B lymphopoiesis is severely compromised in murine senescence. The defect in B lymphopoiesis in senescence predominantly """"""""maps"""""""" to the pro-B to pre-B cell transition, a stage critically dependent upon signaling via the pre-B cell receptor (ix/_.5/VpreB; preBCR) and the growth cytokine IL-7. We propose that in senescence the development ofpre-B cells is subject to increasingly stringent negative selection. This results primarily from decline in expression of the preBCR, poor responses to IL-7, and increased susceptibility to apoptosis. Rather than random loss of pre-B cells in old age, we propose contraction of the pre-B cell pool in a clone-specific manner. Preferentially selected would be those few pre-B ceils which maintain the capacity to undergo preBCR/IL-7 mediated growth and survival. This results in a """"""""reshaping"""""""" of the pre-B and immature B cell specificity repertoires in senescence. To address this hypothesis, we propose 3 Specific Aims.
Specific Aim 1 asks """"""""Is the loss of pre-B cells in old age random or clone-specific?"""""""". In this Specific Aim, Vh family use, CDR3 diversity, capacity to express functional preBCRs, and the role of the microenvironment in altering B lineage development and """"""""read-out"""""""" of the antibody repertoire will be addressed.
Specific Aim 2 asks """"""""Does 'repertoire reshaping' at the pre-B stage affect the read-out of the B cell repertoire in old age?"""""""". Here, Vh use and CDR3 diversity will be assessed in immature B cells from aged mice and compared with that of pre-B cells. Furthermore, the antibody specificity of immature B cells in aged mice will be assessed and the fate of these immature B cells in the periphery will be determined.
Specific Aim 3 asks """"""""Does apoptotic stress result in changes in the pre-B and immature B cell repertoires in senescence?"""""""". Sensitivity to apoptosis and the expression of apoptotic/survival molecules in aged B cells will be determined. The effects of the environment on apoptotic susceptibility among aged B lineage cells will be assessed. Finally, the role of apoptosis in modulating the pre-B/immature B cell repertoires in senescence will be tested. These studies will advance understanding of the immune defects which accompany old age and their cellular and molecular mechanisms.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG025256-04
Application #
7268708
Study Section
Special Emphasis Panel (ZRG1-CMAD (01))
Program Officer
Fuldner, Rebecca A
Project Start
2004-09-30
Project End
2009-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
4
Fiscal Year
2007
Total Cost
$287,299
Indirect Cost
Name
University of Miami School of Medicine
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Riley, Richard L; Khomtchouk, Kelly; Blomberg, Bonnie B (2018) Inflammatory immune cells may impair the preBCR checkpoint, reduce new B cell production, and alter the antibody repertoire in old age. Exp Gerontol 105:87-93
Riley, Richard L; Khomtchouk, Kelly; Blomberg, Bonnie B (2017) Age-associated B cells (ABC) inhibit B lymphopoiesis and alter antibody repertoires in old age. Cell Immunol 321:61-67
Khomtchouk, Kelly; Alter, Sarah; Ratliff, Michelle et al. (2017) In old BALB/c mice, bone marrow pre-B cell and surrogate light chain reduction is associated with increased B cell reactivity to phosphorylcholine, but reduced T15 idiotype dominance. Mech Ageing Dev 162:53-62
Ratliff, Michelle; Alter, Sarah; McAvoy, Kelly et al. (2015) In aged mice, low surrogate light chain promotes pro-B-cell apoptotic resistance, compromises the PreBCR checkpoint, and favors generation of autoreactive, phosphorylcholine-specific B cells. Aging Cell 14:382-90
Riley, Richard L (2013) Impaired B lymphopoiesis in old age: a role for inflammatory B cells? Immunol Res 57:361-9
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
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
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

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