Presentation on theme: "ROLE OF THE IMMUNE SYSTEM Cambridge, September 8th, 2005"— Presentation transcript:
1 ROLE OF THE IMMUNE SYSTEM Cambridge, September 8th, 2005 Calogero CarusoBIOLOGY OF LONGEVITY:ROLE OF THE IMMUNE SYSTEMImmunosenescence GroupDipartment of Pathobiology and Biomedical MethodologiesUniversity of PalermoCambridge, September 8th, 2005
2 AGEING Progressive loss of functions Increased death riskReduced ability to respond to environmental stimuliIncreased susceptibility to disease
4 The immune system INNATE CLONOTYPIC T cells B cells NK cells ? (humoral viaantibodies)T cells(cellular effectors;cytokines)antigen-presentingcellsdendriticphagocytesNK cells ?Inflammation
5 IMMUNE SYSTEM IN AGEING 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 loadinduces age-related increase ofactivated immune cells andhyperproduction ofproinflammatory cytokines.IMMUNE SYSTEM IN AGEINGM. De Martinis et al. FEBS Letters 579 (2005) 2035–2039
6 HUMAN LONGEVITY APPEARS TO HAVE A SIGNIFICANT HERITABLE COMPONENT, CONFIRMING THE OLD ADAGE THAT LONG LIFE RUNS IN FAMILIES.
7 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
9 Studies performed on the Sicilian population confirm our suggestion “So, our hypothesis isthat pro-and anti-inflammatory genes involvedin cardiovascular diseasesmay play an opposite role in human longevity”.Studies performed on the Sicilian population confirm our suggestion
12 IL-10 GENE POLYMORPHISMS -3538A/T-6752A/T-819C/T-6208 C/G-2736A/CIL-10R (CA)nIL-10 G (CA)nATG-1354A/G-1082G/A-592C/A-1082 G Less IL-10 production (from 30 to 50%)
13 GENOTIPIC FREQUENCIES IN MI AND LONGEVITY Lio et al., 2004
14 IL-10 CONCLUSIONSIn 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.
16 THE CCR5 RECEPTORChemokines 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 DeletionThe 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 CONCLUSIONSThe 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.
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.
22 GENOTYPE DISTRIBUTION OF +896AG TLR4 GENE Balistreri CR, Candore G, C, Caruso C.. JAMA 2004.
23 TLR4 CONCLUSIONSIn 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.
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 Inflammatory Exposure and Historical Changesin Human Life-SpansCaleb E. Finch* and Eileen M. Crimmins17 SEPTEMBER 2004 VOL 305 SCIENCEInfections, traumaInflammatory moleculesInflammation in early phases of lifecan play a relevant role in elderlymorbidity and mortality.Tissue injuryDiseaseDeath
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 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 DEPARTMENTUNIVERSITY OF PALERMOGiuseppina CandoreGiuseppina Colonna RomanoDomenico LioFlorinda ListìLetizia ScolaCarmela Rita BalistreriAntonio CrivelloMaria Paola GrimaldiDomenico NuzzoSonya VastoAlessandra Aquino Antonio GiacaloneMatteo Bulati Daniele Di CarloValentina Orlando Vito DittaMariangela Russo
31 CollaborationsStudies on CentenariansDpt. Patologia Sperimentale,Università di Bologna:Istituto Nazionale di Riposo eCura per Anziani, Ancona:Claudio FranceschiStudies on InfarctionUniversità di Bologna: Federico LicastroIstituto di Cardiologia,Università di BolognaAngelo BranziDipartimento di Medicina Interna,Malattie Cardiovascolari e Nefrourologiche,Università di PalermoEnrico Hoffmann