Aging generates a decline in the ability of the individual to mount protective immune responses. The aged immune system also negatively impacts other important systems, such as the cardiac and nervous systems, by contributing to increased inflammation. The aged immune system not only impacts the quality of life of the individual but also the ability to be protected from infectious agents and cancers. We have shown that aging is associated with autonomous defects in B cells which are important for optimal health because they produce antibodies necessary for responses to vaccines and infectious diseases as well as other functions. These defects/biomarkers include: immunoglobulin (Ig) class switch recombination (CSR), activation-induced cytidine deaminase (AID) and the transcription factor E47. AID is necessary for CSR, the process that generates protective antibodies, and is a good measure of B cell function. We hypothesize that a mechanism for the aged impairment in B cell function, for which we have preliminary data, is that microRNA (miR)-155, miR-16 and other miRs are significantly higher in aged as compared with young adult unstimulated human B cells, making them """"""""refractory"""""""" to further stimulation with the result of lower levels of AID induced after B cell stimulation. The objectives of this proposal are to identify miRs up-regulated in unstimulated B cells from elderly individuals, characterize the molecular pathways for their up-regulation as well as their mechanism of action, and begin to correct these defects by designing oligonucleotides which target these miRs. We propose to sort subsets of B cells, perform a miR microarray and correlate levels of the most increased miRs with AID. In the second aim we will identify molecular mechanisms for increases of particular miRs in aged B cells as well as for particular miRs down-regulating AID. In the third aim we will evaluate if lower in vitro CSR can be """"""""rescued"""""""" by adding oligonucleotides blocking particular miR function (antagomirs) to B cell cultures. The experiments proposed in this grant offer an innovative approach to further characterize mechanisms which decrease B cell responses in elderly individuals. These studies should contribute to development of effective therapeutic strategies to protect elderly individuals from diseases typical of old age.

Public Health Relevance

The studies proposed here investigate new molecular mechanisms for decreased human B cell function in the elderly, important for optimal response to vaccines, infectious diseases, and cancer. The results from the studies proposed here will also help design new protocols of intervention for the improvement of antibody responses in the elderly.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AG042826-02
Application #
8635965
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Fuldner, Rebecca A
Project Start
2013-04-01
Project End
2015-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
2
Fiscal Year
2014
Total Cost
$230,250
Indirect Cost
$80,250
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
Frasca, Daniela; Diaz, Alain; Romero, Maria et al. (2017) Obesity induces pro-inflammatory B cells and impairs B cell function in old mice. Mech Ageing Dev 162:91-99
Frasca, Daniela; Blomberg, Bonnie B; Paganelli, Roberto (2017) Aging, Obesity, and Inflammatory Age-Related Diseases. Front Immunol 8:1745
Diaz, Alain; Romero, Maria; Vazquez, Thomas et al. (2017) Metformin improves in vivo and in vitro B cell function in individuals with obesity and Type-2 Diabetes. Vaccine 35:2694-2700
Frasca, Daniela; Blomberg, Bonnie B (2017) Adipose Tissue Inflammation Induces B Cell Inflammation and Decreases B Cell Function in Aging. Front Immunol 8:1003
Frasca, D; Diaz, A; Romero, M et al. (2017) Ageing and obesity similarly impair antibody responses. Clin Exp Immunol 187:64-70
Frasca, Daniela; Diaz, Alain; Romero, Maria et al. (2016) The generation of memory B cells is maintained, but the antibody response is not, in the elderly after repeated influenza immunizations. Vaccine 34:2834-40
Frasca, Daniela; Blomberg, Bonnie B (2016) Inflammaging decreases adaptive and innate immune responses in mice and humans. Biogerontology 17:7-19
Pinti, Marcello; Appay, Victor; Campisi, Judith et al. (2016) Aging of the immune system: Focus on inflammation and vaccination. Eur J Immunol 46:2286-2301
Frasca, Daniela; Ferracci, Franco; Diaz, Alain et al. (2016) Obesity decreases B cell responses in young and elderly individuals. Obesity (Silver Spring) 24:615-25
Frasca, Daniela; Diaz, Alain; Romero, Maria et al. (2015) MicroRNAs miR-155 and miR-16 Decrease AID and E47 in B Cells from Elderly Individuals. J Immunol 195:2134-40

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