Neurology & Neurosurgery - Juniper Publishers
Abstract
Introduction: Multiple Sclerosis (MS) is a
complex neurodegenerative disease whose pathophysiology involves
demyelinating changes, axon injury, oligodendrocytic death, neuron
apoptosis, and inflammation and demyelination of both white and gray
brain matter.
Discussion: The role of T cells/B cells has
been fairly well documented in MS patients. Analysis of inflammatory
infiltrates reveals that CD8+ T cells are found in active lesions while B
cells are mainly concentrated in the meninges. Secretory B cell
products play an important role in the apoptosis of neurons and the
death of oligodendrocytes in MS patients. However, MS cannot be
characterized by immune responses; there are genomic components as shown
by gene knockout studies. Although there is no cure for MS, it has
recently been discovered that increased doses of melatonin may have
therapeutic effects.
Conclusion: While the research of MS is
ongoing, it is clear that the role of innate and adaptive immunity
should not only be the central factor in further understanding the
progression of the disease but also the focus of future therapeutic
targets. In this review, we focus primarily on immune responses
characterized by lesion analysis and inflammatory response in MS
patients.
Keywords: Multiple sclerosis; Innate immunity; Adaptive immunity; Biomarker; T cell; B cell; Interleukin
Abbrevations: MS: Multiple Sclerosis; CNS: Central Nervous System; GWAS: Genome-Wide Association Studies
Introduction
Multiple Sclerosis (MS) involves an immune-mediated
process in which an abnormal response of the immune system is directed
against the body’s Central Nervous System (CNS). Demyelination and
inflammation are the primary factors of MS, affecting the formation of
plaque in the CNS. This results in MS’s clinical manifestations, which
are vision impairment, fatigue, weakness, depression, numbness, bowel
changes, loss of muscle coordination and bladder dysfunction. Depending
on the affected areas of the CNS, most MS patients will experience
phases of deteriorations, flare-ups or exacerbations before the
emergence of a new symptom [1,2]. The cause or etiology of MS is not
fully understood. However, there is a likely
correlation between various factors, influenced by genetic and
environmental dynamics. Despite this, research confirms that MS is an
autoimmune disease. These studies are corroborated by Genome-Wide
Association Studies (GWAS), which identify over 100 MS risk loci,
numerous of which intersect in many gene activations of other autoimmune
diseases [3,4]. Diseases that cause dysregulation in the immune
system are at the highest risk of causing contraction of MS. The
progression of MS is found to be correlated with various biomarkers
including immune cells and members of the IL1 cytokine family [5]. In
this review we attempt to identify the role of innate and adaptive
immunity and provide a comprehensive role of biomarkers in the
pathogenesis of MS. In addition, we hope to highlight possible
strategies/therapeutic targets in order to slow the progression of the
disease and improve the quality of life of MS patients.
Discussion
The role of innate immunity in multiple sclerosis
Multiple sclerosis is generally accepted as an autoimmune
disease that causes neurodegeneration in the brain; however,
some recent studies have suggested that neurodegeneration in
progressive MS may be independent of inflammation. In a study
exploring the validity of these claims, researchers investigated
the correlation between neurodegeneration, inflammation,
and disease development in MS stages. They studied 67 MS
autopsies from various phases of the disease, comparing it to 28
controls free of neurological disease and brain lesions. Analysis
of inflammatory infiltrates in relation to lesion activity revealed
that T cells are actually the source of the most prominent
inflammation in the active lesions. Moreover, T-cell infiltration in
the meninges was highly noticeable in comparison to the cortical
parenchyma, which had little to no T cell infiltrates. It is also
interesting to note that CD8 and CD4 positive T cell infiltration
supported previous studies, which found that CD8 positive T cells
infiltrate the most in MS lesions. Similarly, B-cells and HLA-Dpositive
microglia cells and macrophages revealed a comparable
pattern of inflammation; B-cells were mainly seen in meninges,
with only a few isolated in the parenchyma in concentrations
ten times lower than T cells. The most intense inflammation
was found in patients with relapsing/acute disease, followed
by patients in which the disease was progressing. T- and B-cell
occurrence was similar in those patients, but plasma cell ratio
was different-they were seen more prominently in patients
suffering from a progressive form of the disease [6].
Link between the adaptive and innate immunity
Factors that trigger inflammation are crucial for the
pathogenesis of MS. Given this, single nucleotide polymorphisms
play an important role as they can amplify the expression of
inflammatory cytokines and mediators. Multiple studies have
indicated that MS patients have high pro-inflammatory and
inflammatory cytokine serum levels. One of the most potent
and crucial components of innate immunity is the IL-1 family
[7]. Vigne and colleagues found that IL-36α, IL-36β, and IL-36γ,
members of the IL-1 family are crucial in the production of proinflammatory
cytokines as most CD4 T lymphocytes and murine
bone marrow-derived dendritic cells constantly expressed IL-
36R. This was substantiated by high levels of IL-6, IL-12, IL-1β,
IL-23 and TNF-α seen in bone marrow-derived dendritic cells.
These pro-inflammatory cytokines were affected by IL-36 more
than any other IL-1 cytokine. IL-36 was also found to stimulate
the production of IFN-γ, IL-17 and IL-4 by CD4 T cells. This
clearly demonstrates the key role that IL-36R ligands play, not
only in the relationship between innate and adaptive immunity,
but also in the stimulation of T-helper responses [8].
Importance of serum level of interleukin 36 in relapsing-remitting MS
In a study recruiting 49 relapsing remitting MS patients and
41 healthy individuals, researchers evaluated the implications
of Interleukin (IL)-36 in the pathogenesis of MS. The results
of their study indicated that there is a significantly higher
concentration of IL-36 serum levels in patients with MS [9].
In a separate study examining the expression of IL-36 colonic
epithelial cells in patients suffering from inflammatory bowel
syndrome, it was revealed that ulcerative colitis patients had
higher expression of IL-36α and IL-36γ in comparison with
IL-36β. Monocytes plasma cells and T cells were the main
sources of this increased expression of IL-36α and IL-36γ. IL-
36α is found to be largely responsible for the formation of acute
phase proteins and expression of CXC chemokine, along with
the stimulation of MyD88 adaptor proteins TRAK1, IRAK1 and
TRAF6 [in conjunction with IL-36γ. This stimulation of adaptor
proteins triggers activation of AP-1, NF-κB and phosphorylation
of MAPKs. Furthermore, it was found that siRNAs and MAPK
inhibitors for c-Jun, AP-1 and NF-κB considerably downregulated
IL-36-induced expression of the XCX chemokine [10].
Melatonin effects in peripheral t-helper lymphocytes in RR-MS
Melatonin is known to be a modifier of T helper (Th) 1, Th17
and Treg, the presence of which, along with increased Th22 cells
in peripheral blood, are associated with MS progression. In fact,
the gene encoding the Th22 receptor il22ra2 actually makes
patients more susceptible to MS disease [11]. In a 2017 study,
researchers investigated the effects of in vitro administration
of melatonin on T-helper (Th) 1, Th9, Th17, T22, and Treg
responses. Results of the study showed that melatonin effectively decreased:
CNS infiltration of T cells expression of adhesion molecules and
the following chemokines: IL2, IL12, IFN-gamma, and TNF. In-vitro melatonin in phytohemagglutinin-stimulated
peripheral blood mononuclear cells showed a reduced Th1
response. In addition to Th1, Th9 and Th22 responses were also
found to be reduced by melatonin treatment [12]. The study
further suggested that blocking IL9, IFN gamma, TNF, and IL17A
could be potential forms of treatment since all these cytokines
increase T-cell infiltration of the CNS, causing oligodendrocytic
and neuronal death [12]. Thus, melatonin may be able to improve
the quality of life of MS patients through regulation of Th cells
and chemokines.
Naïve, memory, and effector T cells in progressive MS
In order to better understand T-cell activation, researchers
studied CD26-dipeptidyl peptidase IV and CD49d. CD26 is
associated with T helper (Th) 17 cells and the activation of T
cells while CD49d is seen when T cells enter the central nervous
system. In one study to help determine the role of CD49 in the
progression of MS, researchers used Natalizumab, a monoclonal
antibody that attaches to the CD49d receptor. At the end of
the 15-month treatment period with natalizumab, there was a
statistically significant reduction of inflammatory mediators
along with less damage to tissues CD28+ and CD4+ terminally differentiated effector memory T cells were increased in primary
progressive MS patients [13].
Researchers analyzed the difference in percentages and
absolute numbers of T cells before and after natalizumab
treatment, along with their expression of CD26 and CD49d. They
found that the absolute number of circulating CD4+ and CD8+
CD28+ EM and TEMRA T cells increased post-treatment, which
is consistent with the idea that natalizumab prevents these T
cell subsets from entering the CNS. Additionally, treatment of
natalizumab decreased the percentage of cells expressing CD26
in all cell subsets of CD4+ and CD8+ T cells besides CD26+ CD28-
TEMRA T cells, which already show the lowest expression of
CD26 in untreated patients and controls. Lastly, they found a
decrease in the frequency of T cells expressing CD49d in all cell
subsets of CD4+ and CD8+ [13]. These findings encourage future
studies to look into additional benefits that natalizumab may
provide MS patients.
B lymphocytes role in MS
Lisak et al. [14] investigated the role of secretary B cells
on the apoptosis of neurons and oligodendrocytes. Secretory
products of B cells were taken from both patients with RRMS and
control patients and then were treated onto oligodendrocytes.
Investigators found that in the secretory product secreted from
13 MS patients, 58% oligodendrocytes died from exposure
compared to only 4% in oligodendrocytes treated with secretary
product in control patients. Human neurons, when treated
with secretory products from RRMS patients, showed a similar
trend with over half experiencing neuronal death compared to
only ten percent of neurons when treated with control samples.
As a result, it is evident that although the mechanism of B cell
interaction is not fully understood, it plays a major role in cell
death especially in RRMS patients and needs to be further
investigated [14].
Hydroxylase effects on immunity
25-hydroxycholesterol (25-OHC) not only initiates a
signaling cascade that suppresses the production of IgA but
also has antiviral properties. While 25 OHC needs to be further
investigated, 24S-Hydroxycholesterol 24S-OH-chol has been
fairly well documented. Leoni and colleagues had shown that
24S-OH-chol is synthesized in the brain and its distribution
through plasma may serve as a biomarker for the progression
of MS. In a study conducted on 118 patients who suffered from
MS it was demonstrated that older patients, presumably those
who had suffered from MS for a longer duration, had reduced
24S-OH-chol plasma levels compared to age matched controls.
As a result, the progression of MS may be correlated with a loss
of neuronal cells that synthesize oxysterols [15].
The role of oxysterols
Chalmin and colleagues investigated both how oxysterols
modulate/contribute to T lymphocyte morphology and play
a role in MS autoimmunity through the use of MS Ch25h -/-
mice models. Ch25h is a gene that is highly involved in both
cholesterol and lipid metabolism. They reported that 16 days
post immunization, only 15 % of Ch25h-/- mice developed MS
and 43 % had remained symptom free. The Ch25h knockout had
no influence on immune system activation in the periphery as
CD 4+ T cells and wild type T cells with immunization of myelin
oligodendrocyte glycoproteins revealed the same number of
leukocytes, IFN-g, IL-17A and IgG proliferation. Moreover,
the study demonstrated that Ch25h may actually intensify
inflammatory signals and impair trafficking of CD 44+ and CD4
+ T cells [16]. While here we have highlighted the importance of
the CH25H gene, there are over 100 genetic markers that may
increase the likelihood of MS in a given population.
Conclusion
investigating the role of T cells/B cells and cytokines. These
essentially have served as biomarkers for the progression of
MS and much of the clinical focus has been on finding ways to
regulate them. Currently two of the most effective treatments
available to clinicians are increased use of melatonin and
administration of the monoclonal antibody Natalizumab, both
of which work to regulate inflammation and cytokine activity.
Current clinical trials have also noted the importance of immune
system regulation in slowing down the progress of MS and as a
result the majority of phase 3 clinical trials running today have
a focus on immune regulation. While over 100 genetic markers
have been discovered for MS, gene therapy has yet to become a
viable form of treatment, but perhaps may be an alternative in
the future.
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