new insights in ms immunopathology: inflammation, is it
TRANSCRIPT
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Rutgers, The State University of New Jersey
Suhayl Dhib-Jalbut, MD
Professor and Chairman
Department of Neurology
New Insights in MS Immunopathology: Inflammation, is it
all bad?
Inflammation in MS: Is there Balance?
Modifies after Yong Neuroscientist, 16:408
► Neuroprotection► Axonal
Regeneration► Neurogenesis► Remyelination
► Injury to neural elements
► Death of neurons and oligodendrocytes
► Inhibition regenerative processes
BeneficialOutcomes
DetrimentalOutcomes
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MS
Immune Dysregulation
Genetic Predisposition
-Twins studies
-HLA-DR2 (DRß1*1501)(antigen presentation)
-IL-2Ra(regulatory T-cells)
-IL-7Ra(memory T-cells)
GWAS (>100 alleles)
Environmental Factors
Demographics/Epidemics
Microbial Agents
EBV
Vit. D
Smoking
Salt
Microbiome
Multiple Sclerosis: An Immuno-genetic Disease
Dhib-Jalbut, S 2013
Helper T cell differentiation
IL-12/STAT4 IFN- Pro-inflammatoryTH1
TH2
IL-4
IL-5
IL-10
IL-13
Anti-inflammatory/
AllergyIL-4/STAT6
IL-23
IL-17 Pro-inflammatoryTH17IL-6 + TGF-β
TGF-β RegulatoryTreg
TGFβ
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NOOiTNFMMP
T
IL-10TGF
Tr1Th2Th3
CD4+CD25+
IL‐6
TregFoxp3TGFß
TregFoxp3
TregFoxp3
?EBV
FcR
Glutamate
B7
CD40
IL‐17
DC
Neut
IL‐17
IL‐23
Th17Th17
CCR6
CCL20
IL-6 & TGF-ß
APCThp
Pl Ab+C9neo
Tr1Th2Th3
IL-4IL-5IL-10IL-13TGF-
B
BAFFAPRILTACI
CD40L
CD28
CD40
IL-4 & IL-10
CD4APCThp
B7
IFNTNF
MCP-1MIP-1P-10RANTES
Astrocyte
CD40L
CD28
Th1
ICAM-1
MMP-2/9VCAM-1
IFNTNFLFA-1
Th1VLA-4
BBB
Oligo
Immunopathogenesis of MS (2014) Courtesy of Suhayl Dhib‐Jalbut, MD
IL-12
APC
Thp
CD4
Myelin AgMicrobial Ag
HLATCR
IL‐1TNF
TLR
B
CD8CTL
CD8CTL
CD8p
Oligo
Immunopathogenesis of MS
Ab+C9neoRNOROSTNFMMP
Dhib-Jalbut, S 2014
B7
CD40 CD40L
CD28
Th1
Glutamate
CD8CTL
IFNgTNF
MMP-2/9
BB
PLOligoo
BBB
MCP-1MIP-1aIP-10RANTES
Astrocyte
BBIFNgTNF
Th1VLA-4
ICAM-1VCAM-1
Th0APC
Myelin AgMicrobial Ag
HLATCR
IL-4IL-5IL-10IL-13TGF-b
IL-10TGFb
TregFoxp3
Tr1Th3
IL-6 & IL1-ß
IL-23IL-17
TGFß
IL-6
TregFoxp3
TregFoxp3
CD8p
?EBV
FcR
CD8Reg
CCR6CCL20
DC
Th17Th17Th17Th17
Th17Th17
NeutNeut
S1Pr
S1Pr
S1Pr
TLR
Fingolimod
IFNBNatalizumab
GA
GA
Fampridine K+
IFNBGA
GA
Rituximab
Tr1Th3
Th2
Th0Th0 IL-4
IL-12
B7-CD28
S1PrTFL
BG-12
CD20
BG-12
Epitopespreading Oligo
AlemtuzumabMitoxantrone
Vit D
KIR4.1
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Marker CIS RRMS SPMS PPMS
Cytokines IL12,TNF,IL6sTNFR, IL10
Treg (CD39) Decreased Normal
B-cells(CD19) ++/CSF ++/CS - -
CXCL3 ++ ++ - -
Anti Glycan IgM
+ -
MMP9/sICAM
++
BDNF + Decreased
S100b (CSF) +
NAA (CSF) ++ -
Osteopontin +++ + +
Cont/FeutinVit.D, ANGT
- + -
Fibulin + + -
Summary of Inflammatory markers by disease stage
Immunopathogenesis of MS
Inflammation
Regeneration
Inflammatory Processes Occurring Early in MS Leadto Demyelination and Axonal Loss
TimeOnset of Disease Inflammation Demyelination Axonal loss
Compston A, et al. Lancet. 2008;372:1502-1517. Kuhlmann T, et al. Brain. 2002;125:2202-2212.Paolilo A, et al. J Neurol. 2004;251:432-439.Trapp BD, et al. Curr Opin Neurol. 1999;12:295-302.
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Gray Matter Lesions in MS
Axonal Transection
Type 1 Type 2 Type 3
Neuronal Apoptosis
Trapp and Nave Ann Rev Neurosci 31:247
Pathogenesis of Neurological Dysfunction:Axonal Transection and Degeneration
Inflammatory demyelination followedby Na+ channel redistribution and remyelination leading to restorationof conduction and clinical remission
Axonal transection resulting in degeneration of the distal axonal segment or loss of trophic support of demyelinated axons leads to loss of neuronal function.
Trapp; Neurocscientist 5:48
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Microglia induce focal axonal swellings by releasing reactive oxygen and nitrogen species (ROS and RNS)
Picture from Axonal injury in reverse by Craner & Fugger
Courtesy of Wee Yong
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Modifies after Yong Neuroscientist, 16:408
Proposed Protective Effects of Lymphocytes and Microglia
Removal ofDebris
Release NeurotrophicFactors
Neutralize Toxic Products
Overcome Inhibitory ECM
Mobilize Astrocytes
Removal of non-permissiveproteoglycans
Stabilize BBB Trophic Support
Axtell & Steinman, Immunity 28:675, 2008
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Factors Affecting Remyelination and Oligodendrocyte Recruitment
► Failed oligodendrocyte precursor cell differentiation:● An untimely transition of the acute inflammatory to
a chronic inflammatory environment● Prolonged presence of early inhibitors ● A premature expression of late inhibitors of
oligodendrocyte precursor cell differentiation● Combinations of the above
► Expression of factors that induce astroglial fate of oligodendrocyte precursors
(1)Hinks and Franklin, 1999; (2) Shields et al., 1999; (3) Marin-Husstege et al.;2002;(4) Shen et al., 2005 (5) Nakahara et al 2009;
Strategies to Promote CNS Remyelination in MS
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Examples of Remyelination in Experimental Models
Control Cup + H2O Cup + Fing
Effect of Fingolimodin the Cuprizone Model (3)
(1) Lin et al. Brain 129:1306; (2) Skihar PNAS 106:17992; (3) Kim et al Faseb J. 25:1509
Effect of IFN-gammain the Cuprizone Model (1)
Effect of glatiramer acetatein the Lysolecithin Model (2)
Strategies to Promote CNS Remyelination in MS
Target/Strategy Agent Pre-clinical Clinical
Inhibition of LINGO-1 LINGO-1 inhibitor Mi et al., 2009 yes
Inhibition DR-7 DR-7 inhibitor Mi et al., 2011
Anti myelin basic
protein E2 137-151
Anti-E2 137-151or E2 137
151 peptide
Patent application
20090311246
Antibody-based rHIgM22 antibody Pirko et al., 2004
Neutralization of myelin
associated inhibitors
RhoA inhibitors/PKC inhibitors
Baer et al., 2009
Inhibition of St8SiaIV (PSA) Koutsoudaki et al., 2010
Inhibition of Notch1 Zhang et al., 2009
Oestrogen-receptor ligand
Crawford et al., 2010
Induce oligo’s to remyelinate
HIgM22 Rodriguez et al., 2009 Filed 2012 ?
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CD4+CD25+ Regulatory T-cells in MS
• Reduced suppressive function in MS
• No difference in frequency between MS and controls
• No difference in cytokine secretion patterns (IL-10, TGFß)
Viglieta et al. J Exp Med 2004;199:971
Induction of CD4+CD25+FOXP3+ Regulatory T cells During GA Treatment
CD4+CD25+FOXP3+
CD4+CD25+FOXP3-
Pre-Rx 3mo 6mo 12mo18-24mo
Pre-Rx 3mo 6mo 12mo 18-24mo
Dhib-Jalbut, S. 2008
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Induction of CD4+CD25+FOXP3+ TregsDuring Glatiramer Acetate Treatment
0.0
2.5
5.0
7.5
10.0CD4+CD25+FoxP3+
Mean GA-R
Pre-Rx 3mo 6mo 12mo 24mo
% g
ated
in
CD
4+ c
ell
s
0.0
2.5
5.0
7.5
10.0CD4+CD25+FoxP3+Mean GA-HR/NR
Pre-Rx 3mo 6mo 12mo 24mo
% g
ated
in
CD
4+ c
ells
Dhib-Jalbut S, et al. 23rd Congress of ECTRIMS, 12th Conference of Rehabilitation in MS;October 11-14, 2007; Abstract ID 52136.
Modulation of Tregs by therapy in MS
Saresella et al. FASEB, 22:3500, 2008
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Feed Your Tregs More Fiber
Julia Bollrath and Fiona Powrie. SCIENCE VOL 341 2 AUGUST 2013
Microbiome: Gut-Brain Axis
Healthy State:Satiation peptidesGut motilityGut permeabilityGut secretion(e.g. endocrines,AMPSs, mucins)Immune cellsCytokines, IgAs
Downward Control Upward Control
Alteration of gut microbiota
Microbiota composition Symbiotic vs. Pathogenic
Microbiotics-derived products
Dietaryintervention
Exogenous AntibioticsExogenousProbiotics
Healthy State:Neuro-development
Disease stateNeuro-immune disorders(e.g. MS, NMO, GBS)
Neuro-psychiatric disorders(e.g. ASD, depression,anxiety, stress, defects inmemory and cognition,co-morbidity with IBS andIBD)
Upward Control
Wang Y. and L. Kasper. Brain Behav Immun. 2013. Dec 25. pii: S0889-1591(13)00600-4. doi: 10.1016/j.bbi.2013.12.015. [Epub ahead of print]
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Dalia Raïch-Regué et al., Immunology Letters, 2013
Regulatory Dendritic Cells
Biswas & Mantovani, Nature Immunologyvolume 11 number 10 october 2010
Macrophage Polarization
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Mikita et al, Multiple Sclerosis Journal17(1) 2–15, 2014
Altered M1/M2 activation patterns ofmonocytes in severe relapsingexperimental rat model of multiplesclerosis. Amelioration of clinical status byM2 activated monocyte administration
Pharmacologic modulation of glial cells
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Targeting the Shift from M1 to M2 Macrophages inExperimental Autoimmune Encephalomyelitis MiceTreated with Fasudil
Liu et alPlos One2013
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MODI et al. THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 288, NO. 25, pp. 18533–18545, June 21, 2013
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Summary-Beneficial inflammation
● T-regulatory cells
● M2 Polarization
● Regulatrory DC
● Microglial function modulation
● Astrocyte modulation
● Neurotrophic factors
Inflammation: Favorable & detrimental factors
Kantarci et al. Clinical pharmacology & Therapeutics | VOLUME 95 NUMBER 1 januar y 2014