Accelerated Atherosclerosis in Autoimmune Rheumatic ...

1 Accelerated Atherosclerosis in Autoimmune Rheumatic DiseasesProf. andrea DoriaThe screen versions of these slides have full details of copyright and acknowledgements11 Accelerated Atherosclerosis in Autoimmune Rheumatic DiseasesAndrea DoriaDivision of RheumatologyUniversity of Padova2 Russel Ross N Engl J Med1999;340:115 126 Endothelial DysfunctionFatty-Streak FormationFormation of an advanced lesionUnstable fibrous plaquesSmooth muscle migrationFoam cell formationT-cell activationAdherence and aggregation of plateletsAdherence and entry of leukocytesMacrophage accumulationFormation of necrotic coreFibrous cap formationHemorrhage from plaque microvesselsThinning of fibrous capPlaque ruptureEndothelial permeabilityLeukocyte migrationEndothelial adhesionLeukocyte adhesion3 Pathogenetic Steps in AtherosclerosisRoss R. N Engl J Med1999;340:115-126 LDLV essel lumenAdhesionmoleculesIntima oxidateLDLC ytokinesMacrophageFoam cellMonocyteP"D LDLB reakdown of fibrous cupGrowth factorsMMPCell proliferation Matrix degradationEndotheliumMCP"1 Accelerated Atherosclerosis in Autoimmune Rheumatic DiseasesProf.

2 andrea DoriaThe screen versions of these slides have full details of copyright and acknowledgements24 Triggers and Common Pathway in AtherosclerosisVessel lumenIntimaEndothelial dysfunctionCV risk factorsInfectionsChronic inflammatory diseasesAtherosclerosis/inflammationInna te/adaptive immunityEndothelium5 Key Features of Innate and Adaptive Immunity in AtherogenesisInnate Immunity Rapid immune response to pathogen Antigen recognition driven by pattern recognition receptors which bind to highly conserved structures expressed by pathogensAdaptive Immunity Require three to five days to mature Antigen recognition driven by T and B cell receptors; Very specific antigen recognitionEffectors Phagocytes Pattern recognition receptors Pentraxines (CRP, PTX3) Complement Cytokine (TNF , IL"1, IL"6) Chemokines (MCP"1)Effectors T and B cell T and B cell receptors Cytotoxic T cell Antibodies Cytokine (TNF , IL"2, INF ) ChemokinesInflammationAtherosclerosis6 Innate immunityInfectious AgentsChronic Inflammatory DiseasesCV Risk FactorsAccelerated Atherosclerosis in Autoimmune Rheumatic DiseasesProf.

3 andrea DoriaThe screen versions of these slides have full details of copyright and acknowledgements37aplmImmunocytochemistr y for CRP DistributionWithin the Atherosclerotic Plaque8 Danesh, J. et al., N Engl J Med2004;350:1387 1397 Odds Ratios for Coronary Heart Disease Among 2459 Patients with Coronary Heart Disease and 3969 Controls9 Unstable Carotid Plaque (CARS)Pauletto P, Circulation2000; 102(7):771 778 MacrophagesLymphocytesAccelerated Atherosclerosis in Autoimmune Rheumatic DiseasesProf. andrea DoriaThe screen versions of these slides have full details of copyright and acknowledgements410CD4++++CD28n u lln u lln u lln u llT cells expansion in UA0510152025303540CD4+ CD28 null T cells (%)Stable Angina Unstable AnginaP < G, Circulation1999; 100: 2135"9An Unusual Subset of T-Cells, CD4+CD28null, Is Clonally Expanded in the Peripheral Bloodand Infiltrates Coronary Plaques in UAInfiltration of selected CD4++++CD28n u lln u lln u lln u llT cells clones into the unstable plaqueL = Left anterior descending coronary arteryR = Right coronary artery, culprit lesion Liuzzo G, Circulation2000; 101: 2883"811CD4+CD28nullLymphocytes Undergo clonal proliferation Form long"lived clonal population Produce IFN" high levels (Liuzzo G, Circulation1999.)

4 100: 2135"9) Coexpress the CD57 NK cell marker Have cytolytic activity (Nakajima T, Circulation2002; 105: 570"5; Nakajima T, Circ Res2003; 93: 106"113; Nakajima T, Circulation2002; 105: 570"5) Are autoreactive Enhanced number with increasing age in the blood of healthy subjects (Warrington KJ Blood2003;101:3543"9)12 Frequency of CD4+CD28 - T Cells in 87 RA and 30 Control Subjects Gerli R, et al., Circulation2004,109:2744 8 Accelerated Atherosclerosis in Autoimmune Rheumatic DiseasesProf. andrea DoriaThe screen versions of these slides have full details of copyright and acknowledgements513 ControlsCD4+CD28+ CD4+CD28-Common carotid IMT (mm)Common Carotid IMT in RA Patients Subdivided According to the Presence or Absence of CD4+CD28- Cell ExpansionAll RA**Gerli R, et al., Circulation2004,109:2744 8 and Autoimmunity Anti-oxLDL Anti- 2 GPI Anti-HSP60/65 Doria A, Sherer Y, Meroni PL, Shoenfeld Y.

5 Rheum Dis Clin N Am2005; 31: 329"54 Anti-ECA Anti-HDL Anti-APO A-1 Anti-LPL15 Oxidized LDL and other lipoproteins can be actively taken up by scavenger receptor mediated endocytosis, transforming macrophages into the so called foam cellsAnti"oxLDLoxLDL Some anti"oxLDL can enhance oxLDL uptake by macrophages through the involvement of the Fc receptors rather than viathe usually employed scavenger receptor favouring foam cell formation and macrophage activationAccelerated Atherosclerosis in Autoimmune Rheumatic DiseasesProf. andrea DoriaThe screen versions of these slides have full details of copyright and acknowledgements616 Raised levels in some conditions linked to coronary artery diseasein humans Lehtimaki T, et al., Arterioscl. Thromb. Vasc. Biol 19, 23"7, 1999 Maggi E, et al., Arterioscler Thromb 14, 1892"1899, 1994 Saloen , et al., Lancet 339, 883"7, 1992 Meraviglia MV et al.

6 , Stroke2002,33: 1139"1141 George J,et al., Immunol Lett1999;68:263"6 Anti-oxLDL and Atherosclerosis Immunization with oxLDL of animals results in suppression rather than aggravation of early atherogenesis Palinski W. et al., Proc Natl Acad Sci USA92, 821"825, 1995 George J, et al., Atherosclerosis138,147"52, 1998 Ameli S, et al., Arterioscler Thromb Vasc Biol16,1074"9, 1996 Anti"oxLDL mAbs inhibit uptake of oxLDL by macrophages Show PX, et al., Atherosclerosis , Thrombosis & Vascular Biology21, 1: 333"9, 200117 Anti-oxLDL and AtherosclerosisProtectivePathogeneticHel p to clear the high levels of oxLDLIgM anti"oxLDLIgG anti"oxLDLAid the uptake of oxLDL by macrophages turning them into foam cells within the atherosclerotic plaques 18 Generally they are directed to phospholipids binding proteins ( 2 glycoprotein I, prothrombin, etc.)

7 Detected by different tests as: Lupus anticoagulant, Anticardiolipin antibodies Anti 2 GPI Anti prothrombin Anti ethanolamine Anti annexin Anti phospholipids Major cause of thromboembolic disorder in patients with Autoimmune diseases and otherwise healthy subjects (antiphospholipid syndrome) Antiphospholipid AntibodiesAccelerated Atherosclerosis in Autoimmune Rheumatic DiseasesProf. andrea DoriaThe screen versions of these slides have full details of copyright and acknowledgements719 Polar(-NH2)Polar(-OH,-SH)Characters of amino acid residuesPositively chargedNegatively chargedHydrophobicglycineThe Primary Structure of Human 2 GPI and Location of Attachment Sites for Oligosaccharide Chains2021 2 GPI Adhered on Endothelial Cells Is a Target for Anti-Phospholipid Antibodies 2 GPI adhesion to endothelium in vivo(McIntyre 1993, La Rosa 1994)++++++ 22 GPIGPI 22 GPIGPI 2 GPI binding to endothelial monolayers in vitro(Del Papa 1995, 1997, 1998) 2 GPI binds endothelium through the PL"binding site located at the fifth domain and through annexin II (Del Papa 1998; Keying 2000)EndotheliumAccelerated Atherosclerosis in Autoimmune Rheumatic DiseasesProf.

8 andrea DoriaThe screen versions of these slides have full details of copyright and + Mg2++ + Mg2++heparinTwo Step Complex Formation Between OxLDL and 2 GPII ntermediate complexesElectrostatic and dissociable complexes, formed with 2GP ligands ( "carboxyl), such as oxLig"1 and oxLig"2 Matsuura E, et al., Lupus2005; 14: 736"41oxLDLFree 2 GPI oxLDL+++---(Schiff base etc.)Stable complexesStable complexes ( ,Schiff base adducts), formed with "aldehydesoxLDL23 Age-related + risk Factors--------HealthyNo Atherosclerosis --OxLDL/ 2 GPI++Blood Infection (Sepsis)Infectious EndocarditisPremature Atherosclerosis + CVDIgMOxLDL/ 2 GPI+++Chronic HyperglycemiaDM-2 CVD AtherosclerosisIgG/IgMOxLDL/ 2 GPI+++?SScPremature Atherosclerosis + CVDIgG/IgMOxLDL/ 2 GPI++++Chronic Autoimmune VasculitisSLEAPSC linical manifestationAntibodyLipid ModificationOxidative StressInflammationDiseaseSerum OxLDL/ 2 GPI Complexes May Be a Marker of Vascular Inflammation Matsuura E, et al.

9 , Lupus2005; 14: 736"4124 2 GPIoxLDLDa Koike T, 1998 The Role of 2 GPI in Atherogenesis Anti- 2 GPIA ccelerated Atherosclerosis in Autoimmune Rheumatic DiseasesProf. andrea DoriaThe screen versions of these slides have full details of copyright and acknowledgements925 Immunolocalization of 2 GPI (Apolipoprotein H) in Human Atherosclerotic Plaques: Potential Implications for Lesion ProgressionGeorge et al., Circulation99999999:2227, 1999A and Brabbit anti" 2 GPI antibodyC, normal rabbit IgGD, hematoxylin" eosinE, anti"CD4F, anti"CD826 In LDL"receptor"d eficient mice or Apo"E knock"out mice immunization with 2 GPI enhances atherosclerotic lesions which contain abundant CD4+ cells George J et al., Circulation1998; Afek A et al., Pathobiology1999 Immunizationwith Human 2 Glycoprotein I The transfer of lymphocytes from mice immunized with 2 GPI to mice of similar genetic background increases atherosclerotic lesions compared to those occurring in animals tranferred with lymphocytes from control miceT cell depletionimpairs reproduction of the experimental model !

10 ! 27 The presence of antiphospholipid antibodies was found to be a risk factor for various manifestations of coronary artery disease such as angina, myocardial infarction or cardiac death, as well as being associated with subclinical Atherosclerosis Vaarala O et al., Circulation 1995, 91:23; Sherer Y, Cardiology2001, 95: 20 Sherer Y et al., Am J Cardiology 2000,86:1306"1311 Vaarala O et al., Thromb Haemost 1996,75:456 Shoenfeld Y, et al., 2000,1:37"40 Glueck et al., Am J Cardiol1999 83:1490; Nityanand S et al., J Intern Med1995, 238:437 It has also been shown that patients with primary antiphospholipid syndrome have a high prevalence of increased carotid intima"media thickness or plaque Ames PRJ, et al., Lupus2002; 11: 208"214 G. Medina, et al., Ann Rheum Dis2003;62:607"610 PG Vlachoyiannopoulos et al., Rheumatol2003;42:645"651 Antiphospholipid Antibodies in Patients with Clinical and Subclinical AtherosclerosisAccelerated Atherosclerosis in Autoimmune Rheumatic DiseasesProf.