S. pneumoniae antigen phosphorylcholine will be assessed.
Specific Aim 3 focuses upon the importance of proinflammatory cytokines (TNFa) and effector cells (NK) in triggering the down-regulation of preBCR, altering both B lymphopoiesis and antibody repertoires in aged mice. These studies will advance understanding of the immune defects that accompany old age and their cellular and molecular mechanisms.

Public Health Relevance

The development of new antibody producing B cells is compromised in old age. This may result in both poor antibody protective responses to pathogens in disease as well as to vaccination. Our studies focus on the mechanisms that affect antibody producing B cell production in old age, primarily the role of the pre-B cell receptor complex. Insight into the defects in B cell production in old age may reveal their influence on developing and maintaining effective immune barriers to infectious disease. The development of new antibody producing B cells is compromised in old age. This may result in both poor antibody protective responses to pathogens in disease as well as to vaccination. Our studies focus on the mechanisms that affect antibody producing B cell production in old age, primarily the role of the pre-B cell receptor complex. Insight into the defects in B cell production in old age may reveal their influence on developing and maintaining effective immune barriers to infectious disease.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01AG025256-10
Application #
8723008
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Fuldner, Rebecca A
Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Miami School of Medicine
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Ratliff, Michelle; Alter, Sarah; Frasca, Daniela et al. (2013) In senescence, age-associated B cells secrete TNF? and inhibit survival of B-cell precursors. Aging Cell 12:303-11
Scholz, Jean L; Diaz, Alain; Riley, Richard L et al. (2013) A comparative review of aging and B cell function in mice and humans. Curr Opin Immunol 25:504-10
Frasca, Daniela; Romero, Maria; Diaz, Alain et al. (2012) A molecular mechanism for TNF-?-mediated downregulation of B cell responses. J Immunol 188:279-86
Landin, Ana M; Frasca, Daniela; Harrison, Patrick et al. (2011) E47 retroviral rescue of intrinsic B-cell defects in senescent mice. Aging Cell 10:327-37
Frasca, Daniela; Romero, Maria; Landin, Ana Marie et al. (2010) Protein phosphatase 2A (PP2A) is increased in old murine B cells and mediates p38 MAPK/tristetraprolin dephosphorylation and E47 mRNA instability. Mech Ageing Dev 131:306-14
King, Anne M; Keating, Patricia; Prabhu, Anjali et al. (2009) NK cells in the CD19- B220+ bone marrow fraction are increased in senescence and reduce E2A and surrogate light chain proteins in B cell precursors. Mech Ageing Dev 130:384-92
Alter-Wolf, Sarah; Blomberg, Bonnie B; Riley, Richard L (2009) Old mice retain bone marrow B1 progenitors, but lose B2 precursors, and exhibit altered immature B cell phenotype and light chain usage. Mech Ageing Dev 130:401-8
Frasca, Daniela; Landin, Ana Marie; Riley, Richard L et al. (2008) Mechanisms for decreased function of B cells in aged mice and humans. J Immunol 180:2741-6
Frasca, Daniela; Landin, Ana Marie; Lechner, Suzanne C et al. (2008) Aging down-regulates the transcription factor E2A, activation-induced cytidine deaminase, and Ig class switch in human B cells. J Immunol 180:5283-90
Frasca, Daniela; Riley, Richard L; Blomberg, Bonnie B (2007) Aging murine B cells have decreased class switch induced by anti-CD40 or BAFF. Exp Gerontol 42:192-203

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