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In The Name Of God
Dr Alsahebfosoul
Immunology Department
Isfahan University of Medical Sciences
 Onset most commonly between ages 20 and 40
 Affects women about twice as often as men
PREVALENCE
In northern Europe ,Scandinavia ,British island, North America
(about 1-2 in 1000 ) .
Uncommon among Turkmen ,Uzbeks , Kazakhs ,Chinese , African
blacks
EPIDEMIOLOGY
 >2 million individuals are affected by MS disease worldwide.
 Iran
Isfahan
20-60/100000
73.4 / 100000
 Isfahan is considered as an area with a medium to high

risk of MS

Caucasians are more at risk than other races
ANNUAL COST
 It costs approximately $ 35,000 per year for
the
treatment of MS.
 The individual costs of RR drugs (per year):
Novantrone* - $5,000 - $10,000
Copaxone – $16,000
Avonex & Betaseron - $19,000
Rebif - $23,000
 In a lifetime, someone with MS will likely pay
$ 3.2 million in treatment costs.
MS AS A COMPLEX DISEASE
Environment
Pathogens
Chemicals
Smoking
Diet
Sun exposure
Vitamin D
Epigenetic,
Post-genomic
And regulatory events
Gene rearrangements
Somatic mutations
Messenger RNA splicing
And/or editing
Retroviral sequences
Methylation
MicroRNAs
Genome allelic variants
Single nucleotide polymorphisms
Copy number variation
Insertion-deletion polymorphisms
Disease modifier genes
Disease susceptibility genes
ETIOLOGY
Complex with multiple causal factors
Environmental agents
Chemicals
UV light
Migration
Infectious agents
EBV, HHV-6, measles virus, HERV
Chlamydophila pneumonia . H.Pylori
Genetic predisposition
HLA- DRB1*1501
HLA-DR2
IL-2R and IL-7 receptor mutations
Latitude
SES
Migration
Environmental
factors
Vitamin D
Infection
As you increase latitude, mainly above and below 40°
latitude, MS is more common in against latitude for sibling
data
the prevalence of MS in low-risk regions in areas nearer
the equator is increasing(South America and Spain)
Your socioeconomic status can also affect the
occurrence of MS
If you move before the age of 15, your risk is that of the
people in the country you move to
If you move after the age of 15,your risk stays fixed at that
of the country you grew up in.
The MS risk in the Iranian migrants in Gothenburg was
several times higher than in Iran
Reduction in MS release rate with
increasing vitamin D
The viral infections may include chicken pox, measles,
or certain herpes.
Hygiene Hypothesis
Birth month
Birthday in Spring
ENVIRONMENTAL FACTOR :
VITAMIN D
Increase vitamin D
Decrease MS risk
MS :
ENVIRONMENT AND GENES
Genome allelic
variants
SNPs in HLA region as the strongest
susceptibility loci for MS
women are in general more to
have an Auto immune Disease.
Sex
women being affected 2–3 times more than men
African American men were shown to have an
approximate 40% lower MS risk than white men
Genetic
Factor
Racial group
Family history
Whites are more than twice as
likely as other races to develop MS
a normal population
0.1%
parent, brothers, or sisters
second-degree relative
both of your parents
Half siblings
full siblings
Monozygotic twins
3%
0.1%
20%
1.5%
3-4%
30%
FIGURE1
Its cause may be genetic or of environmental origin (infectious)
MHC genes in chromosome six,
particularly DR15 and DQ6 alleles
More common in people living further from the equator
It is an inflammatory disease with an
auto-immune basis
Blood-brain barrier not permeable
unless triggered by a virus
EXAMPLES OF GENE DEFECTS
57 candidates genes with risk factors
MHC II (HLA-DR:DRB1*1501 )
non-MHC genes(IL2Ra , IL7Ra)
AIRE-1 (autoimmune regulator-1 gene) mutation (usually deletion)
Epistasis (interaction of susceptibility genes)
Gene
Chro
IL2R
10
Regulation of T-cells
IL7R
5
Homeostasis of the memory T-cell pool
CD58
1
Influences T-cell proliferation and differentiation
CLEC16A
16
Provides signals for decisions between tolerance
and immunity
CD226
18
HLA-G
6
Function
Adhesion and co-stimulation T-cells
Regulating immune reactivity in the CNS
Gene
Chr Function
Disease
IL7R α
5
Homeostasis of the memory T-cell pool
T1D
IL2R α
10
Regulation of T-cells
T1D & Graves'
disease
CLEC16A
16
Provides signals for decisions between
tolerance and immunity Addison's disease
T1D
CD226
18
Adhesion and co-stimulation T-cells
T1D, RA, Graves‘
disease, Crohn's
disease
CD58
1
Influences T-cell proliferation and
differentiation
RA
Gene
SNP
HLA-DRB1*1501
CD40
rs6074022
rs1883832
NOTCH4
rs422951
(MHC Class III)
HLA-DQA2
year
association
Article title
population
HLA-DRB1*1501 intensifies the impact of IL-6
promoter polymorphism on the susceptibility to
multiple sclerosis in an Iranian population
Iran
2010
Yes
Association of SNPs of CD40 Gene with Multiple Sclerosis
in Russians
Russians
2013
Yes
SNP-based analysis of the HLA locus in Japanese multiple
sclerosis patients
Japanese
2012
Yes
Fine Mapping and Functional Analysis of the Multiple
Sclerosis Risk Gene CD6
Spanish
2013
YES
Australian
2013
Yes
Spanish
2013
NO
rs3997849
(MHC Class II)
HLA-DRB1,
HLA-DRB5 (MHC Class II)
rs660895
NRM (MHC Class I)
rs2269704
HLA-DQB1
rs1694112
CD6
Non HLA
rs11230559
rs2074225
rs650258
The influence of non-HLA gene polymorphisms and
interactions on disease risk in a
Western Australian multiple sclerosis cohort
IL7R/CD58,
CLEC16A/CTLA-4,
and TYK2/IRF5
Fok1
rs2228570
Taq1
Rs731236
Vitamin D3 Receptor (VDR) Gene rs2228570 (Fok1) and
rs731236 (Taq1) Variants Are Not Associated with the Risk for
Multiple Sclerosis: Results of a New Study and a Meta-Analysis
Overview of published genome-wide association studies in MS
Oksenberg, J. R. & Baranzini, S. E. (2010) Multiple sclerosis genetics—is the glass half full, or half empty?
Nat. Rev. Neurol. doi:10.1038/nrneurol.2010.91
Established non-MHC susceptibility genes and variants in MS
Oksenberg, J. R. & Baranzini, S. E. (2010) Multiple sclerosis genetics—is the glass half full, or half empty?
Nat. Rev. Neurol. doi:10.1038/nrneurol.2010.91
Non-MHC regions containing associated SNPs
HLA-DRB1*1501 ALLELE & SUSCEPTIBILITY TO MS
Author
Type of MS
Country
Year
association
Shahbazi
Iran
2010
Yes
Ghabaee
Iran
2009
Yes
RR & PP MS
Iran
2000
Yes
CPMS
Iran
1998
NO
Spain
2013
Yes
Kalanie
Amirzargar
Elena García
Time until DRB1*1501 positive and negative
* Expanded Disability Status Scale ( EDSS )
HLA-DQA1*0102 ALLELE & SUSCEPTIBILITY TO MS
Author
place
Year
Kalanie
Iran
2000
NO
2006
Yes
Marrosu
association
Marrosu
Mediterranean
island of Sardinia
1993
Low
Haegert
Mediterranean
island of
Sardinia
1993
Low
HLA-DQB1*0602 ALLELE & SUSCEPTIBILITY TO MS
Author
population
Year association
Karin Weiner lachmi
Caucasian
2013
No
Olivier Andlauer
Stanford
2012
No
Ghabee
Iran
2009
NO
Zivadinov
northeastern Italy
2003
NO
Amirzargar
Iran
1998
NO
Marrosu
Southern European regions such
as Sardinia
1993
NO
Marrosu
Sardinia
1993
NO
Haegert
Northeastern Italy
1993
NO
MICRO RNA
can post-transcriptionally regulate
entire sets of genes
are involved in regulation of the
immune system and in the
generation of T regulatory cells
Cell 2009
2-∆∆Ct
2-∆∆Ct
All miRNAs in the network are
upregulated in MS patiens
Article
Population
year
Zare
Iran
2013
Impaired neurosteroid synthesis in multiple
sclerosis
Noorbakhsh
Iran
2011
IL-17A mRNA
Interleukin-17A and interleukin-17F mRNA
expression in peripheral blood mononuclear
cells of patients with multiple sclerosis.
Babaloo
Iran
2010
miRNA
MicroRNAs as Diagnostic and Therapeutic
Targets in Multiple Sclerosis
Pahlevan
Kakhki
Iran
2013
miRNA
MicroRNA profiling of multiple sclerosis lesions
identifies modulators of the regulatory protein
CD47.
Junker A
German
2009
miRNA
(miR-614, miR-572, miR-648,
miR-1826, miR-422a and miR22)
Circulating microRNAs involved in multiple
sclerosis.
Siegel SR
USA
2012
hsa-miR-145
Multiple Sclerosis: MicroRNA Expression
Profiles Accurately Differentiate Patients with
Relapsing-Remitting Disease from Healthy
Controls
Keller A
South
Africa
2009
Gene
Title
miRNA
MicroRNAs and multiple sclerosis: from
physiopathology toward therapy
micro-RNAs
(miR-338, miR-155 and miR-491)
Article
Population
year
Shahkarami
Isfahan, Iran
2013
Sadeghi
Isfahan, Iran
2013
Shaygannejad
Isfahan, Iran
2013
Detection of Chlamydia Pneumoniae in the
Cerebrospinal Fluid of Multiple Sclerosis Patients and
other Neurological Disorders
Etemadifar
Isfahan, Iran
2012
CD24
CD24 gene allele variation is not associated with
oligoclonal IgG bands and IgG index of multiple
sclerosis patients.
Saadatnia
Isfahan, Iran
2012
MS & Guillain-Barre
Linkage of Multiple Sclerosis and Guillain-Barre
Syndrome: A Population-Based Survey in Isfahan, Iran
Etemadifar
Isfahan, Iran
2012
Epilepsy & MS
Epileptic seizures in early-onset multiple sclerosis: a
population-based study in Isfahan, Iran.
Roomizadeh
Isfahan, Iran
2011
Ndufv2
investigation of relationship between Ndufv2 gene and
multiple sclerosis disease
Akbari chelar
Isfahan, Iran
2011
Gene
Title
INF beta-1a
Neutralizing antibodies in multiple sclerosis patients on
weekly intramuscular Avonex and biosimilar interferon
beta-1a (CinnoVex): comparing results of measurements
in two different laboratories
Apo E
Polymorphism of Apo lipoprotein E gene and the risk
of MS
VDR
What is the Real Fate of Vitamin D in Multiple
Sclerosis?
Chlamydia Pneumonia
In CSF
Gene
Title
Article
Population
year
Female /Male
Increasing female preponderance of multiple
sclerosis in Isfahan, Iran: a population-based
study.
Maghzi
Isfahan, Iran
2010
HLA-DRB1
Characterization of D6S2806 and D6S2879
short tandem repeat loci in HLA-DRB1 region
in Iranian population
Vallian
Isfahan, Iran
2010
CD14,CD4,CD8
multiple sclerosis center,tel has homer
:laquinimiod suppress antigen presentation in
RRMS :in vitro high-throughput gene
expression study
shaygannejad
Isfahan, Iran
2010
EBV genotypes
Viral pathophysiology of multiple sclerosis:
A role for Epstein-Barr virus infection?
Etemadifar
Isfahan, Iran
2010
CD24
CD24 gene polymorphism is associated with
the disease progression and susceptibility to
multiple sclerosis in the Iranian population.
Etemadifar
Isfahan, Iran
2009
Gene
Title
Article
Population
Year
RETN resistin
(Rs1862513)
A polymorphism in the resistin gene promoter and the risk of
multiple sclerosis.
HosseinNezhad
Iran
2013
RAR
Impact of Vitamin A Supplementation on RAR Gene Expression
in Multiple Sclerosis Patients.
Bitarafan
Iran
2013
cytochrome c
oxidase (COX)
Investigation of cytocrom c oxidase gene subunits expression
on the Multiple sclerosis
Safavizadeh
Iran
2013
CXCR1 &
CXCR2
Quantitative evaluation of CXCL8 and its receptors (CXCR1
and CXCR2) gene expression in Iranian patients with MS
Almasi
Iran
2013
IL2
The association of -475 and -631 interleukin-2 gene
polymorphism with multiple sclerosis in Iranian patients
Sayad
Iran
2013
MBP/PLP
Regional regulation of glutamate signaling during cuprizoneinduced demyelination in the brain.
Azami Tameh
Iran
2013
mitochondrial gene
Multiple sclerosis and mitochondrial gene variations: a review
Andalib
Iran
2013
IL-6
Evaluation of cytokines in multiple sclerosis patients treated
with mesenchymal stem cells
Mohyeddin
Bonab
Iran
2013
Article
Population
year
Relationship between NF-κB1 -94 ins/del ATTG
polymorphism and susceptibility of multiple sclerosis
in Iranian MS patients
Zahednasab
Iran
2013
CCR5
Is the CCR5 Δ 32 mutation associated with immune
system-related diseases?
Ghorban
Iran
2013
IL-10
Is the IL-10 promoter polymorphism at position -592
associated with immune system-related diseases?
Karimabad
Iran
2013
(HHV6) sequence
Monitoring of Active Human Herpes Virus 6 Infection
in Iranian Patients with Different Subtypes of Multiple
Sclerosis
Ramroodi
Iran
2013
APOE
Apolipoprotein E polymorphisms status in Iranian
patients with MS
Rafiei
Iran
2012
human caveolin 1
(CAV1)
Haplotypes across the human CAV1 gene upstream
purine complex significantly alter gene expression:
implication in neurodegenerative disorders.
Heidari
Iran
2012
HLA-DRB1 and HLADQB1
The influence of the HLA-DRB1 and HLA-DQB1 allele
heterogeneity on disease risk and severity in Iranian
patients with multiple sclerosis.
Kollaee
Iran
2012
IL-4
Association of interleukin-4 polymorphisms with
multiple sclerosis in southeastern Iranian patients.
Arababadi
Iran
2012
CD94,CD178 and
TRAIL
Evaluation of apoptosis-related genes: Fas (CD94),
FasL (CD178) and TRAIL polymorphisms in Iranian
multiple sclerosis patients.
Mohamadzadeh
Iran
2012
Gene
Title
NF-κB1
Gene
Title
Article
Population
year
CXC chemokine
SDF-1α (CXCL12)
The SDF-1 3'a genetic variation of the chemokine SDF-1α
(CXCL12) in parallel with its increased circulating levels is
associated with susceptibility to MS: a study on Iranian
multiple sclerosis patients.
Azin
IRAN
2012
CCR2 and CCR5
Ccr2-64i and Ccr5 Δ32 Polymorphisms in Patients with
Late-Onset Alzheimer’s disease; A Study from Iran (Ccr264i And Ccr5 Δ32 Polymorphisms in Alzheimer’s disease)
IRAN
2012
CD24
Investigation of CD24 and its expression in Iranian
relapsing-remitting MS
Kollaee
IRAN
2011
MICB
MICB gene expression on peripheral blood mononuclear
cells and susceptibility to multiple sclerosis in north of Iran.
Abediankenari
IRAN
2011
CAV1
The human caveolin 1 gene upstream purine complex and
neurodegeneration--a common signature.
Heidari
IRAN
2011
Olig2, MBP,
Nogo-A and GFAP
mRNAs
Castration attenuates myelin repair following lysolecithin
induced demyelination in rat optic chiasm: an evaluation
using visual evoked potential, marker genes expression and
myelin staining.
Sherafat
IRAN
2011
paraoxonase 1
(PON1)
Lack of association between paraoxonase 1 Q192R
polymorphism and multiple sclerosis in relapse phase: A
case-control study.
Moghtaderi
IRAN
2011
FOXP3
FOXP3 gene expression in multiple sclerosis patients preand post mesenchymal stem cell therapy.
Mohajeri
IRAN
2011
Gene
Title
Article
Population
year
HLA-DRB1*1501
and TNF-alpha
Interaction of HLA-DRB1*1501 allele and TNF-alpha
-308 G/A single nucleotide polymorphism in the
susceptibility to multiple sclerosis.
Shahbazi
IRAN
2011
IL7Ra
Variation in SNPs of the IL7Ra gene is associated
with multiple sclerosis in the Iranian population.
Heidari
IRAN
2011
CXCR3, CCR5 and
CCR6
Expression of chemokine receptors on Th1/Th2
CD4+ lymphocytes in patients with multiple
sclerosis.
Andalib
IRAN
2011
Mostafavian
IRAN
2011
Amini
IRAN
2011
Javadian
IRAN
2011
Polymorphism of Apo lipoprotein E and Angiotensin
converting enzyme genes and the risk of multiple
sclerosis.
Mousavian
IRAN
2011
COX5B
Investigation of Relationship Between COX5B Gene
Expression and Multiple Sclerosis Disease
Motaei
IRAN
2011
microRNA
(miR-338,
miR-155 & miR491)
Impaired neurosteroid synthesis in multiple sclerosis
Noorbakhsh
IRAN
2011
Epidemiology of Multiple sclerosis in
Mashhad
HLA-DRB1*15
HLA allele frequencies in Iranian multiple sclerosis
patients
IL7Ra
Association and Expression Study of IL7Ra Gene
Polymorphisms In Iranian Multiple Sclerosis Patients
Gene
Title
Article
Population
year
IL-17A and IL-17F
Interleukin-17A and interleukin-17F mRNA expression in
peripheral blood mononuclear cells of patients with
multiple sclerosis.
Babaloo
IRAN
2010
CTLA-4
CTLA-4 gene polymorphisms (-318C/T, +49A/G,
+6230A/G) in Iranian patients with multiple sclerosis.
Heidari
IRAN
2010
non-HLA
The role of non-HLA single nucleotide polymorphisms in
MS susceptibility.
Bahreini
IRAN
2010
HLA-DRB1*1501 allele and
IL-2
High frequency of the IL-2 -330 T/HLA-DRB1*1501
haplotype in patients with multiple sclerosis
Shahbazi
IRAN
2010
TNFa & TGF-b & IL6 &
IL10
Cytokines genes polymorphisms and risk of multiple
sclerosis.
Izad
IRAN
2010
Foxp3
Effect of IFN-beta therapy on the frequency and function
of CD4(+)CD25(+) regulatory T cells and Foxp3 gene
expression in relapsing-remitting multiple sclerosis
(RRMS): a preliminary study.
Namdar
IRAN
2010
human CAV1
Skew in the human caveolin 1 gene upstream purine
complex homozygote haplotype compartment in multiple
sclerosis.
Yeganeh
IRAN
2009
CTLA4
CTLA4 exon 1 and promoter polymorphisms in patients
with MS
Yousefipour
IRAN
2009
IL-2, IFN-g, and IL-12
IL-2, IFN-gamma, and IL-12 gene polymorphisms and
susceptibility to multiple sclerosis.
Shokrgozar
IRAN
2009
Gene
Title
Article
Populati
on
year
CCR5-delta
CCR5-delta 32 allele is associated with the
risk of developing multiple sclerosis in the
Iranian population.
Shahbazi
IRAN
2009
HLA-DRB, DQA and
DQB
Optic neuritis, multiple sclerosis and HLA:
results of a 4-year follow-up study
Amirzargar
IRAN
2005
IFN- gamma
Interferon-gamma gene polymorphism in
Iranian patients with MS
Izad
IRAN
2004
mitochondrial DNA
(mtDNA)
Lack of association between Leber's
hereditary optic neuropathy primary point
mutations and multiple sclerosis in Iran.
Houshmand
IRAN
2004
HLA class II (DRB1,
DQA1 and DQB1)
HLA class II (DRB1, DQA1 and DQB1)
associated genetic susceptibility in Iranian
multiple sclerosis (MS) patients
Amirzargar
IRAN
1998
Apolipoprotein E
(apoE)
Apolipoprotein E polymorphism in Southern
Iran: E4 allele in the lowest reported
amounts.
Barzegar
IRAN
2008
CTLA4 exon 1
CTLA-4 exon 1 A/G polymorphism in Iranian
patients with multiple sclerosis.
Borhani
IRAN
2008
IL-1, IL-1R and TNFa
IL-1, IL-1R and TNFalpha gene
polymorphisms in Iranian patients with
multiple sclerosis.
Sarial
IRAN
2008
mitochondrial tRNA
Investigation on mitochondrial
tRNA(Leu/Lys), NDI and ATPase 6/8 in
Ahari
IRAN
2007
Gene
Title
Article
Population
year
TNF-alpha
TNF-alpha, TNF-beta and IL-4 gene
polymorphisms in Iranian patients with
multiple sclerosis.
Kamali
IRAN
2007
ICAM-1
Intercellular adhesion molecule-1 gene
polymorphism in Iranian patients with
multiple sclerosis.
Mousavi
IRAN
2007
IL-2,IL-6,
TNF-alpha
Profile of cytokine gene polymorphisms in
Iranian multiple sclerosis patients.
Amirzargar
IRAN
2007
Fcg RIIA & Fcg RIIIA
Investigation of Fcg RIIA and Fcg RIIIA
Polymorphism in Multiple Sclerosis:
A Case Control Study
Nikseresht
IRAN
2006
IL-8 and CXCR2
IL-8 (-251 A/T) and CXCR2 (+1208 C/T)
gene polymorphisms and risk of multiple
sclerosis in Iranian patients.
Kamali
IRAN
2006
mitochondrial genome
Mitochondrial D-loop variation in Persian
multiple sclerosis patients:
K and A haplogroups as a risk factor
Hassani
IRAN
2006
Thank you so Much For Your Attention