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Citation: Ghasemi N, Razavi Sh, Nikzad E. Multiple sclerosis: pathogenesis, symptoms, diagnoses and cell-based
therapy. Cell J. 2017; 19(1): 1-10.
Introduction
thinking, and emotional problems (1).
Multiple sclerosis (MS), the most prevalent
neurological disability, is an autoimmune-medi- Subtypes of MS are considered important not
ated disorder that affects the central nervous sys- only for prognosis but also for treatment decisions
tem (CNS) and often leads to severe physical or and include: relapsing remitting MS (RRMS), pri-
cognitive incapacitation as well as neurological mary progressive MS (PPMS), secondary progres-
problems in young adults (1). Multifocal zones sive MS (SPMS), and progressive relapsing MS
of inflammation due to focal T-lymphocytic and (PRMS). RRMS is the most common subtype (ap-
macrophage infiltrations, and oligodendrocyte proximately 87%) which characterized by unpre-
death are the primary causes of myelin sheath de- dictable acute attacks followed by periods of re-
struction (2) that result in the formation of CNS mission (3). During RRMS, inflammatory attacks
plaques composed of inflammatory cells and their on myelin and nerve fibers occur. Activated im-
products, demyelinated and transected axons, and mune cells cause lesions in the CNS which gener-
astrogliosis in both white and gray matter. These ate symptoms of visual impairments, tingling and
lesions can cross-talk with the correct transmission numbness, episodic bouts of fatigue, intestinal and
of nerve impulses and lead to neuronal dysfunc- urinary system disorders, spasticity, and learning
tion such as autonomic and sensorimotor defects, and memory impairment. Approximately 10-15%
visual disturbances, ataxia, fatigue, difficulties in of MS patients are diagnosed with PPMS which
largely affect the nerves of the spinal cord. PPMS pa- of MS (15, 16). Pathogen-associated molecules
tients tend to have fewer brain lesions. Induced symp- simultaneously bind to toll-like receptors on APCs
toms include problems with walking, weakness, stiff- and production of specific cytokines that include
ness, and trouble with balance. Nearly 65% of patients interleukin (IL)-12, IL-23 and IL-4 begins that these
with RRMS will subsequently develop SPMS which cytokines induce CD4+ T cell differentiation intoTh1,
is considered the second phase of this disease. Many Th2, or Th17 phenotypes which have ability to release
individuals experience increased weakness, intestinal special cytokines. Interferon gamma (IFNγ) or type II
and urinary system disorders, fatigue, stiffness, men- interferon and tumor necrosis factor alpha (TNF-α)
tal disorders, and psychological impairment. Finally, are proinflammatory cytokines critical for innate and
PRMS is the least common type of MS that occurs in adaptive immunity. These cytokines are produced
approximately 5% of patients and is associated with by Th1 cells (17).They have the ability to promote
symptoms such as eye pain and double vision, along inflammation by suppressing Th2 differentiation.
with sexual, intestinal and urinary system dysfunc- Th2 cells secrete the anti-inflammatory cytokines,
tion, dizziness, and depression. Generally MS is de- IL-4 and IL-13 (18, 19). IL-4 reduces pathological
tected between the ages of 20 and 40 years, but less inflammation via increase in M2 macrophage (or
than 1% can occur in childhood and approximately repair macrophages) and alternative activation of M1
2-10% after 50 years of age (4, 5). macrophages that promote inflammation. The effects
of IL-13 on immune cells is similar to IL-4. This
This pathologic condition affects women more than
cytokine, by secretion of matrix metalloproteinase,
men (sex ratio 2.5:1) and the prevalence varies by
has anti-inflammatory properties especially during
geographic area, ranging from 120 per 100,000 indi-
allergic inflammation (20). Th17 is another CD4+
viduals (6, 7). The etiology of MS remains unclear,
T cells which induces a large number of cytokines
however it can be considered a multifactorial disease
(IL-17, IL-21, IL-22 and IL-26) which are capable of
and include a genetic predisposition combined with
promoting inflammation (Fig.1A) (21).
environmental influences (8).
B lymphocytes and their cytokines are other
The initial treatment strategy for MS is largely based
factors in the pathogenesis of MS. Lymphotoxin [or
on disease-modifying drugs such as interferon-β and
transforming growth factor beta (TGF-β)] and TNF-α
glatiramer acetate (9, 10). The effects of these treat-
produced by these cells promotes inflammation. In
ments are partially for symptomatic alleviation and do
addition, these cells are capable of producing IL-10
not stop the ongoing neurodegeneration.
which is an anti-inflammatory cytokine. Hence, B
Currently, a stem cell-based regenerative medicine lymphocytes have both positive and negative effects
paradigm has been proposed for the treatment of MS in the development of MS (22).
(11-13). Adult stem cells, including hematopoietic and
Many studies have shown that in addition to the
mesenchymal stem cells (MSCs), are undifferentiated
above-mentioned cells, CD8+ T cells (or cytotoxic T
cells used to treat MS due to their immunomodulatory
cells) can be found in MS lesions (23). These cells, via
effects and neuroprotective potential (14).
the production of cytolytic proteins such as perforin,
We review the pathogenesis, a number of envi- mediate suppression and inactivation of CD4+
ronmental factors, genetic susceptibility, diagnos- T cells. Moreover, these cells thorough increase
tic criteria, and treatment of MS. vascular permeability, glial cells destroy and trigger
of oligodendrocyte death play an important role in the
Pathogenesis of multiple sclerosis pathogenesis of MS. In addition to CNS inflammation,
the myelin repair process due to oligodendrocyte
Inflammation of the white and gray matter death is also impaired (16).
tissues in the CNS due to focal immune cell
infiltration and their cytokines are the incipient Fas ligand (FasL) is produced by lymphocyte
cause of damage in MS. Many studies have cells. This ligand binds to Fas receptors [cell surface
suggested T helper (Th) cell (also known as receptor that belongs to the TNF receptor superfamily]
CD4+ T cells) intervention and adaptive immune on oligodendrocyte cells which begins the apoptosis
responses which initiated by interaction between process of these cells (24). Therefore, the numbers
antigen presenting cells (APCs) with T lymphocytes of myelin synthesis cells reduce and will impair
play an important role in the initiation and progression synthesis of the myelin sheath (Fig.1B).
Fig.1: Immune cells and their cytokines which involved in the pathogenesis of multiple sclerosis (MS).
and differentiation (36). In addition, this vitamin in the human leukocyte antigen (HLA) region of
has a role in gene expression and regulation chromosome 6 exists a group of genes associated
of immunity (37), as well as induction of B with an increased risk of MS. Within this region
lymphocyte apoptosis (38), IL-10 synthesis (39), HLA-DR2+ (53), HLA-DQ6 (1), DQA 0102 and
and suppression of proinflammatory cytokines DQB1 0602 (54), HLA-DRB1 (54), DR15 (55),
such as IFN-γ (40) and IL-2 (41). DRB1*1501, and DRB1*1503 (56) are genes
susceptible to the onset of MS. In addition to these
Vitamin B12 is an important factor in the
alleles, IL-7 and IL-2 receptor alpha are other
generation of myelin shell components. Thus,
sensitive genes associated with MS (57). Unlike
deficiency of this vitamin can be a major cause for
the aforementioned genes, HLA-C554 and HLA-
neurological diseases such as MS. The results of
DRB1*11 have protective effects (1).
a previous study on MS patients have indicated
that the application of vitamin B12 benefitted the
Clinical manifestations
clinical course of MS (42).
Usually, MS symptoms are unpredictable and
Beyond vitamin deficiency, low-term sunlight
uncertain. Since this disease can affect any region
exposure has been identified as a potential risk of the CNS, it can generate almost any neurologic
factor for MS. The results of a previous study symptom. In addition, symptoms vary greatly
have demonstrated a reverse association among among patient and within one patient over time.
exposure to ultraviolet radiation and the incidence During the course of MS, some abnormalities
of MS (30). In justifying this relationship, it can be appear to be more dominant or have a greater
said that sun light is a principal source of vitamin effect on functional ability. Table 1 lists the more
D3 and via induction of T regulatory (Treg) cells common symptoms of MS that may appear during
and anti-inflammatory cytokines such as IL-10 and different courses of the disease (58).
TNF-α, it may have immunomodulatory effects in
MS (43). Diagnosis of multiple sclerosis
According to previous reports, diet could be Early detection of MS is important because it
an environmental factor involved in MS (44). gives us the opportunity to seek treatment and
Studies reported a significant negative association plan for the future. An exact diagnosis of MS
between MS risk and high fish intake (45), a is based on medical history and neurological
positive significant association between high examination using imaging techniques such as
animal fat-based caloric intake and MS risk (46), magnetic resonance imaging (MRI), lumbar
a non-significant lower risk between incidence of punctures (LP) for cerebrospinal fluid (CSF)
MS and a higher intake of linoleic acid (28), and a analysis, evoked potentials, and blood samples
positive significant association between obesity in analysis (59). Obtaining a history about the
adolescent girls and MS risk (47). onset of the first symptoms, any neurological
disorders as well as illnesses such as diabetes
Genetic susceptibility and thyroid diseases, food habits, geographic
A genetic predisposition may be involved in locations, and history of medications taken and
MS. Studies show that the risk of MS in family substance abuse is important. In addition, an
members of a patient depends on the amount of eye examination and evaluation of Babinski’s
genetic information they share (48-50). Thus, the reflexes can be useful. MRIs can identify any scar
risk rate in monozygotic-twins that have 100% tissue formation and damage in the CNS. Evoked
genetic similarity is approximately 25%. In all potentials test (60) that include visual, brain stem
individuals who have 50% genetic similarities auditory, and somatosensory evoked potentials
such as dizygotic twins and first degree relatives, offers information about demyelination in the
this risk is 2-5% (51, 52). In addition, the risk optic nerve and CNS. In addition, CSF analysis
in second degree relatives with 25% genetic for myelin basic protein and immunoglobulin-
similarity is 1-2%, whereas in third degree gamma (IgG) determinations (61) and blood
relatives with 12.5% genetic similarity, this risk sample analysis for detect of vitamin deficiencies
is less than 1% (48-50). It has been shown that may be diagnostically helpful (62).
Cell-based therapy for multiple sclerosis cell activation and migration through the blood
Currently, there is no definite cure for brain barrier) (69), and methotrexate (reduces
MS. However, immunomodulating and anti- inflammation) (70) are used in RRMS and SPMS.
inflammatory agents can diminish its progression Generally, these agents do not halt the ongoing
and decrease some of the pathological symptoms. progression of neurodegeneration. Therefore,
Immunomodulating agents including interferon other strategies such as stem cell-based therapy
beta and glatiramer acetate are used in non- are proposed as potential novel paradigms for the
symptomatic MS, RRMS, and SPMS (63). These treatment of MS.
agents can lessen some of the MS symptoms by
inhibition of immune cell activation, decrease of Access to human MS neural tissue is limited and
proinflammatory cytokines production, matrix neural tissue biopsies are rarely performed. Hence,
metalloproteinase activity reduction, induction of a variety of mammalian species - mice, rats, goats,
anti-inflammatory cytokine secretion (64), and pigs, sheep, rabbits, and non-human primates can
by increasing expression of Foxp3 in CD4+ and be used for cell transplantation in order to study
CD25+Treg cells (65). various aspects of MS (71). The mouse model is
the most common animal model for MS due to
Others agents such ascorticosteroids (inhibit its high biologically similarity with humans. In
lymphocyte proliferation and secretion of pro- addition, mice are small, relatively easy to handle,
inflammatory cytokines) (66), mitoxantrone cost-effective, and undergo rapid reproduction.
(inhibit macrophage mediated myelin degradation Thus, mice could be efficient research tools for
and diminish the production of pro-inflammatory more accurate, reproducible experiments in cell-
cytokines) (67), cyclophosphamide (increases based therapy. Prior to the conduction of any
Th2 cells) (68), mycophenolate (inhibits immune clinical trial, the medications in question should
be studied in larger animal models that are more showed that hES-MSCs considerably decreased
similar to human physiological and anatomical clinical signs and prevented neuronal demyelination.
structures, and their results must be acceptable. The EAE disease-modifying effect of hES-MSCs
was much higher than BM-MSCs (76).
On the other hand, stem cell therapy for treatment
of MS has been conducted with various intentions, Available evidence indicated that placental
including: cell replacement, upregulation of nerve MSCs showed therapeutic effects in an EAE
growth factors, down regulation of inflammatory mouse model of MS. These effects were caused
cytokines and apoptotic factors. To date, cell by reduction of anti-inflammatory proteins such
transplantation experiments that have been as TNF-α-stimulated gene/protein 6 (TSG-6)
conducted for MS treatment pursued at least one in the inflammatory regions (77). Trubiani et al.
of these points. (78) reported that human periodontal ligament
stem cells (hPDLSCs) seemed to be ideal sources
MSCs are stem cells with the capability to
for MS treatment due to their ability to secrete
differentiate into other cells. They display several
neurotrophic factors and by modulate expression
significant anti-proliferative, anti-inflammatory
of TNF-α, IL-1β, IL-10, Nrf2, and Foxp3.
and anti-apoptotic features (14). These cells are
proven to be potentially effective in MS treatment Recently, it has been reported that olfactory
due to their immunomodulatory properties ensheathing cell (OEC) transplantation in
(regulation and maintenance of Treg lymphocyte a cuprizone model of MS improved myelin
function) (72) and paracrine effects (via bioactive restoration through modification of MBP and
growth factor secretion and IL-6 and TGF-β phospholipid P (PLP) levels of the myelin sheath
production) (73). (79). Ravanidis et al. (80) demonstrated that
subcutaneously transplanted neural precursor cells
Previously, Mikaeili Agah et al. (74) reported
improved the clinical outcome and pathological
that human Wharton’s jelly stem cell-derived
features of EAE by modulating chemokine levels.
oligodendrocyte progenitor cells (hWJ-MSC-
derived OPCs) transplanted into the brain Bai et al. (81) reported that MSCs can reduce
ventricles of an MS mouse model significantly mouse neural functional deficits through
diminished the clinical signs of MS and induced modulation of the immune response and
functional improvements. In addition, histological remyelination process and by promotion of the
examinations demonstrated that hWJ-MSC-derived development of oligodendrocytes and neurons.
OPCs transplantation promoted the regeneration
Successful experiments in animal models of
of myelin sheaths in the brain lesions. Pluchino et
neurodegenerative diseases such as MS have shown
al. (75) reported similar functional improvements
that neurotrophic factor secreting cells (NTF-SCs)
following transplantation of adult neural stem
differentiated from MSCs can play a pivotal role
cell into an animal model of MS. The result of
in impeding various neurodegenerative processes.
this study demonstrated that significant numbers
NTF-SCs, by secreting a group of nerve growth
of transplanted cells migrated into demyelinating factors necessary for neuronal development and
lesions and differentiated into mature cells. They survival, pave the way for use of NTF cells as
observed functional recovery due to remyelination treatment for MS patients (13). Transplanted
improvement following increased oligodendrocyte hES-MSCs, placental MSCs, hPDLSCs, NTF-
progenitor cells and decreased astrogliosis. As SCs, and OECs in MS models have resulted in
seen, these studies with hWJ-MSC and adult neural remyelination improvements due to suppression
stem cell were conducted for cell replacement and of the inflammatory response, modulation of
not considered for other cell therapy purposes. the immune response, and nerve growth factors
MSCs derived from human embryonic stem cells secretion (13, 76-79). However, other types of
(hES-MSCs) appeared to be a better cell source stem cells are required which not only have these
effects but also can be easily differentiated into
compared to human bone marrow-derived MSCs
oligodendrocyte cells.
(BM-MSCs) for treatment in a mouse model of MS
[experimental autoimmune encephalitis (EAE)] due Adipose-derived stem cells (ADSCs) are a
to BM-MSCs increased IL-6 expression. The results population of MSCs that are an abundant and easily
accessible cell source for clinical applications. Stem Cell Technology and Isfahan University of
These cells can differentiate into other cells outside Medical Sciences for their financial support (Grant
their lineage such as neurons, NTF-SCs, and no. 189067). The authors declare that they have no
Schwann cells (82-84). ADSCs have the ability to conflicts of interest.
secrete many identified NTF factors such as brain-
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