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