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Immunosenescence Group Dipartment of Pathobiology and Biomedical Methodologies University of Palermo www.unipa.it/immunopatologia Cambridge, September.

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Presentation on theme: "Immunosenescence Group Dipartment of Pathobiology and Biomedical Methodologies University of Palermo www.unipa.it/immunopatologia Cambridge, September."— Presentation transcript:

1 Immunosenescence Group Dipartment of Pathobiology and Biomedical Methodologies University of Palermo Cambridge, September 8th, 2005 BIOLOGY OF LONGEVITY: ROLE OF THE IMMUNE SYSTEM

2 AGEING Progressive loss of functions Increased death risk Reduced ability to respond to environmental stimuli Increased susceptibility to disease

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4 Inflammation The immune system CLONOTYPIC INNATE B cells (humoral via antibodies) T cells (cellular effectors; cytokines) antigen-presenting cells dendritic cells phagocytes NK cells ?

5 M. De Martinis et al. FEBS Letters 579 (2005) 2035–2039 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

6 HUMAN LONGEVITY APPEARS TO HAVE A SIGNIFICANT HERITABLE COMPONENT, CONFIRMING THE OLD ADAGE THAT LONG LIFE RUNS IN FAMILIES.

7 Notes: * Osteoporosis includes Osteoporosis, hip, wrist, and vertebral fracture. POR= Prevalence Odds Ratio; CI= Confidence Interval; COPD= Chronic Obstructive Pulmonary Disease PREVALENCE ODDS ESTIMATES FOR DISEASE

8 CYTOKINES ADHESION MOLECULES TOLL-LIKE RECEPTORS PYRIN ACUTE PHASE PROTEIN CHEMOKINE RECEPTORS PROTEASE INHIBITOR

9 “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

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

11 IL-10 IN AGE RELATED DISEASES

12 IL-10 GENE POLYMORPHISMS -3538A/T A/T-819C/T C/G-2736A/C IL-10R (CA)nIL-10 G (CA)n ATG -1354A/G -1082G/A -592C/A G Less IL-10 production (from 30 to 50%)

13 GENOTIPIC FREQUENCIES IN MI AND LONGEVITY Lio et al., 2004

14 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.

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

16 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 1α and 1β (MIP-1α, MIP-1β) latch into CCR5 leading monocytes to the inflammatory site.

17 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)

18 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.

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

20  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.

21 +896 A  G Aspartic acid  Glycin LPS responsiveness Pro-inflammatory citokynes production TLR4 Asp299Gly Polymorphism

22 GENOTYPE DISTRIBUTION OF +896A  G TLR4 GENE Balistreri CR, Candore G, C, Caruso C.. JAMA 2004.

23 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.

24 What is the meaning of these data?

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26 Epidemiologic studies suggest that the pathogenic burden, which every individual has been exposed, may be linked to an increased risk of atherosclerosis.

27 Inflammation in early phases of life can play a relevant role in elderly morbidity and mortality. Inflammatory molecules Infections, trauma Tissue injury Disease Death Inflammatory Exposure and Historical Changes in Human Life-Spans Caleb E. Finch* and Eileen M. Crimmins 17 SEPTEMBER 2004 VOL 305 SCIENCE

28 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.

29 CONCLUSIONS: Genetics of inflammation, infections, CVD and longevity Longevity Decreased life-long infection incidence Socio-oeconomic and sanitary condition improvement 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.

30 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

31 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, Università di Palermo Enrico Hoffmann

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