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
Hallmarks
 The HALLMARKS of immunosenescence are:
•
T-cell senescence
Lymf
APC
B cell
Cytokines
Cytotox
ic T-cel
CD8+
•
Helpe
r T-cel
Differentiation
Naïve Tcell
Plasmacel
CD4+
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
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:
hCRP
IL-10
IL-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
IL-6
150
IL-6 (pg/ml)
100
50
10
5
0
Global Decline Mild Decline
Stable
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
YOUNG
MIDDLE AGE
ELDERLY
Antigen-inexperienced
Antigen-exposed
Antigen-overexposed
Ag
Naïve
Ag
Polyclonal expansions
Central Memory and Effector-Memory
Oligoclonal expansion
Late-stage Effector
Memory
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
CD45RA+CCR7+
(naive)
CD27+CD28+
(memory)
CD27+CD28(memory)
CD27-CD28+
(memory)
CD27-CD28Most latedifferentiated
memory cells
”senescent”
or ”terminally”
differentiated
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