Diapositiva 1

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Calogero Caruso
BIOLOGY OF LONGEVITY ROLE OF THE IMMUNE SYSTEM
Immunosenescence Group Dipartment of Pathobiology
and Biomedical Methodologies University of
Palermo www.unipa.it/immunopatologia Cambridge,
September 8th, 2005
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Inflammation
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• Antigenic load is associated with a loss of early
  memory cells, an increase of highly
  differentiated CD8 cells, a gradual reduction of
  the immunological space and an immune risk
  phenotype (IRP) predicting mortality.
• As a consequence, a peculiar chronic inflammatory
  status characterizes immunosenescence.
• Lifelong chronic antigenic load
• induces age-related increase of
• activated immune cells and
• hyperproduction of
• proinflammatory cytokines.

IMMUNE SYSTEM IN AGEING
M. De Martinis et al. FEBS Letters 579 (2005)
20352039
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HUMAN LONGEVITY APPEARS TO HAVE A SIGNIFICANT
HERITABLE COMPONENT, CONFIRMING THE OLD ADAGE
THAT LONG LIFE RUNS IN FAMILIES.
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PREVALENCE ODDS ESTIMATES FOR DISEASE
Notes Osteoporosis includes Osteoporosis, hip,
wrist, and vertebral fracture. POR Prevalence
Odds Ratio CI Confidence Interval COPD
Chronic Obstructive Pulmonary Disease
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CHEMOKINE RECEPTORS
ACUTE PHASE PROTEIN
PYRIN
ADHESION MOLECULES
TOLL-LIKE RECEPTORS
CYTOKINES
PROTEASE INHIBITOR
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So, our hypothesis is that pro-and
anti-inflammatory genes involved in
cardiovascular diseases may play an opposite
role in human longevity.
Studies performed on the Sicilian population
confirm our suggestion
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CHEMOKINE RECEPTORS
ACUTE PHASE PROTEIN
PYRIN
ADHESION MOLECULES
GAP-JUNCTION
TOLL-LIKE RECEPTORS
CYTOKINES
PROTEASE INHIBITOR
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IL-10 IN AGE RELATED DISEASES
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IL-10 GENE POLYMORPHISMS
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GENOTIPIC FREQUENCIES IN MI AND LONGEVITY
Lio et al., 2004
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IL-10 CONCLUSIONS

• In our study the high producer IL-10 1082GG
  polymorphism showed the highest frequency in
  centenarians and the lowest frequency in AMI
  patients.
• Therefore high IL-10 production seems to be
  protective towards cardiovascular diseases and
  can be seen as a longevity factor.

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CHEMOKINE RECEPTORS
ACUTE PHASE PROTEIN
PYRIN
ADHESION MOLECULES
GAP-JUNCTION
TOLL-LIKE RECEPTORS
CYTOKINES
PROTEASE INHIBITOR
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THE CCR5 RECEPTOR

• Chemokines and their receptors form a regulatory
  network that controls the development,
  recruitment and activation of leukocytes.
• The chemokine CCR5 plays an important role both
  in clonotypic and natural immune system, where it
  is highly expressed on macrophages, CD4 T cells
  and endothelial cells.
• In inflammation, macrophage inflammatory protein
  1a and 1ß (MIP-1a, MIP-1ß) latch into CCR5
  leading monocytes to the inflammatory site.

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CCR5 gene 32 bp Deletion
The 32bp (?32) deletion causes frame shift
mutation at position 185 which is localized by
the 2nd extracellular loop of the receptor
sequence. The 185 aa deletion stops the
maturation of the protein. (Samson et al.,
Nature, 1996)
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CCR5 CONCLUSIONS

• The CCR5 ?32 receptor polymorphism seems to be
  associated with a lower risk to develop
  atherosclerosis and AMI. The presence of this
  mutation in CCR5 receptor abolishes (reduces) the
  receptor from the cell surface. This impairs the
  recruitment of monocytes at the vascular wall.
  The mutation might result in an increased chance
  of longevity in a modern environment with reduced
  pathogen load and improved control of severe
  infections by antibiotics.

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CHEMOKINE RECEPTORS
ACUTE PHASE PROTEIN
PYRIN
ADHESION MOLECULES
GAP-JUNCTION
TOLL-LIKE RECEPTORS
CYTOKINES
PROTEASE INHIBITOR
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• Toll-like receptors (TLRs) represent a primary
  line of defence against invading pathogens in
  mammals, plants and insects. Recognition of
  microbial components by these receptors triggers
  the initial innate immune response that
  ultimately leads to inflammatory gene expression
  and clearance of the infectious agent.

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TLR4 Asp299Gly Polymorphism
896 A?G
Aspartic acid? Glycin
LPS responsiveness Pro-inflammatory citokynes
production
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GENOTYPE DISTRIBUTION OF 896A?G TLR4 GENE
Balistreri CR, Candore G, C, Caruso C.. JAMA
2004.
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TLR4 CONCLUSIONS

• In our study TLR4 polimorphism seems associated
  with reduced risk to develop aterosclerosis and
  AMI, likely because it lowers the
  pro-inflammatory signal in the monocytes.
• The mutation might result in an increased chance
  of longevity in a modern environment with reduced
  pathogen load and improved control of severe
  infections by antibiotics.

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What is the meaning of these data?
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Epidemiologic studies suggest that the
pathogenic burden, which every individual has
been exposed, may be linked to an increased risk
of atherosclerosis.
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Inflammatory Exposure and Historical Changes in
Human Life-Spans Caleb E. Finch and Eileen M.
Crimmins 17 SEPTEMBER 2004 VOL 305 SCIENCE
Inflammatory molecules
Infections, trauma
Inflammation in early phases of life can play a
relevant role in elderly morbidity and
mortality.
Tissue injury
Disease
Death
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The presence of pro-inflammatory gene
polymorphisms may fuel the inflammatory response
promoting pro-inflammatory status and
atheromatous plaque vulnerability. Conversely,
people genetically predisposed to a weak
inflammatory activity, have less chance to
develop CHD and, therefore, more chance to live
longer. In fact, cardiovascular diseases are a
late consequence of an evolutionary
pro-inflammatory response programmed to resist
infections in earlier life.
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CONCLUSIONS Genetics of inflammation,
infections, CVD and longevity
Genetic polymorphisms responsible for a low
inflammatory response might result in an
increased chance of long life-span in an
environment with a reduced pathogen burden, such
as a modern day and health environment, which
also permit to obtain a lower grade survivable
atherogenic inflammatory response.
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IMMUNOSCENESCENCE GROUP PATHOBIOLOGY AND
BIOMEDICAL METHODOLOGY DEPARTMENT UNIVERSITY OF
PALERMO Giuseppina Candore
Giuseppina Colonna Romano
Domenico Lio Florinda Listì
Letizia Scola Carmela Rita Balistreri Antonio
Crivello Maria Paola Grimaldi
Domenico Nuzzo Sonya
Vasto Alessandra Aquino Antonio Giacalone
Matteo Bulati Daniele Di Carlo
Valentina Orlando Vito Ditta
Mariangela Russo
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Collaborations Studies on Centenarians Dpt.
Patologia Sperimentale, Università di Bologna
Istituto Nazionale di Riposo e Cura
per Anziani, Ancona Claudio
Franceschi Studies on Infarction Dpt.
Patologia Sperimentale, Università di Bologna
Federico Licastro Istituto di Cardiologia,
Università di Bologna Angelo
Branzi Dipartimento di Medicina Interna,
Malattie Cardiovascolari e Nefrourologiche, Unive
rsità di Palermo Enrico Hoffmann
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