Download The Role of Autoantibodies in Diagnosis of Multiple Sclerosis

INTERNATIONAL TRENDS IN IMMUNITY
ISSN 2326-3121 (Print) ISSN 2326-313X (Online)
VOL.2 NO.1
http://www.researchpub.org/journal/iti/iti.html
JANUARY 2014
The Role of Autoantibodies in Diagnosis of
Multiple Sclerosis
Mahsa Kiani Aslani, Kabir Magaji Hamid, Nikoo Hosseinkhan Nazer and Abbas Mirshafiey*

-
Abstract Multiple sclerosis (MS) is a severe chronic
inflammatory disorder of the central nervous system (CNS)
manifested by chronic inflammation, myelin loss, gliosis,
varying degrees of axonal and oligodendrocyte pathology
and progressive neurological dysfunction and large
infiltration of a heterogeneous population of cellular and
mediators of the immune system. The inflammatory lesions
are manifestation of a heterogeneous population of cellular
and soluble mediators of the immune system, such as T cells,
B cells, macrophages and microglia, as well as a broad
range of cytokines, chemokines, antibodies, complement
and other toxic substances. Identification of autoantigens
and autoantibodies in demyelinating diseases is essential
for understanding the immunopathogenesis mechanism of
MS. Recently, CSF analysis in MS has been recommended
as a tool for monitoring disease activity and diagnosis. In
this review we discuss the most significant autoantibodies
which could be used as biomarkers for diagnosis, prognosis
and treatment in MS and the hope is that biomarkers speed
up the MS monitoring.
Key words- Multiple sclerosis, autoantibodies, diagnosis,
biomarker
INTRODUCTION
M
ultiple sclerosis (MS) is a chronic inflammatory
demyelinating disease of the central nervous system
(CNS) manifested morphologically by inflammation,
demyelination, axonal loss and gliosis. The inflammatory
lesions are characterized by high infiltration of various
populations of cellular and soluble mediators of the immune
system, such as T cells, B cells, macrophages and microglia, as
well as a broad range of cytokines, chemokines, antibodies,
complement and other toxic substances.[1-3]
Received Sept 9th, 2013. Accepted with revision accepted Nov. 5th, 2013
Departmant of Immunology, School of Public Health, Tehran University of
Medical Sciences, Tehran-14155, Box: 6446, Iran. *Correspondence to Prof.
Abbas Mirshafiey , Departmant of Immunology , School of Public Health ,
Tehran University of Medical Sciences , Tehran-14155, Box: 6446 , Iran.
Fax:+98-21-66462267, E-Mail: [email protected]
29
The cellular components involved in the neuroinflammation
and neuroimmune activation in the cerebrospinal fluid (CSF)
are brain microglial cells, ependymal cells, macrophages,
astrocytes and mast cells. Microglial cells which constitute
around 10% of the CNS are the first to respond to neuronal
injury.[1,4,5] MS is considered as an autoimmune disease in
which T cell reactivity to self-antigens expressed in the brain,
particularly myelin antigens plays a pivotal role in MS
pathogenesis. [6] In this connection, the essential contribution
of B cells and autoantibodies have been demonstrated in the
pathogenesis of MS, leading to interest in the use of such
autoantibodies as diagnostic or prognostic biomarkers.[7]
Therefore, autoantibodies profile against epitopes derived from
MS brain tissue could serve as diagnostic markers and/or as
basis for the identification of a subgroup of MS.[8]
Autoantibadies (IgG and IgM) localized against demyelinated
axons and oligodendrocytes and also antibody-antigen immune
complexes were detected in foamy macrophages in active
lesion areas.[9] These observations provide further evidence on
the role of antibodies, complement and macrophages in plaque
development, which strongly suggest that they can induce
axonal injury, an important cause of disability in MS. They may
provide novel therapeutic strategies to limit tissue degeneration
in the disease.[10]
Identification of autoantigens in demyelinating diseases is
essential for understanding the MS pathogenesis, so that
immune responses against these antigens could be considered
as biomarkers for diagnosis, prognosis and treatment responses.
Knowledge of antigen-specific immune responses in individual
patients is also a prerequisite for antigen-based therapies.[9] In
the late of nineteenth century, Heinrich Irenaϋs Quincke and
Heinrich Georg Queckenstedt developed the methods of
sampling and studying cerebrospinal fluid (CSF) .[11]CSF
sampling was initially developed for therapeutic purposes in
the treatment of hydrocephalus, but shortly became a very
useful diagnostic test for infections and other disorders.[12]
In addition to establishing a diagnosis for MS, cerebrospinal
fluid(CSF) has historically been a very attractive tissue source
for neuroimmunologists. Oligoclonal bands(OCBs) are
immunoglobulins (IgG, IgM, or IgA) that are generated by
plasmablasts and plasma cells in the CSF or CNS compartment.
In chronic infections of the CNS, the OCBs are directed against
the causative agent. Therefore, identifying the molecular target
of OCBs in patients with MS may provide clues to the
INTERNATIONAL TRENDS IN IMMUNITY
ISSN 2326-3121 (Print) ISSN 2326-313X (Online)
VOL.2 NO.1
http://www.researchpub.org/journal/iti/iti.html
pathogenesis of this disorder. However, it is also conceivable
that OCBs are a determinant of the disease that may not reflect
the prognosis or therapeutic effects.[12]
The diagnosis of MS is ultimately a clinical decision that does
not require laboratory tests if neurologic dysfunction in time
and space can be established. However, CSF analysis is
extremely helpful in patients with an atypical clinical
presentation, age of onset, or magnetic resonance imaging
(MRI) findings.[12,13] It is also of paramount importance to
exclude some infectious and inflammatory mimics .[12,14] For
this purpose, CSF studies are undertaking routinely in some
European countries.[12]
Diagnostic CSF findings in MS patients include qualitative
IgG oligoclonal banding and the quantitative IgG index.[12,15]
Two or more OCBs detected by separation of CSF proteins
which are not demonstrable in corresponding serum but reflect
a local Bcell response and define the positive IgG OCBs in
MS .[12,16] Despite its high sensitivity, IgG OCBs are not
specific for MS. OCBs can be seen in various inflammatory and
non-inflammatory disorders.
JANUARY 2014
common pathology observed in MS lesions. In this pattern,
demyelination occurs through specific antibodies and
complement. Type III is related to distal oligodendropathy,
degenerative changes which occur in distal followed by
apoptosis. Type IV results in primary oligodendrocyte damage
followed by secondary demyelination. The latter pattern is seen
only in a small subset of primary progressive MS
patients.[22,28,29]
It is known that antibodies against myelin basic protein (MBP)
are present in early multiple sclerosis.[30,31] Another potential
target antigen for autoreactive antibodies might be myelin
oligodendrocyte glycoprotein (MOG), which is specific to the
central nervous system and is located exclusively on the surface
of myelin sheaths and oligodendrocytes.[32] Antibodies
against MOG cause demyelination in vitro[33] and in animal
models of multiple sclerosis [34,35] and have been found in
active lesions in patients with multiple sclerosis.[36]
A substantial subgroup of patients with multiple sclerosis
mount a persistent autoantibody response to the extracellular
immunoglobulin domain of MOG30 with a predominance of
anti- MOG IgM antibodies.[30,31] In this review, we studied
whether the presence of serum anti-MOG and anti-MBP
antibodies predicts conversion to clinically definited multiple
sclerosis among patients who have a clinically isolated
syndrome and findings on MRI and cerebrospinal fluid analysis
that are suggestive of multiple sclerosis.[37]
IMMUNOPATHOGENESIS OF MS
MS, as an inflammatory demyelinating disease of the CNS is
believed to have an immunopathological etiology arising from
gene-environment interactions. The initiation factors of the
inflammatory response remain yet unknown. However, MS is
considered as a complex disease depending on genetic as well
as environmental factors.[1,17] Genetic factors have a
significant role in susceptibility to MS, such as genes related to
interleukin-1 receptor (IL-1R), immunoglobulin Fc receptor,
Apo protein E, IL-1β, immunoglobulin heavy chain, T cell
receptor, tumor necrosis factor (TNF)-α, MBP, IL-2R, IL-7R
and Human leukocyte antigen(HLA) genes.[18-23]
AUTOANTIBODIES AND DIAGNOSIS
In this connection, the most important antigens are myelin
oligodendrocyte glycoprotein (MOG) and aquaporin4( AQP4).
Although T cell responses to the quantitatively major myelin
proteins, myelin basic protein (MBP) and proteolipid protein
(PLP), are likely to be of importance in the course of MS. The
cell-mediated autoimmune responses to other myelin antigens,
in particular quantitatively minor myelin antigens, such as
myelin-associated glycoprotein (MAG) and the central nervous
system-specific myelin oligodendrocyte glycoprotein (MOG),
could also play a prevalent role in initiation or progression of
the disease. The incidence of responses to MBP, PLP, and
MAG did not differ greatly between MS patients and control
individuals. A predominant T cell reactivity to MOG in MS
suggests an important role for cell-mediated immune response
to this antigen in the pathogenesis of MS.[38]
In general, MS begins with the formation of acute
inflammatory lesions characterized by disruption of the blood
brain barrier (BBB). Breakdown of the BBB usually lasts for
about a month and then resolves, leaving a site of damage that
can be investigated by conventional magnetic resonance
imaging (MRI). The pathological features of MS plaques are
BBB leakage, destruction of myelin sheaths, oligodendrocyte
damage and cell death, axonal damage and axonal loss, glial
scar formation and the presence of inflammatory infiltrates that
mainly consist of lymphocytes and macrophages.[22,24,25]
Despite the major advances in the current understanding of
pathogenesis of MS, exact details of the inflammatory cascade
of MS remain unknown. It has been demonstrated that axonal
degeneration is the major feature of irreversible neurological
disability in MS patients. Axonal injury initiates the disease
onset and correlates with the degree of inflammation within
lesions.[22,26,27] Four different patterns of pathology with
resulting demyelination have been identified in MS lesions:
Type I is T cell mediated where demyelination is macrophage
mediated, directly or by macrophage toxins. In type II lesions,
both T cells and antibodies are involved and are the most
ANTI-MOG ANTIBODY
Antibody against MOG is seen in patients with different
diseases, such as childhood multiple sclerosis, acute
demyelinating encephalomyelitis (ADEM), anti-AQP4
negative NMO, and optic neuritis, but hardly in adult MS.[9] It
has been recently reported that the only antibodies recognizing
conformation-dependent epitopes of MOG have a
demyelinating potential in the animal model of multiple
sclerosis, EAE .[39]
This fact that, whether antibody to MOG can be a diagnostic
marker for MS is still controversial. Recent studies reported
that serum specific anti-MOG epitope antibody might be an MS
specific marker. Although serum anti-MOG epitope IgG could
30
INTERNATIONAL TRENDS IN IMMUNITY
ISSN 2326-3121 (Print) ISSN 2326-313X (Online)
VOL.2 NO.1
http://www.researchpub.org/journal/iti/iti.html
not differentiate MS from neuromyelitis optica (NMO), it may
be a useful marker for monitoring disease activity.[40]
NMO-Ab and MOG-Ab could be potential biomarkers to
determine visual prognosis in patients with optic neuritis
(ON) .[41] Anti-MOG antibodies, measured either by ELISA
or FACS were espeicially identified in children with
demyelination. In acute disseminated encephalomyelitis
(ADEM) these antibodies were highly reactive. The presence of
autoantibodies was not related with EBV serostatus, age,
gender or disease course.
This study independently has
confirmed the recent published results of seroprevalence and
specificity of the assay. Due to their low sensitivity, anti-MOG
antibodies can not serve as disease-specific biomarkers, but
they are able to support the diagnosis of ADEM in difficult
cases.[42] The high-titer of MOG-IgG antibodies are strongly
detected in pediatric patients with ON, indicating that
anti-MOG-specific antibodies may have a direct role in the
pathogenesis of ON in this subgroup.[43]
JANUARY 2014
ANTI-MBP ANTIBODY
This autoantibody is specifically bound to disintegrating
myelin around axons in the lesions of acute MS and EAE
model.[50] In other words, a specific myelin protein
autoantibody intervenes target membrane damage in
demyelinating disease of central nervous system.[44]
Furthermore, Monosymptomatic unilateral optic neuritis (ON)
is a common first manifestation of multiple sclerosis (MS) in
which increased numbers of autoimmune T and B cells,
indicating different myelin autoantigens including myelin basic
protein (MBP) and its peptides, have been implicated in a
hypothetical immunopathogenesis. Using an immunospot assay
to detect specific antibodies secreted by individual cells, it was
analyzed the B-cell repertoire to MBP and its amino acid
residues 1-20, 63-88, 110-128, and 148-165 in blood and CSF
from patients with ON and MS, and from controls. The
autonomy of the autoimmune B-cell response in CSF was
further supported by the pronounced asynchrony of the
repertoire to the four MBP peptides in CSF compared with
blood in individual patients. The large number of MBP- and
MBP peptide-reactive B cells in CSF in early MS, as
manifested by ON, could play a major role in the
immunopathogenesis and perpetuation of MS. Alternatively,
they could represent myelin breakdown or restoration.[51]
ANTI-AQP4
Aquaporin-4 is the first specific molecule which has been
defined as a target for the autoimmune response in any form of
MS. It is also the first example of a water channel being the
target of any autoimmune disorder.[44,45]
In the past, neuromyelitis optica (NMO) was included only in
the optic nerves and spinal cord. However, the discovery of
highly specific anti-aquaporin-4 (AQP4) antibody for NMO
enabled us to identify more diverse clinical manifestations .[46]
The pathogenesis mechanism of optic neuritis developed
rapidly from the end of the 19th century to the beginning of the
20th century accompanying with progress in morpho-anatomy
and physiology.[47] The process of optic neuritis is generally
considered as a new phase, started by the advent of molecular
immunology and genetic. Researches showed that optic neuritis
associated with anti-aquaporin(AQP) 4 antibodies is refractory
to steroid therapy and causes injuries to the optic nerve-optic
chiasma-optic tract, resulting in a broad array of visual field
abnormalities. Specifically, the disease becomes severe in
individuals who possess anti-AQP4 antibodies that target
astrocytes, together with anti-myelin oligodendrocyte
glycoprotein (MOG), the antibodies that target myelin
oligodendrocytes. Furthermore, measurement of glial fibrillary
acidic protein (GFAP) levels in cerebrospinal fluid may be
useful in the diagnosis of anti-AQP4 antibody positive optic
neuritis.[47] Although,the anti- AQP4 antibody is specific for
NMO, but is also found in limited forms. The presence of this
antibody in acute transverse myelitis (ATM) has been
associated with recurrence and conversion to NMO, but its
influence on disability has not yet been described.[48]
According to previous study, and compared with anti-AQP4
antibody-negative ones, anti-AQP4 antibody-positive patients
show significantly higher frequencies of severe ON, TM,
longitudinal spinal-cord segments and they are more
predisposed to ON or TM relapse. Also, seropositive NMO and
HR-NMO patients are more likely to develop relapses of ON or
TM. Anti-AQP4 antibody may play some roles in the diagnosis
and prognostic predication of demyelinating diseases in central
nervous system.[49].
In recent studies, the prevalence and titer of total, free, and
bound cerebrospinal fluid anti–myelin basic protein antibodies
as well as free/bound ratios were determined in four groups of
patients with multiple sclerosis and three groups of controls.
All patients with clinically active MS have increased the levels
of total anti-MBP, which may be present in either free or bound
forms. Patients whose disease are in remission have
undetectable anti-MBP levels, and some patients with clinically
stable disease with residual disability may have detectable
antibody titers. Chronically progressive MS is usually
associated with high levels of antibody in the bound rather than
the free form, resulting in a low or normal free/bound ratio. In
contrast, exacerbation of MS is characterized by relatively high
levels of free anti-MBP in the cerebrospinal fluid, resulting in a
high free/bound antibody ratio. The bound anti-MBP was also
detected in elevated levels in 1 patient with subacute sclerosing
panencephalitis and 2 of 8 patients with postinfectious
encephalomyelitis. Although the elevated levels of
cerebrospinal fluid anti-MBP are not specific for MS, they are
strongly associated with disease activity and may be involved
in the pathogenesis of demyelination in patients with MS.[52]
ANTI-PLP ANTIBODY
PLP is a component of oligodendritic glial sheaths of neuronal
processes that is specifically expressed in the CNS .[53] In the
pathogenesis of multiple sclerosis, autoimmune T cells reactive
with proteolipid protein may play a crucial role, that is linked
with HLA-DR2, w15.[54,55] In other word, equal numbers of
CD4+ T cells recognizing myelin basic protein (MBP) and
31
INTERNATIONAL TRENDS IN IMMUNITY
ISSN 2326-3121 (Print) ISSN 2326-313X (Online)
VOL.2 NO.1
http://www.researchpub.org/journal/iti/iti.html
proteolipid protein are found in the circulation of normal
individuals and multiple sclerosis patients .[56]
JANUARY 2014
particularly detects serum antibodies identified against three
major myelin autoantigens: MBP, PLP and MOG. The
mentioned method detects antibody binding to recombinant
antigens in their native conformation on MBP, PLP and MOG
transfected mammalian (hamster ovary) cells. By using FACS
analysis serum anti-MBP, anti-PLP and anti-MOG IgG
autoantibodies were identified in MS patients and controls.
Compared with healthy controls the titres of IgG
autoantibodies directed against membrane-bound recombinant
myelin antigens were highly raised for PLP, no quite significant
for MBP and not significant for MOG. The titres of anti-MBP
antibodies were low in contrast to high titre of anti-MOG
antibodies in both groups suggesting a nonspecific binding. The
cell-based assay detection of autoantibodies directed against
recombinant myelin antigens could be a useful tool for
preparing the serological markers in diagnosis and progression
of MS. Indeed, it permits obtaining molecular characteristics of
disease in each patient in term of an antibody response against
certain myelin and non-myelin antigens. It has been shown that
in RRMS patients the increased level of serum antibodies
against PLP is important, so that it might be considered in
search for specific immunomodulatory therapy in MS.[61]
In addition, intrathecal immunoglobulin synthesis and
activation of the complement cascade occurs in patients with
MS. Some researches aimed the status of the relation between
intrathecal immunoglobulin synthesis and complement
activation by comparing total intrathecal synthesis of lgA, IgG,
and IgM, the number of cells secreting anti -MBP and anti- PLP
antibodies of the IgG isotype and intrathecal activation of the
complement cascade in patients with possible onset symptoms
of MS or clinically definited MS. Early activation of the
complement cascade was correlated with intrathecal synthesis
of IgM. Intrathecal IgG, lgA and IgM synthesis were also
correlated weakly with the presence of cells secreting
anti-MBP or anti-PLP autoantibodies. Full activation of the
complement cascade had no correlation with any amount of
intrathecal antibody synthesis. These findings recommend a
complicated relation between different immunoglobulin
isotypes and complement activation which may have similarly
complex roles in the pathogenesis of MS.[62]
THE COMPARISON BETWEEN ANTI-PLP AND
ANTI-MBP IN MS
The human myelin basic protein (hMBP) and proteolipid
protein (PLP) were utilized as antigens in a solid-phase
radioimmunoassay to determine relative frequencies of
anti-MBP and anti-PLP in CSF of optic neuritis and multiple
sclerosis patients.[57] These results recommend that there are
at least two immunologically distinct forms of MS, a common
form which strongly associated with anti-MBP and more
frequent standing out inflammatory characteristics in CSF and
CNS, and an infrequent form related to anti-PLP in CSF and
tissue, and less plentiful inflammation. Antigen-specific
affinity chromatography was used to purify Anti-MBP from
CNS tissue IgG which could react with synthetic peptides of
hMBP. The anti-MBP epitope on the hMBP molecule was
restricted between residues 75 and 106. The PLP epitope for
anti-PLP has not yet been determined. These observations have
theoretical implications for expected next specific
immunotherapy of MS .[57]
On the other hand, the solid phase radioimmunoassays was
utilized to purify Myelin basic protein and proteolipid protein
(PLP) from non-MS human brain for detecting their specific
antibodies in cerebrospinal fluid of optic neuritis and clinically
definite multiple sclerosis patients. Considering the total of 370
clinically definite MS patients with active and inactive disease,
77% had increased CSF anti-MBP and 1% had increased CSF
anti-PLP.[58] To study the intrathecal synthesis of anti-myelin
basic protein and anti-proteolipid protein antibodies in patients
in the early stages of multiple sclerosis, the cerebrospinal fluid
cells that secrete anti-MBP or anti-PLP antibodies were
detected in 10 of 15 and in 21 of 23 patients with acute ON,
while they were detected in nine of 18 and in six of 18 patients
with other neurological diseases, respectively. Patients with
ON had significantly more anti-PLP-secreting cells compared
with patients with other neurological diseases (P < .01). No
difference was observed for anti-MBP-secreting cells. A
significant correlation between the time of onset and the
number of anti-PLP-secreting cells was found in patients with
idiopathic ON (P < .02). These data suggest that anti-PLP
antibodies are more specific finding in demyelinating disease
than anti-MBP antibodies. Furthermore, they suggest that
anti-PLP antibodies may arise as a consequence of the
demyelinating process.[59]
In addition, Anti-PLP IgG antibody-secreting cells were
detected in blood from most MS patients, but such cells were
49-fold more frequent in CSF (mean 1 per 625 cells).
PLP-reactive T and B cells were also identified in blood and
CSF from control patients, but in lower number. A strong and
persistent autoimmune response to PLP as well as to other
myelin proteins, enriched in CSF could be pathogenetically
important in MS.[60] In general, the methods of, ELISA and
Western blotting are not able to detect reactivity against
epitopes showed by native antigens expressed on myelin
sheaths. It has been described as a cell-based assay that
ANTI-HHV-6 IN MS
The viral infections are thought to play a significant role in the
pathogenesis of multiple sclerosis (MS) potentially through
molecular mimicry.[63] Some of the strongest associations
with MS onset have been reported for human herpesviruses,
particularly Epstein-Barr virus (EBV) and human herpesvirus 6
(HHV-6), so that the observed effect was directly related to
anti-HHV-6 IgG titers which may indicate that either HHV-6
infection or factors associated with an altered humoral immune
response to HHV-6 may have an impact on MS clinical course.
Therefore, anti-HHV-6 IgG titer, as an important
non-autoantibody may be a useful prognostic factor in
relapsing-remitting MS clinical course.[64] In a research has
been shown the intrathecal production of antibody to
lymphotropic herpesviruses in MS patients and the presence of
human herpesvirus 1 to 7 DNAs in cerebrospinal fluid (CSF),
32
INTERNATIONAL TRENDS IN IMMUNITY
ISSN 2326-3121 (Print) ISSN 2326-313X (Online)
VOL.2 NO.1
http://www.researchpub.org/journal/iti/iti.html
whereas the study did not give additional support to the
possibility that HHV-6 is a common cause of MS, but the role
of virus in a subset of patients cannot be excluded.[65]
JANUARY 2014
autoreactive T cells committed to myelin determinants in
relapsing-remitting multiple sclerosis patients. Clin
Immunol 2012 15;144(2)117-126.
[7] Somers V, Govarts C, et al. Autoantibody profiling in
multiple sclerosis reveals novel antigenic candidates. The
Journal of Immunology 2008 ;180 (6) 3957-3963.
[8] Erdağ E, Tüzün E. Switch-associated protein 70
antibodies in multiple sclerosis: relationship between
increased serum levels and clinical relapse. Inflamm Res
2012;12-0488-9.
[9] Derfuss T, Meinl E. Identifying autoantigens in
demyelinating diseases: valuable clues to diagnosis and
treatment? Curr Opin Neurol 2012 ;25(3)231-8.
[10] Sádaba MC, Tzartos J, Paíno C, García-Villanueva M,
Alvarez-Cermeño JC, Villar LM, Esiri MM. Axonal and
oligodendrocyte-localized IgM and IgG deposits in MS
lesions. J Neuroimmunol 2012 ;15 (1-2)86-94.
[11] Murray, T.J. Multiple Sclerosis: the History of a Disease.
Investigations, 1st ed. Demos Medical Publishing, New
York, 2005, pp. 363–390.
[12] Amer Awad a, Bernhard Hemmer b, Hans-Peter Hartung c,
Bernd Kieseier c,Jeffrey L. Bennett d, Olaf
Stuve .Analyses of cerebrospinal fluid in the diagnosis and
monitoring of multiple sclerosis. Journal of
Neuroimmunology 2010;1–7.
[13] Merra, T.R. Multiple sclerosis with onset after age of 60. J.
Am. Geriatr. Soc1984;32:16–18.
[14] Herndon, R.M. Multiple sclerosis mimics. Adv.
Neurol2006; 98: 161–166.
[15] Mayringer, I., Timeltaler, B., Deisenhammer, F.
Correlation between the IgG index, oligoclonal bands in
CSF, and the diagnosis of demyelinating diseases. Eur. J.
Neurol 2005;12: 527–530.
[16] Link, H, Huang, Y-M., Oligoclonal bands in multiple
sclerosis cerebrospinal fluid:an update on methodology
and clinical usefulness. J. Neuroimmunol2006;180: 17–28.
[17] BBruno R, Sabater L. Multiple sclerosis candidate
autoantigens except myelin oligodendrocyte glycoprotein
are transcribed in human thymus. European journal of
immunology 2002;32(10):2737-47.
[18] Mirshafiey A, Matsuo H. Novel immunosuppressive
therapy by M2000 in experimental multiple sclerosis.
Immunopharmacol Immunotoxicol 2005;27(2):255-65.
[19] Mirshafiey,
A,
Jadidi-Niaragh,
F.
Immunopharmacological role of the leukotriene receptor
antagonists and inhibitors of leukotrienes generating
enzymes in multiple sclerosis. Review, Immunopharmacol
Immunotoxicol 2010;32(2):219-27.
[20] Evangelou N, Jackson M. Association of the APOE
epsilon4 allele with disease activity in multiple sclerosis. J
Neurol Neurosurg Psychiatry 1999;67(2):203-5.
[21] Haines JL, Ter-Minassian M, Bazyk A. A complete
genomic screen for multiple sclerosis underscores a role
for the major histocompatability complex. The Multiple
Sclerosis Genetics Group. Nat Genet1996;13(4):469-71.
It should be noted that an identical sequence was found in both
myelin basic protein (MBP, residues 96–102), a candidate
autoantigen for MS, and human herpesvirus-6 (HHV-6 U24,
residues 4–10) that is a suspected viral agent associated with
MS.[63]
CONCLUSION
Human myelin basic protein (hMBP) and proteolipid protein
(PLP) were proposed as antigens to determine relative
frequencies of anti-MBP and anti-PLP in the CSF of optic
neuritis and MS patients. In addition, some studies showed that
optic neuritis is associated with anti-aquaporin(AQP) 4
antibodies together with anti-myelin oligodendrocyte
glycoprotein (MOG) antibodies that target myelin
oligodendrocytes. The cell-based assay detection of
autoantibodies directed against recombinant myelin antigens
could be a useful tool for preparing the serological markers in
diagnosis and progression of MS.
The correlation of B cells and autoantibodies in CSF
examination has been demonstrated in MS leading to interest in
the use of such autoantibodies as diagnostic or prognostic
markers and as a basis for immunomodulatory therapy.
Although their main role is to exclude differential diagnosis,
however , the new methods are using in this field and it is
expected that these biomarkers, lonely or with other alternative
disease markers along with MRI, is able to help the clinician to
predict disease progression in patients with various phenotypes
of MS.
References
[1] Farhad Jadidi Niaragh , Abbas Mirshafiey. Histamine and
Histamine Receptors in Pathogenesis and Treatment of
Multiple Sclerosis. Neuropharmacology 2010;59(3)
180–189.
[2] Bruck W. The pathology of multiple sclerosis is the result
of focal inflammatory demyelination with axonal damage.
J Neurol 2005;25( 2) 3-9.
[3] Mirshafiey A. Venom therapy in multiple sclerosis.
Neuropharmacology 2007;53(3)353-361.
[4] Kulkarni AP, Kellaway LA, et al. Neuroprotection from
complement-mediated inflammatory damage. Ann N Y
Acad Sci 2004;1035:147-64.
[5] Mirshafiey A, Mohsenzadegan M. TGF-beta as a
promising option in the treatment of multiple sclerosis.
Neuropharmacology 2009;56(6-7)929-36.
[6] Elong Ngono A, PettréS, et al. Frequency of circulating
33
INTERNATIONAL TRENDS IN IMMUNITY
ISSN 2326-3121 (Print) ISSN 2326-313X (Online)
VOL.2 NO.1
http://www.researchpub.org/journal/iti/iti.html
[22] Mirshafiey A, Mohsenzadegan M. Antioxidant therapy in
multiple sclerosis. Immunopharmacol Immunotoxicol
2009;31(1):13-29.
[23] Myhr KM, Raknes G, Nyland H, Vedeler C.
Immunoglobulin G Fc-receptor (FcgammaR) IIA and IIIB
polymorphisms related to disability in MS. Neurology1999;
52(9):1771-6.
[24] F Jadidi-Niaragh, A Mirshafiey . Th17 cell, the New
Player of Neuroinflammatory Process in Multiple
Sclerosis . Scandinavian Journal of Immunology2011;
74(1):1-13.
[25] Morales Y, Parisi JE, Lucchinetti CF. The pathology of
multiple sclerosis: evidence for heterogeneity. Advances in
neurology 2006 ;98:27-45.
[26] Bar-Or A. Immunology of multiple sclerosis. Neurologic
Clinics 2005;23(1):149-75.
[27] Bjartmar C, Wujek JR, Trapp BD. Axonal loss in the
pathology of MS: consequences for understanding the
progressive phase of the disease. J Neurol Sci 2003;15
(2):165-71.
[28] Goldman MD, Cohen JA, Fox RJ, Bethoux FA. Multiple
sclerosis: treating symptoms, and other general medical
issues. Cleve Clin J Med 2006 ;73(2):177-86.
[29] Lucchinetti C, Bruck W, Parisi J, Scheithauer B,
Rodriguez M, Lassmann H. Heterogeneity of multiple
sclerosis lesions: implications for the pathogenesis of
demyelination. Ann Neurol 2000;47(6):707-17.
[30] Reindl M, Linington C, Brehm U. Antibodies against the
myelin oligodendrocyte glycoprotein and the myelin basic
protein in multiple sclerosis and other neurological
diseases:a comparativestudy.Brain1999;122:2047-56.
[31] Egg R, Reindl M, Deisenhammer F, Linington C, Berger T.
Anti-MOG and anti-MBP antibody subclasses in multiple
sclerosis. Mult Scler 2001;7:285-9.
[32] Brunner C, Lassmann H, Waehneldt TV, Matthieu JM,
Linington C. Differential ultrastructural localization of
myelin basic protein, myelin oligodendroglial glycoprotein,
and 2',3'-cyclic nucleotide 3'-phosphodiesterase in the
CNS of adult rats. J Neurochem 1989;52:296-304.
[33] Kerlero de Rosbo N, Honegger P, Lassmann H, Matthieu
JM. Demyelination induced in aggregating brain cell
cultures
by
a
monoclonal
antibody
against
myelin/oligodendrocyte glycoprotein. J Neurochem 1990;
55:583-7.
[34] Linington C, Bradl M, Lassmann H, Brunner C, Vass K.
Augmentation of demyelination in rat acute allergic
encephalomyelitis by circulating mouse monoclonal
antibodies directed against a myelin/oligodendrocyte
glycoprotein. Am J Pathol 1988; 130:443-54.
[35] Stefferl A, Brehm U, Storch M. Myelin oligodendrocyte
glycoprotein
induces
experimental
autoimmune
encephalomyelitis in the “resistant” Brown Norway rat:
disease susceptibility is determined by MHC and
MHC-linked effects on the B cell response. J Immunol
1999;163:40-9.
34
JANUARY 2014
[36] Genain CP, Cannella B, Hauser SL, Raine CS.
Identification of autoantibodies associated with myelin
damage in multiple sclerosis.Nat Med1999;5:170-5.
[37] Thomas Berger,Paul Rubner, Franz Schautzer, Robert Egg,
Hanno Ulmer, Antimyelin Antibodies as a Predictor of
Clinically Definite Multiple Sclerosis after a First
Demyelinating Event. N Engl J Med 2003;349:139-45.
[38] de Graaf KL, Albert M. Autoantigen conformation
influences both B- and T-cell responses and
encephalitogenicity. J Biol Chem 2012 18; (21):17206-13.
[39] N Kerlero de Rosbo, R Milo, M B Lees, D Burger, C C
Bernard, and A Ben-Nun Reactivity to myelin antigens in
multiple sclerosis. Peripheral blood lymphocytes respond
predominantly to myelin oligodendrocyte glycoprotein. J
Clin Invest1993; 92(6): 2602–2608.
[40] Xu Y, Zhang Y, Liu CY, Peng B, Wang JM, Zhang XJ, Li
HF, Cui LY. Serum antibodies to 25 myelin
oligodendrocyte glycoprotein epitopes in multiple
sclerosis and neuromyelitis optica: clinical value for
diagnosis and disease activity. Chin Med J
2012;125(18):3207-10.
[41] Kezuka T, Usui Y, Yamakawa N, Matsunaga Y, Matsuda
R, Masuda M, Utsumi H, Tanaka K, Goto H. Relationship
between NMO-antibody and anti-MOG antibody in optic
neuritis. J Neuroophthalmol. 2012 ;32(2):107-10.
[42] Lalive PH, Häusler MG, Maurey H, Mikaeloff Y, Tardieu
M, Wiendl H, Schroeter M, Hartung HP, Kieseier BC,
Menge T. Highly reactive anti-myelin oligodendrocyte
glycoprotein antibodies differentiate demyelinating
diseases from viral encephalitis in children. Mult Scler
2011 ;17(3):297-302.
[43] Rostasy K, Mader S, Schanda K, Huppke P, Gärtner J,
Kraus V, Karenfort M, Tibussek D, Blaschek A,
Bajer-Kornek B, Leitz S, Schimmel M, Di Pauli F, Berger
T, Reindl M. Anti-myelin oligodendrocyte glycoprotein
antibodies in pediatric patients with optic neuritis.Arch
Neurol 2012;69(6):752-6.
[44] Mirshafiey A, Kianiaslani M. Autoantigens and
autoantibodies in multiple sclerosis. Iran J Allergy Asthma
Immunol. 2013 ;28 (4):292-303.
[45] Shannon R. Hinson, Michael F. Romero. Molecular
outcomes of neuromyelitis optica (NMO)-IgG binding to
aquaporin-4 in astrocytes. Proc Natl Acad Sci U S A 2012;
109(4): 1245–1250.
[46] Kim SH, Kim W. Clinical spectrum of CNS aquaporin-4
autoimmunity. Neurology 2012;78(15):1179-85.
[47] Kezuka T. Optic neuritis--immunological approach to
elucidate pathogenesis and develop innovative therapy.
Nihon Ganka Gakkai Zasshi. 2013;117(3):270-91.
[48] Alvarenga MP, Alvarenga RM, Alvarenga MP, Santos AM,
Thuler LC. Anti-AQP(4) antibody in idiopathic acute
transverse myelitis with recurrent clinical course:
frequency of positivity and influence in prognosis. J Spinal
Cord Med 2012 ;35(4):251-5.
[49] Yang Y, Wu WP, Huang DH, Wu L. Prognostic value of
aquaporin-4 antibody in patients of inflammatory
INTERNATIONAL TRENDS IN IMMUNITY
ISSN 2326-3121 (Print) ISSN 2326-313X (Online)
VOL.2 NO.1
http://www.researchpub.org/journal/iti/iti.html
demyelinating diseases in central nervous system.
Zhonghua Yi Xue Za Zhi 2012;92(43):3032-5.
[50] Claude P.Genain, Barbara Cannella. Identifying
autoantigens in demyelinating diseases: valuable clues to
diagnosis and treatment?Nature Medicine 5 1999;
170-175.
[51] Söderström M, Link H, Xu Z, Fredriksson S. Optic
neuritis and multiple sclerosis: anti-MBP and anti-MBP
peptide antibody-secreting cells are accumulated in CSF.
Neurology. 1993;43(6):1215-22.
[52] Kenneth G. Warren, Ingrid Catz. Diagnostic value of
cerebrospinal fluid anti–myelin basic protein in patients
with multiple sclerosis. Annals of Neurology 1986; 20 (1)
20–25.
[53] Carmen Villmann, Barbara Sandmeier. Myelin Proteolipid
Protein (PLP) as a Marker Antigen of Central Nervous
System Contaminations for Routine Food Control. Journal
of agricultural and food chemistry 2007 ;22(17):7114-23.
[54] Takayuki Kondo, Takashi Yamamura. TCR repertoire to
proteolipid protein (PLP) in multiple sclerosis (MS):
homologies between PLP-specific T cells and
MS-associated T cells in TCR junctional sequences . Int
Immunol 1996 ;8(1):123-30.
[55] Takashi Ohashi, Takashi Yamamura. Analysis of
proteolipid protein (PLP)-specific T cells in multiple
sclerosis: identification of PLP 95–116 as an
HLA-DR2,w15-associated determinant. Int Immunol
1995;7(11):1771-8.
[56] J Zhang, S Markovic-Plese. Increased frequency of
interleukin 2-responsive T cells specific for myelin basic
protein and proteolipid protein in peripheral blood and
cerebrospinal fluid of patients with multiple sclerosis. J
Exp Med 1994; 179(3): 973–984.
[57] Kenneth G. Warren,, Ingrid Catz, Edward Johnson, Bruce
Mielke. Anti-myelin basic protein and anti-proteolipid
protein specific forms of multiple sclerosis. Annals of
Neurology 1994;35(3) 280–289.
[58] Warren KG, Catz I. Relative frequency of autoantibodies
to myelin basic protein and proteolipid protein in optic
neuritis and multiple sclerosis cerebrospinal fluid. J Neurol
Sci 1994;121(1):66-73.
[59] Sellebjerg FT, Frederiksen JL, Olsson T. Anti-myelin
basic
protein
and
anti-proteolipid
protein
antibody-secreting cells in the cerebrospinal fluid of
patients with acute optic neuritis. Arch Neurol
1994;51(10):1032-6.
[60] Jia-Bin Sun, Tomas Olsson, Wei-Zhi Wang, Bao-Guo
Xiao, Vasilios Kostulas, Sten Fredrikson, Hans-Peter Ekre,
Hans Link, .Autoreactive T and B cells responding to
myelin proteolipid protein in multiple sclerosis and
controls. European Journal of Immunology 1991; 21(6)
1461–1468.
[61] Jaśkiewicz E, Michałowska-Wender G, Pyszczek A,
Wender M.Recombinant forms of myelin antigens
expressed on Chinese hamster ovary (CHO) cells as a tool
JANUARY 2014
for identification of autoantibodies in serum of multiple
sclerosis patients. Folia Neuropathol 2010;48(1):45-8.
[62] Finn Sellebjerg, Peter Garred, Michael Christiansen.
MBP,anti-MBP and anti-PLP antibodies and intratecal
complement activation in multiple sclerosis. Mult Scler
1998;4(3) 127-131.
[63] Maria V. Tejada-Simon, Ying C. Q. Zang ,Jian Hong,
Victor M. Rivera ,Jingwu Z. Zhang . Cross-reactivity with
myelin basic protein and human herpesvirus-6 in multiple
sclerosis. Annals of Neurology 2003; 53(2) 189–197.
[64] Simpson S Jr, Taylor B, Dwyer DE, Taylor J, Blizzard L,
Ponsonby AL, Pittas F, Dwyer T, van der Mei I.
Anti-HHV-6 IgG titer significantly predicts subsequent
relapse risk in multiple sclerosis. Mult Scler
2012;18(6):799-806.
[65] Malin Enbom, Fu-Zhang Wang, Sten Fredrikson,Claes
Martin, Helena dahl and Annika Linde. Similar humoral
and cellular immunological reactivities to human
herpesvirus 6 in patients with multiple sclerosis and
controls. Clin Diagn Lab Immunol 1999;6(4):545-9.
35