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Inflammation: Can we silence the secret killer?
Prakash Nagarkatti, Ph.D.Vice President for ResearchUniversity of South CarolinaColumbia, SC 29208
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InflammationInflammation is a natural response from the
immune system against infections or tissue injury
Infection Poison Ivy
Nickel Lupus Allergy Bee bitePhotographs: Wikipedia
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Cells of Innate Immunity
No antigen-specificityNo Memory
Photographs: Wikipedia
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Cells of Adaptive Immunity:Lymphocytes-B and T
Antigen-specificityMemory
Photographs: Wikipedia
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Nature of inflammation in Type-I Hypersensitivity
(allergies)
Histamine, tryptase,
kininegenase, ECFA
Leukotriene-B4, C4, D4, prostaglandin D, PAF
Newlysynthesized mediators
Mast cells
IgETH2
IL-4,IL-5, IL-13 B cell
Plasma cell
Macrophage/Dendritic cells
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Anaphylaxis
Egg Albumin
Repeat Inj. 2 Weeks later
Dies from asphyxia
Anaphylaxis:
Photographs: Wikipedia
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Guinea Pig dies from anaphylaxis.Egg albumin IgE Abs Mast cells
Histamine
•Bronchoconstriction•Vasodilation
Lungs
Photographs: Wikipedia
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List of Allergens Grasses/Pollens Weeds Foods-->nuts, soy, fish, shell fish,
eggs, wheat, dairy, etc. Epidermal-->dog, cat, mouse Insect bites House dust Molds Drugs Chemicals
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Skin test for allergyInflammation mediated by IgE
Abs and mast cells
Photographs: Wikipedia
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Type II hypersensitivity
Role of complement and phagocytes in inflammation
ComplementMacrophage/Neutrophil/NK
Ab-dependent Cell-mediatedcytoxicity
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Type II hypersensitivity induced by exogenous agents
RBC antigenAbsorbed drugor drug metabolite Ab to drug
Complement
Lysis
Drug-induced reaction to red blood cells
Photographs: Wikipedia
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Red cells:Penicillin, chloropromazine, phenacetin
Granulocytes:Quinidine, amidopyridine
Platelets: sulphonamides, thiazides
Examples of drug-inducedtype II hypersensitivity
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Blood Group AgsBlood Group Ag Ab
A A anti-B
B B anti-A
AB A&B None
O ---- anti-A&anti-B
Abs against blood group Ags are naturally present and are IgM type.
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Transfusion Reaction
+Complement
Red cell lysis
Result:Anaphylactic Shock due to Complement activation.
IgMRBC
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Hemolytic Disease of the New Born RhD-ve mother
RhD +ve fetus
Anti-RhD Abs
RhD +ve fetusPhotographs: Wikipedia
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Prophylaxis (RhoGAM)
RhD-ve mother
RhD +ve fetus
Anti-RhD Abs
RhD +ve fetusMid-term injection of RhoGAM and a second injection within a few days of delivery
Photographs: Wikipedia
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Type III HypersensitivityInflammation driven by immune
complexesImmune complexes not cleared
Activation of Complement
C3a & C5a
Mast cell degranulation
Inflammation
Photographs: Wikipedia
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Systemic lupus erythematosus (Lupus)
Butterfly rashPhotographs: Wikipedia
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Rheumatoid ArthritisAuto Abs against Fc portion of IgG
often called rheumatoid factor.Abs against collagen. Immune complexes deposited in
joints.Complement activation leads to
inflammation---Type III hypersensitivity.
Photographs: Wikipedia
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Type IV Hypersensitivity Inflammation driven by T cells:
Th1 and Th17 cells that activate macrophages
Delayed, takes 24-48 hoursExamples:
Contact Hypersensitivity:Nickel Chromate Poison Ivy
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Mechanism of Type IV Hypersens.
Skinpoison Ivy
Th1
Inflammation
urushiol
serum protein
Mo
APC
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Contact Dermatitis
Contact dermatitis to Nickel
Photographs: Wikipedia
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Reaction to Poison Ivy
Photographs: Wikipedia
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Tuberculin-type Hypersensitivity
Tuberculosis Patient
PPD(Ag derived from M.tuberculosis)
Erythema & Induration Used as a diagnostic Test Not accurate.
Tuberculin test
Photographs: Wikipedia
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Experimental Autoimmune Encephalomyelitis(EAE) (Multiple Sclerosis)
Inject Myelin Basic Protein(MBP) in an adjuvant
MBP is processed by dendritic cellsand presented to Th cells
Th1/Th17 cellsget activated
Myelin SheathAxon
Th cells cross blood-brain barrierTh
Th
Th
Macrophage
hind leg paralysis
Th
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MS: Inflammation in Brain causing demyelination
Photographs: Wikipedia
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Detecting immunomodulatory properties of chemicals
Tier I: Broad effect on naïve immune system: Effect on BM, thymus, LNs: Histopathology and studying markers on immune cells
Tier II: Effect following immunization: Study the immune response to antigens: Ab response by B cells, cytokine response by T cells, cytotoxicity by T cells, NK cells, hypersensitivity reactions, inflammation, etc
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SummaryInflammation is a double-edged sword
Acute inflammation is critical for clearing infections but sometimes it can have serious consequences as seen in many hypersensitivity reactions.
If the inflammation persists and become chronic, that can also have deleterious effects on the host as seen in autoimmune diseases.
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Chronic Inflammation
Chronic Inflammation is the underlying cause of all major clinical disorders.
Clinical disorders with inflammatory component:1. Autoimmune diseases: > 80 disorders 2. Cancer3. Cardiovascular disease4. Neurodegenerative diseases5. Obesity6. Diabetes
Image Source: Wikipedia
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Obesity: Role of inflammation M1 and M2 macrophages
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What are the mechanisms that control inflammation?
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Activation-induced cell death
Fas(CD95)Activationof T cells
Fas ligand
Apoptosis(cell-death)
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Fas-FasL interactions leading to apoptosis
Fas
FasL
Apoptosis
T cell
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Mutations in Fas or FasL leads to ALPS
Mutations in Fas or Fas ligand genes in humans leads to development of Autoimmune lymphoproliferative syndrome (ALPS).
Patients with ALPS have chronic, enlargement of lymph nodes and spleen.
Increased risk of B-cell lymphomas, and autoimmune complications.
Picture: Blood
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Regulatory T cells (Tregs)FOXP3+
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Role of Foxp3 on Tregs in controlling inflammation
Foxp3 is a transcription factor that is critical for the differentiation of Tregs.
Genetic mutations in Foxp3 in humans leads to fatal autoimmune disorder known as Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX)syndrome.
Foxp3 mutations lead to massive lymphoproliferation, diabetes, dermatitis, thyroiditis and enteropathy.
Source: Diapedia
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Treatments for Inflammation in allergies: Blocking endproducts Symptomatic
Receptor blockersantihistamine, antileukotriene
Bronchodialatorsβ-agonists (inhahants)
Prevent mast cell degranulationCa influx inhibitor (chromolyn sodium)Phosphodiesterase inhibitor (theophylline)
Immunotherapy: Desensitization: Triggers IgG and TregsAnti-IgE(Fc) Ab
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Treatment of Inflammatory and Autoimmune diseases
Immunosuppressive drugs:CorticosteroidsImuran (Azathioprine)Cytoxan (cyclophosphamide)MethotrexateCyclosporin A
Biologics:Rituximab: Antibody against CD20
expressed on B cells. Used against B cell cancers and autoimmune diseases
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Adalimubab: (Humira): Antibody against TNF—reduces pain and joint destruction
Tocilizumab (Actemra): Antibody against IL-6 receptor
The above increase the risk of severe infections.
Treatment of Inflammatory and Autoimmune diseases
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Impact of Imbalance
Pro-Inflammation
Anti-Inflammation
RegulatoryEffector
TregsFas-FasLTh1/Th17
Botanicals Botanicals
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Almost half of all pharmaceuticals are derived from natural products:morphine (opium)digitalis (foxgloves)quinine (Cinchona tree)vincristine (periwinkle)taxol (Pacific yew tree)aspirin (willow tree)
Why botanicals?
Pacific Yew TreeImage Source: Wikimedia Commons
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Aryl hydrocarbon (AhR) signaling pathway: Do some dietary supplements act through
AhR?
Role for dietary ligands of AhR in immune regulation?
TCDD
Image Source: Wikimedia Commons
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Screening natural compounds on FoxP3 induction
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AhR dietary ligands
Resveratrol: Plant polyphenol in red grapes
Extends the lifespan in yeast, worms, flies, mice
Plant-derived indoles: I3C (Indole-3-carbinol)
and DIM (3,3'-diindolylmethane ).
Image Source: Wikimedia Commons
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Treatment: Day 2Vehicle or Resveratrol(100- 250 mg/kg) byOral gavage
Experimental Autoimmune Encephalomyelitis (EAE): A model for
MS
MOG35-55 peptide (s.c.): Day 0
PTX (i.p.):Day 0 and 2
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Inflammatory Bowel Disease The two most common forms: Ulcerative
colitis and Crohn’s disease. It is estimated that ~1.4 million people in the
US suffer from IBD. There are various animal models of colitis
Image Source: Wikimedia Commons
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C Control
DSS
Resveratrol
DSS+Resveratrol
Resveratrol attenuates dextran sodium sulfate(DSS)-induced colitis
Control Resveratrol DSS DSS+ Resveratrol
J Pharmacol Exp Ther. 2010 Mar;332(3):829-39
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00.5
11.5
22.5
33.5
44.5
5
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
Aver
age
Clin
ical
Sco
res
Days After MOG Immunization
EAE +vehicleEAE + I3C
EAE + DIM
*
*
* p < 0.003
Treatment with I3C and DIM attenuates inflammation in the CNS of EAE mice
Br J Pharmacol. 2013 Jul;169(6):1305-21
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RES and indoles trigger Tregs
VEH5.6%
94.4%
RES100/D120.9%
79.1%RES200/D1
23.5%
76.5%
RES100/D814.3%
85.7%CD4
FoxP
3Tregs in SJL/J mice with EAE: D15
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Epigenetic Regulation of gene expression
Photographs: Wikipedia
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Resveratrol-mediated regulation of miRs
J Pharmacol Exp Ther. 2014 Jul;350(1):99-109
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miRNA Profiles induced by various AhR ligands
56Veh 1 2 3 4 5 6 7
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57
AhR ligands sharing miRs
# 1
# 5
# 3# 4
# 2
FoxP3miR-190miR-217miR-490
IL-17miR-203miR-320miR-494
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Th
Th 17
T regs
Foxp3 Promoter hypo-methylationIL-17 Promoter hyper-methylation
FoxP3miR-190miR-217miR-490
Some Botanicals act as AhR ligands and reciprocally regulate Tregs & Th17 cells through epigenetic mechanisms
IL-10TGFβ
IL-17
AhR
AhR ligands
IL-17miR-203miR-320miR-494Th 17
Apoptosis
FasL
Fas
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THC and Cannabidiol (CBD)
Psychoactive Non-psychoactive
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Cannabinoid Receptors
CB1 receptorCB2 receptor
∆9 THC
Psychotropic Effects???
Endocannabinoids
Immune System
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0
1000
2000
3000
4000
5000
6000
7000
6h 12h 24h 48h
PBSConA+VehConA+CBD(5mg/kg)ConA+CBD(20mg/kg)ConA+CBD(50mg/kg)CBD(50mg/kg)
***
**
** *
**
#
#
#
AST
(IU/L
)Cannabidiol (CBD) treatment attenuates
hepatitis
a) Vehicle; b) ConA+Veh;
c) ConA+CBD (50mg/kg); d) CBD alone
*p<0.05, **p<0.01
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THC-induced hypermethylation of IFN-γand hypomethylation of IL-4 and IL-10
promoters
J. Leuk. Biol. 97:677, 2015
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Genome wide DNA Methylation
DNA methylation in the promoter region of Arg-1 by MeDIP-Seq
Vehicle
RES
Major CpG islands
Chromosome
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Histone methylation and gene expression in THC treated activated T lymphocytes
J. Biol. Chem. 289:18707, 2014J. Biol. Chem. 201:15460, 2016
ChromosomeVehicleTHC H3K4me3
VehicleTHC H3K27me3
VehicleTHC mRNA
miRNA
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Histone methylation pattern affecting gene expression
H3K27me3
H3K4me3
H3K36me3
H3K9me3
H3K27me3
H3K4me3
H3K36me3H3K9me3
Vehicle
THC
Ifn-γ
10 kb 10 kb
Tbx21
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Gut microbiota play an important role in regulating inflammation
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ControlTNBS+I3CTNBS
Effect of botanicals on microbiota
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SummaryAcute inflammation
Infection
Toxicity to Tissues/Organs
Dysregulation
DysregulationChronic Inflammation
Clinical disorders:• Autoimmune • Cardiovascular • Neurological • Obesity• Cancer
Epigenetic Regulation/Microbiota
FoxP3+ TregsFas-FasL
Image Source: Wikipedia
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