Immunosenescence-
Results of BELFRAIL (and INCIVAR)
By Adriaensen Wim
Department of Public Health and Primary Care, KU Leuven & UCL, Belgium
What is Immunosenescence?
Aging of the immune system
While all components of innate and adaptive immunity are changed with age, the clinical impact of these changes is not clear, and mechanisms of and markers for immunosenesenescence are controversial.
contribute to morbidity and mortality in the elderly
Increased incidence of infectious diseases, cancers, cardiovascular diseases and neurodegeneration.
Decreased response to vaccination
HallmarksThe HALLMARKS of immunosenescence are:
• T-cell senescence
• Inflammageing or low grade chronic systemic inflammation
Inflammageing seems to underlie most of the age-related diseases (atherosclerosis, diabetes, osteoporosis, sarcopenia, etc) and seems to be related to mortality of all causes in older persons
Lymf
Naïve T-cell
B cell
Helper T-cel
Cytotoxic T-cel
APC
Plasmacel
CD8+ CD4+
Diff
ere
ntia
tion
Cytokines
Longitudinal studies
BELFRAIL (started in 2008) a population-based prospective cohort study of the very elderly in
Belgium (80 years or older) Investigate association of hallmarks of immunosenescence
and functional performance or mortality
INCIVAR (started in 2012) Community-based cohort study Investigate consequence of immunosenescence: reduced
Influenza vaccination response
Hallmark 1:Inflammageing
BELFRAIL - Inflammageing
Extensive set of serum inflammatory markers
IL-6 best mortality predictor
Lesser extent:hCRPIL-10IL-1β
IL-6 robust marker in very elderly
Can be 100 times as high as in adults Good marker in this age-category
Was most robustly associated with both impaired global functioning (cross-sectional) and global functioning decline (longitudinal).
Elevated serum inflammatory markers could maybe summarize global functional burden, because inflammation may be a common underlying cause of physical and mental impairment or have a final common pathway.
Previous literature
Cytokine dysregulation is believed to play a key role in the remodeling of the immune responses and physiological changes.
IL-6, TNF-α and CRP have been found to be related or to predict physical disability, with IL-6 as the most robust predictor
Il-1b, IL-6, IL-8, TNF-α and CRP have been associated with cognitive decline and dementia
is not validated in very elderly individuals, not consistent
Ideal inflammatory markers of clinical relevance to predict GLOBAL functioning?
Cross-sectional: Global impairment
Longitudinal: Global decline
Hallmark 2:T-cell senescence
BELFRAIL : T-cell Senescence
Primarily in the CD8+ T-cell subset
filling up the immunological space with memory/effector cells. Resistance to apoptosis Telomere shortening
Shrinkage of the T-cell repertoire
Ag Ag
YOUNGAntigen-inexperienced
MIDDLE AGEAntigen-exposed
ELDERLYAntigen-overexposed
Naïve Polyclonal expansionsCentral Memory and Effector-Memory
Oligoclonal expansion Late-stage EffectorMemory
What causes these changes with age in immunity?
CMV infection is associated with accumulation of the most late-differentiated CD8 cells and decreased CD8+ naïve cells
Chronic CMV hypothesis
Immune Risk Profile
A set of bioparameters associated increased health risk
two geographically-limited Swedish longitudinal studies: OCTA and NONA studies Non-institutionalised individuals aged > 85 years in very good
health
associated with poor immune function: CMV seropositivity an inversed CD4/CD8 ratio expansion of CMV specific CD8 memory cells (CD8+CD28-cells) poor T-cell proliferative response low levels of B cells
CD27-CD28-Most late-differentiatedmemory cells”senescent” or ”terminally”differentiated
CD45RA+CCR7+(naive)
CD27+CD28+(memory)
CD27+CD28-(memory)
CD27-CD28+(memory)
Middle-aged Old, not IRP Old, IRP Wikby et al., 2006
Immune Risk Profile
IRP was found to be associated with high mortality at 2,4 and 6 years follow-up.
CD4/CD8 ratio
Surrogate marker CD4/CD8
R>5 - Naïve Dominated phenotype
Physical impairment when infected with CMV
Influenza Vaccination Response
About 90% of all influenza-related deaths occur among people aged at least 65 years
Protective antibody measures: 17-53% in persons aged > 65 years 70-90% in younger populations
Influenza vaccine efficacy is generally assessed based on measuring of the titer of anti-hemagglutinin Altough T cell response and not humoral antibodies, control the infection
and correlate better with protection against influenza in older person
INCIVAR study (Influence of CMV infection on Influenza vaccination response) humoral – cellular response after seasonal vaccin 100 CMV- 100 CMV+ persons
Conclusions
Immunosenescence has large impact in the very elderly
Inflammageing
IL-6 as robust marker for global functioning and mortality
T-cell senescence
CD4:8 ratio as marker for functioning and mortality
CMV as driving force
Reduced vaccination response
Thank you for your attention!
Acknowledgements:
- Jean-Marie Degryse
- Cathy Matheï
- Gijs Van Pottelbergh
- Bert Vaes
- Pierre Wallemacq
- Graham Pawelec
- Evelyna Derhovanessian
- Karin Hahnel
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