convincing your patient that inflammation matters final ... · convincing your patient that...
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Convincing your Patient that Inflammation Matters
Leonard H Calabrese
Professor of Medicine
Cleveland Clinic Lerner College of Medicine
RJ Fasenmyer Chair of Clinical Immunology
Department of Rheumatic and Immunologic Disease
Cleveland Clinic
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Convincing your Patient that Inflammation Matters
Convincing your Patient that Inflammation Matters
• The immune response – how can we got our heads around it?
• IL6 in health and disease
• Rheumatoid Arthritis and HIV as inflammatory diseases
• The big picture
Why do we have an immune system and howdoes the immune system decide on when and how to respond?
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History of Immunology Break
Figure 1.3 The Immune System, 3ed (© Garland Science 2009)
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How do we sense infection?How do we sense infection?
• 1950s Self vrs non-self Burnet & Medewar
• 1980s: Innate Immunity is the First Line of Defense
PAMP/PRR system (Charles Janeway)PAMP = pathogen-associated molecular pattern
PRR = pattern recognition receptor
distinguishes “infectious self” from “noninfectious self”
Danger Hypothesis
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How do we sense infection?How do we sense infection?• 1950s Self vrs non-self Burnet & Medewar
• 1980s: Innate Immunity is the First Line of Defense
PAMP/PRR system (Charles Janeway)
PAMP = pathogen-associated molecular pattern
PRR = pattern recognition receptor
distinguishes “infectious self” from “noninfectious self”
• 1990s: “Danger Model” (Polly Matzinger)
endogenous danger signals are released from infected cells
• 2007: Danger associated molecular pattern
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CCF Art Department
Deep puncture wound
Muscle
Fat
Skin
Organization of the Immune System
Anatomical andPhysiological Barriers
Innate Immunity
Adaptive Immunity
Ciliaryclearance
Intact skin
Lowstomach pH
Lysozyome intears and saliva
0-4 hours 4-96 hours Late > 96 hours
B cellsNeutrophils
TLR’sDendritic cells
Host defensepeptides
Complement
NLR’s
T cells
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• All defenses without MEMORY
• early response ( minutes to 3-5 days) consisting of CELLUALR and SOLUBLE elements
• Expressed by GERMLINE encoded receptors
• Does not recognize every antigen but rather highly conserved structures DAMP
Immune Response - Innate
Components of Innate Immunity: Barriers
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hematopoietic stem cell
common myeloid progenitor
common erythroid megakaryocyte progenitor
erythroblast
erythrocyteplatelets
megakaryocyte
unknownprecursor
common granulocyteprecursor
basophil
eosinophil
neutrophil
dendritic cell macrophage mast cellNK celleffector T cell
plasma cell
B cell T cell
NK/T cell precursor
Common lymphoid progenitor
Figure 1.14 The Immune System, Third Edition
monocyte
Copyright (©2009) from The Immune System, Third Edition by Parham. Reproduced by permission of Garland Science/Taylor & Francis Books, LLC
How do actually sense DANGER?The story to PAMPs DAMPs and TOL
MASP-1
MASP-2
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History of TLRsHistory of TLRs
• Christiane Nusslein-Vollhard1985/1995*
• Max –Plank Tubingen
Copyright (©2012) from Immunobiology, Eighth Edition by Murphy. Reproduced by permission of Garland Science/Taylor & Francis Books, LLC.
Figure 3.8 Immunobiology, Eighth Edition
Jules Hoffman Strasbourg
Immune defense connection 1995/2011*
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TLR HistoryTLR History
• 1994 first human gene resembling TLR Nobuo Nomura
• 1997 Ruslan Medshitov and Charles Janeway linked TL signaling to NF-kB
TLR History TLR History
• Beutler used TNF production as a phenotypic endpoint to identify the LPS receptor.
• Beutler thus discovered the key sensors of microbial infection in mammals, demonstrating that one of the mammalian Toll-like receptors, TLR4, acts as the membrane-spanning component of the mammalian LPS receptor complex
• Nobel 2011
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Copyright (©2012) from Immunobiology, Eighth Edition by Murphy. Reproduced by permission of Garland Science/Taylor & Francis Books, LLC.
• 10 human TLR• Surface or endosome • Critical to numerous cells• Activates NF-kB, MAP inflammatory cytokines • Enhance APC and induction of adaptive immunity
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Copyright (©2005) from The Immune System, Second Edition by Parham. Reproduced by permission of Garland Science/Taylor & Francis Books, LLC.
.
Figure 8.15 The Immune System, Second Edition
CCF Art Department
Deep puncture wound
Muscle
Fat
Skin
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Copyright (©2009) from Immunobiology, Eighth Edition by Murphy. Reproduced by permission of Garland Science/Taylor & Francis Books, LLC.
Figure 1.9 The Immune System, Third Edition
Inflammation The good the bad and the ugly
Inflammation The good the bad and the ugly
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History of IL-6: Diverse Systemic Roles
• The molecule now known as IL-6 was first discovered in the mid-1980s by Kishimoto
− B-cell differentiating factor
− T-cell activation factor
− Hepatic stimulatory factor
− Osteoclast-inducing factor
• Pleiotropic cytokine
• FAMILY-LIF, OSM,CNF, cardiotropin, IL-11and the recently described cytokines IL 27 and IL 31
• Chromosome 7, 28-21KD
1. Hirano T. Proc Jpn Acad Ser B Phys Biol Sci. 2010;86(7):717-730. 2. Kishimoto T. Arthritis Res Ther. 2006;8(suppl 2):S2.
Note: Many of these findings are based on animal and in vitro studies.IL, interleukin.
B cell
T cell Osteoclast
Liver
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IL-6 Is a Pleiotropic Cytokine With Multiple Sources and Targets
Note: Many of these findings are based on animal and in vitro studies.IL, interleukin.
1. Cronstein BN. Bull NYU Hosp Jt Dis. 2007;65(suppl 1):S11-S15. 2. Naka T, et al. Arthritis Res. 2002;4(suppl 1):S233-S242. 3. Jones SA, et al. J Interferon Cytokine Res. 2005;25(5):241-253.
B cell T cell FibroblastMacrophage Endothelial cell
IL-6
Osteoclastactivation
Neutrophilrecruitment
Macrophageactivation
Endothelial cellactivation
T-cell differentiation
B-cell differentiation
Hepatic acute phase protein
production
Differentiation of megakaryocytes
into platelets
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gp130
IL-6R
IL-6
ADAM17
Signaling Signaling Signaling
sIL-6R
+
IL-6
IL-6 Classic Signaling IL-6-Trans-Signaling
J.Scheller et al. / Biochimica et Biophysica Acta 1813 (2011)
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Interleukin-6 (IL-6)
IL 6 in Health and Disease
RA, rheumatoid arthritis.
3
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IL6 infusion studies
• Unlike TNF/IL1 IL6 infusion is without acute toxicity with no hypotension/shock
• IL6 is pyrogenic, and at doses of .1-10 ugr/kg, produces modest fever, malaise
• Significant rise in acute phase proteins• Catabolic – with dose dependant increase in O2
consumption and BMR• Endocrine effects with increased ACTH, cortisol, GH but
decreased TSH• Anemia, leukocytosis, thrombocytosis
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Physiologic role of IL6 in exercise
• IL6 rises in concert with exhaustive exercise by 1-2 logs
• Muscle, mononuclear cells, CNS
• May be a response to acute ‘injury’
• Metabolic effects – increase ACTH, cortisol, GH, catabolism
• May limit ‘acute inflammation’ by increasing negative regulators of inflammation
• Sedentary –high IL6 vrs. Trained – low -IL6
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Role of IL6 in Health and Disease
• Immunologic effects– Innate
– Adaptive
• Non-immune effects– Hematologic
– Endocrine/metabolic
– Bone metabolism
– Endothelial effects
© Genentech USA, Inc. All rights reserved.34
Acute to Chronic Inflammation
Inflammation is an adaptation to stress
The body tries to end/rid the stress as quickly as possible with as little collateral damage as possible
The cells and machinery of the acute response are not optimal for chronic response
The integrated immune response must be designed to shift its component assets to bridge and transition from acute to chronic inflammation
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Gabay C and Kushner I. N Engl J Med 1999;340:448-454
Characteristic Patterns of Change in Plasma Concentrations of Some Acute-Phase Proteins after a Moderate Inflammatory Stimulus
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CRP Plays Several Roles in the Inflammatory Process
IL-6IL-1β
Liver
CRP
1. Rhodes B, et al. Nat Rev Rheumatol. 2011;7(5):282‐289. 2. Jones SA, et al. J Exp Med 1999;189(3):599-604.
Note: Many of these findings are based on animal and in vitro studies.CRP, C-reactive protein; IL, interleukin; IL-6R, IL-6 receptor.
CRP plays a role in activation of the early complement pathway
Inflamed tissue
Activated neutrophil
Activated monocyte
CRP mediates
shedding of IL-6R
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CRP and CAD
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CRP and CAD
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Effects of IL-6 on Markers of Atherothrombotic Risk
McInnes IB, et al. Oral Presentation at ACR 2010. Atlanta, GA. Abstract 1441.
Lipid Core
Thrombosis
VLDLReceptor
RA Synovitis
Vascular endothelium
MacrophageFoam Cell
Fibrinogen
IL-6
VLDL
LDLLDL
Receptor
nucleus
sPLA2-IIA
LDL modification
Tissue Retention of VLDL& LDL
ProinflammatoryHDL
Atheroprotective HDL
SAAsPLA2-IIA
HDL Composition
R-D
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IL-6 May Alter Lipid Levels During Inflammation
TNF-α IFN-β
• ↓ TC• ↓ HDL• ↓ LDL
• ↑ TG
TNF-α IL-1
IFN-γIFN-α
Khovidhunkit W, et al. J Lipid Res. 2004;45(7):1169-1196.
Note: Many of these findings are based on animal and in vitro studies.HDL, high-density lipoprotein; IFN, interferon; IL, interleukin; LDL, low-density lipoprotein; TC, total cholesterol; TG, triglyceride; TNF, tumor necrosis factor; VLDL, very low-density lipoprotein.
Increased VLDLOR
Directly increased fatty acid synthesis in the liver and/or
adipose tissue lipolysis
Altered synthesis or secretionOR
Altered metabolism and clearance
Proposed mechanisms to explain lipid changes
IL-6
IL-6
Damage / Destruction / Symptoms(RA, SLE, PsA, IBD, AS, MS)
Inflammation(TNF, IL-1, IL-6, IL-17,
IL-23, IL-18, IL-15, Others)
Immune-mediated Inflammatory DiseasesImmune-mediated Inflammatory DiseasesInitiation
SusceptibilityTriggersAccelerants
Immune responses AdaptiveInnate
DM, CHF, Alzheimer's, Transplant, Sepsis, Allergy, Vasculitis, ASO, HIV
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RA - inflammation is more than in the joint!
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Meta-analysis of Studies on Overall and Cause-Specific Cardiovascular Diseases in Patients with Rheumatoid Arthritis
All CVDGabriel 1999
del Ricon 2001Watson 2003
Turesoson 2004Goodson 2005Solomon 2006
Bergstrom, 2009aBergstrom, 2009b
Peters 2009Pooled RR
FemalesMales
AMIdel Ricon 2001Solomon 2003
Turesoson 2004Fischer 2004
Goodson 2005Maradit-Kremers 2005
Solomon 2006Sodegrën 2007
Pooled RRFemales
Males
CVAGabriel 1999
del Ricon 2001Watson 2003
Solomon 2003Turesoson 2004
Solomon 2006Nadareishvili 2008
Pooled RRFemales
Males
CHFNicola 2005
0 1 2 3 4 5 6 7
Relative risk of new cardiovascular events
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Causes and manifestations of rheumatoid cachexia. CVD, cardiovascular disease
Kitas & Gabriel Ann Rheum Dis 70:8-14,2011
Potential causes Manifestations
Systemic inflammation
↑Pro-inflammatory cytokines
Pain and fatigue
↓Physical activity
Low testosterone levels
Smoking
Corticosteroids
↓Muscle mass
↑Total fat mass
? ↑Visceral fat
? ↑CVD-related risk
46464646
High-Sensitivity C-Reactive Protein and Risk of Nontraumatic Fractures in the Bruneck Study Georg Schett, MD; Stefan Kiechl, MD; Siegfried Weger, MD; Angelo Pederiva, MD; Agnes Mayr, MD; Manuele Petrangeli, MD; Friedrich Oberhollenzer, MD; Rolando Lorenzini, MD; Kurt Redlich, MD; Roland Axmann, MD; JochenZwerina, MD; Johann Willeit, MD
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Epidemiology of Increased Cardiovascular Risk in Inflammatory Arthritis
Systemic Inflammatory Diseases and Cardiovascular Risk
Increased CV risk AUTOIMMUNE
• Rheumatoid arthritis• Lupus• Psoriatic Arthritis• Ankylosing Spondylitis• Wegener’s
granulomatosis• Takayasu’s arteritis• Kawasaki’s disease• Systemic Sclerosis
increased CV risk Infections
• HIV• Hepatitis C • Others?
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Change in Mortality for HIV Disease
50505050
HIV CVD pathogenesis
Potential culprits
TNFIL1IL6 others
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5151
Launching of new NIH sponsored trial melding therapeutics from the world of rheumatology and the world of HIV disease based on work supported by RJF
An example of unique collaboration with significant potential for success
ANTI-IL6 therapy of HIV disease
ConclusionsConclusions
• In treated patients with mostly suppressed viral replication, soluble markers of inflammation, and coagulation are strong correlates of non-AIDS defining complications
• These associations are stronger for fatal events
• IL-6 was the strongest and most consistent correlate of outcome, independent of virologic and immunologic indices of disease progression