Vol.1, No.3, 80-86 (2011)
opyright © 2011 SciRes. Openly accessible at http://www.scirp.org/journal/oji/
Open Journal of Immunology
Myelin-associated serological targets as applicable to
diagnostic tools to be used at the preclinical and
transient stages of multiple sclerosis progression
Dmitry Kostyushev1*, Ivan Tsarev1, Dmitry Gnatenko1, Mikhail Paltsev3, Sergey Suchkov1,2
1I.M. Sechenov First Moscow State Medical University, Moscow, Russia; *Corresponding Author: dkostushev@gmail.com
2Moscow State Medical Dentistry University, Moscow, Russia;
3National Research Center “Kurchatov Institute”.
Received 4 July 2011; revised 18 October 2011; accepted 11 November 2011.
MS is a sev ere progr essi ve autoimmune disease
with slight short-term relapses in its course.
Autoagression against vulnerable myelin-ass-
ociated Ags results in multiple lesions through-
out the CNS. Abnormal responses against ner-
vous issues are mainly affected b y cell-mediated
and humoral immunity. The first one plays a key
role in the restructuring of myelin, while the last
one is a biomarker of MS and does not partici-
pate in the gradation of the disease. Wide-scale
autoimmune attack towards nervous tissues
leads to a stepwise demyelination with concom-
itant release of myelin Ags (epitope spreading),
formation of Abs and, consequently, systema-
tization of pro-inflammatory responses. Monito-
ring of antimyelin-antibodies (Abs: OSP, MOBP,
BMP, MOG, PLP) in peripheral blood and cere-
brospinal fluid (CSF) is just a brick for making
the preclinical diagnosis of MS and timely im-
plementation of predictive measures and pre-
ventive treatment. Major autoAbs and their tar-
get antigens a re discusse d in this chapter with a
special emphasize on the possibility of their
impact for identification of pre-morbid stages
and differential diagnosis of MS.
Keywords: Multiple Sclerosis; Antibodies;
Autoimmunity; Pre-Clinical Diagnosis; Diagnosis;
Prediction; Proteomics
Multiple sclerosis (MS) is an autoimmune demyeli-
nating disorder of the CNS resulting in axon loss and
development of disability. Autoantibodies (autoAbs) are
one of the major features and crucial mechanisms in MS
pathogenesis known to illustrate this autoagression. The
major feature in the pathogenesis of MS is a primary
myelin damage, which is mediated by autoAbs and trig-
gers a process of releasing pathogenically valuable mye-
lin-associated epitopes into the bloodstream to form a set
of the principal sensitizing factors to provoke the im-
mune system and then to maintain the progression of the
The worldwide median estimated incidence of MS is
2.5 per 100,000 and prevalence is estimated at approxi-
mately 1.5 million cases. Usually onset of MS is be-
tween age 20 years and 40 years. Men are affected app-
roximately twice as rare as women.
There are three groups of autoAbs to be specific for MS:
anti-myelin autoAbs (e.g., anti-MBP, anti-MOG and anti-
neurofilament autoAbs); non-myelin autoAbs (e.g., anti-
HSP autoAbs, among others); and autoAbs demonstrating
different levels of specificity and functionality (e.g., cata-
lytic autoAbs [i.e., antibody proteases]). Clonal expan-
sion of B cells and T cells as hallmarks of inflammation in
the CNS are found in MS. The viral mimicry hypothesis
was formulated to explain the initiation of this disorder.
But a poor understanding of the etiology of MS has com-
plicated the development of effective therapeutics.
During the last 10 years, it has been found that Abs
contributed to the degradation of a number of autoanti-
gens. These and related “antibody-enzymes”, also termed
abzymes, were shown to be able to cleave DNA, RNA,
carbohydrates, peptides, and proteins. Recently, abzyme-
dependent catalytic degradation of an autoantigen, MBP,
was associated with the clinical course of the neurode-
generative disease MS and its rodent model, experimen-
tal autoimmune encephalomyelitis. Autoantibody-medi-
ated degradation of MBP was shown to be site-specic
with cleavage sites localized within the immunodomi-
nant epitopes of the protein molecule. Ample data indi-
cate that a significant portion of MS cases is characterized
D. Kostyushev et al. / Open Journal of Immunology 1 (2011) **-**
Copyright © 2011 SciRes. Openly accessible at http://www.scirp.org/journal/oji/
by the presence in the blood of autoantibodies against
myelin protein components. Moreover, high-resolution
microscopic analysis detected myelin-specific autoanti-
bodies in the areas of demyelination (plaques) in human
MS and a MS-like disease of marmosets, suggesting
their direct contribution to the myelin destruction.
Nonetheless, the mechanisms responsible for the induc-
tion of autoantibodies and their possible contributions to
MS progression are still unknown and are somewhat
contro- versial.
2.1. Anti-Myelin Basic Protein Antibodies
Diagnosis of multiple sclerosis without using immu-
nodiagnostics methods requires long-term observation
and magnetic resonance imaging. Analysis of anti-MOG
and anti-MBP antibodies is an inexpensive, rapid and
fairly accurate method for the early prediction of multi-
ple sclerosis. This can be extremely useful for assessing
the clinical state and proper selection of the treatment
strategy to be used in patients at the initial stages of de-
myelination [1]. At the same time there is no correlation
between the status of multiple sclerosis based on either
the McDonald or Poser and antibody status of patient
blood serum in the sub-clinical stage of disease [2,3].
Studies with using part of MBP as an epitope showed
selective reactivity of antibodies to the two MBP frag-
ments 43 - 68 and 146 - 170 distinguished the other neu-
ronal disorders and multiple sclerosis patients. That, due
to the author’s opinion, let use anti-MBP antibody as an
additional marker to monitor the disease progression [4].
Anti-MBP antibodies can be observed both in patient
with clinically confirmed diagnosis and some healthy
people. In this case, mononuclear cells obtained from the
healthy people produce in response to MBP such sub-
stances as tumor-necrosis factor-alpha (TNF-α) and inte-
rleukin-10 (IL-10), whereas in MS patient, in addiction
to increasing expressing proteins, γ-interferon, inter-
leukins 4 and 5 is excreted [5].
So comments on the role of antibodies in the patho-
genesis and diagnosis is still quite controversial. And,
because of this, now can be effective only to the indi-
vidual approach to each patient’s immune responses.
2.2. Antiganglioside Antibodies
Antiganglioside antibodies detected in serum in many
neurological diseases. It just appears at the immunologi-
cal analysis of patients with multiple sclerosis. The most
studied are antibodies to GM-1 ganglioside (anti-GM1).
It is not sufficiently reliable marker for the accurate di-
agnosis of “multiple sclerosis”, but it is a good tool for
determining the current phase of the disease in the
back-and-remitting type of disease [6]. At the same time,
the presence of different antibodies against gangliosides
in patient serum may be used as a criterion for classify-
ing MS for types. Thus, for the relapsing-remitting MS
is more typical anti-GM1-antibodies, and for progressive
MSthe more common group of AGA-antibodies [7].
In addition, we must note, that anti-GM3 antibodies are
typical for primary-progressive MS unlike to secondary-
progressive MS and other neuronal disorders. Also acti-
vating T-cells these antibodies increase damage to the
myeline sheath [8].
2.3. Anti-Myelin Oligodendrocyte
Glycoprotein Antibodies
MOG (myelin oligodendrocyte glycoprotein) is a
small 218 amino acid transmembrane glycoprotein of Ig
superfamily, mainly expressed by oligodendrocytes (OD)
and external lammels and located at the surface of mye-
lin. The abundance of MOG is significantly lower com-
pared with the other components of myelin (0.01% -
0.05%). The centrifugal location at the surface of myelin
fibers make it particularly vulnerable both to the action
of cell and humoral immune responses, including MOG-
specific autoAbs, which induce the destruction of myelin
(demyelination) in animal models. However, such Abs
are poorly known in humans. Located at the surface of
myelin sheath, native glycosylated MOG can be a strate-
gic target for the autoimmune attack by anti-MOG auto-
Abs at the early time points. The usage of such specific
biomarkers in the diagnosis of pre-clinical stages of MS
seems to be very perspective, e.g. these Abs possibly
play one of the major roles in initiation and progression
of pathogenic reactions, typical for MS. In addition,
cell-based assay provides a detection of valuable sero-
logical markers in the primate model of MS at the early
stages of the disease [8-11].
As mentioned above, the preferential position of
MOG in the nerve fibers is the surface of myelin sheath.
Nevertheless, it is rather intriguing that target sites of
autoimmune attack also can be located in the deep bot-
tom of the CNS. Subsequently, circulating T and B cells
are ready for the specific autoaggression against key
epitopes of MOG. There are several mostly discussed
mechanisms whose participation is likely to induce MOG-
specific expansion of B cells. MOG-specific T cells are
also able to infiltrate the naïve CNS and to create condi-
tions for immune responsiveness and to provoke the
activation and further expansion of B cells in T cells-
enriched areas. These processes are the crucial elements
of the “epitope spreading”, the phenomenon, which con-
D. Kostyushev et al. / Open Journal of Immunology 1 (2011) **-**
Copyright © 2011 SciRes. Openly accessible at http://www.scirp.org/journal/oji/
sists in autoAgs and pseudo-autoAgs widespread alloca-
tion over nervous tissues, later induction of autoimmune
attack by immunocompetent cells and cyclic events of
degenerative-destructive lesions along with restorative
reinstitution of myelin sheath [12] (Figure 1).
Furthermore, another phenomenon can explain the
autoaggression against sets of MOG epitopes. Despite the
overwhelming expression of MOG gene in the CNS, its
mRNA is also detected in other non-CNS organs (e.g.
thymus, liver, spleen), as well as small concentrations of
protein in peripheral blood. As it may be inferred from
above, local imbalances resulted in the collapse of immu-
nological priorities (target Ags) in peripheral organs, is
able to provoke generation of new autoreactive immuno-
competent populations. In its turn, they affect the restruc-
turing of the myelin sheath directly in the CNS [13-16].
Application of anti-MOG autoAbs in diagnosis of pri-
marydemylination and secondaryMS requires pre-
cise differentiation and complete description of the next
Time intervals of reliable and diagnostically signifi-
cant peak in titers of anti-MOG
autoAbs, which could be applied as serological tool
for the diagnosis of initial disease;
stages or its transition to the complicated course;
pathogenic role of anti-MOG autoAbs, as this type of
Abs can be found both in healthy individuals and in
patients with MS;
capability of reliable prognosis. Such prognosis must
predict the events, which stimulate accelerated demye-
lination and aggravation of the disease within concrete
intervals of serum anti-MOG autoAbs levels [17-20].
Figure 1. This graph shows the period between immunization,
appearance of antibodies and clinical manifestation. As it can
be seen from above, the detection of antibodies and early
clinical manifestation starts at 10 days. However, positive tests
for antibodies in all animals have been recorded already at day
18, whereas clinical manifestation is usually observed after 40
day from the beginning of the assay.
Development of economically beneficial, reliable and
precise tests for detection of autoAbs/changes in auto
Abs titers is necessary for pre-clinical diagnosis of MS
and possible evolution of the disease. Conventional me-
thods to count titers of anti-MOG autoAbs and, besides,
identification of autoAbs to MOG analogues (recom-
binant MOG (rMOG)) can be used for these purposes. In
the study on the association of autoAbs against rMOG in
patients with MS, a significant enlargement of autoAbs
has been detected. Moreover, individuals with progress-
sive type of MS showed higher rMOG indexes (marker
for intratecal production of anti-MOG Abs) compared
with relapse-remitting one [21].
Some data suggest that circulating anti-MOG autoAbs
are exclusive markers of demyelination, and their use for
differentiation and prediction of different clinical or pre-
clinical stages is impossible [22].
Collectively, application of anti-MOG Abs is con-
strained because of the incomplete information about the
role of these Abs (as direct inducers of pathological pro-
cesses or only as epiphenomenon) in etiology and pro-
gression of the disease, controversial data about their
role in MS and in healthy individuals.
2.4. Myelin-Associated Oligodendrocytic
Basic Protein
One of the most significant constituents of myelin
sheath in etiopathogenesis of MS is myelin-associated
oligodendrocytic basic protein (MOBP), a potential tar-
get for the autoreactive T cell clones. In murine models,
MOBP-reactive T cells can trigger MS-like disease,
caused by perivascular and parenchymal infiltration,
destruction and degeneration of axons, optic neuritis and
large-scale demyelinating processes in the CNS. The
leading role of MOBP in autoimmune responses and
complex pathology of the CNS is still unclear. Never-
theless, analysis of T cells, autoreactive towards MOBP,
suggests MOBP15-36 to be the major target of autoim-
mune attack in SJL/L mice by virtue of its encephalito-
genic potentialities (encephalitogenic epitopes). Autore-
activity of cell immunity towards MOBP is supposed to
be a qualitatively new biomarker of MS [23,24].
2.5. Oligodendrocyte-Specific Protein
Oligodendrocyte-specific protein (OSP)/claudin-11 is
a 207 amino acid hydrophobic protein of myelin sheath
with 4 transmembrane domains. The prevalence of OSP
in the myelin sheath is the third among other proteins in
the CNS and accounts approximately 7% of total. OSP is
one of the candidate autoAgs, involved in the patho-
physiology of MS. It is known that demyelination is
D. Kostyushev et al. / Open Journal of Immunology 1 (2011) **-**
Copyright © 2011 SciRes. Openly accessible at http://www.scirp.org/journal/oji/
primary affected by the reactivity of CD4+ T cells, en-
cephalitogenic towards OSP55-80 in the SJL/L mice
model of optic neuritis. The major target of humoral im-
munity (autoreactive autoAbs) is OSP114-120 [25,26]. In-
vestigation of mice with the knockout of OSP gene showed
that the main function of OSP is the formation of tight
junctions between myelin components and the integrity
maintenance of its structure. Presumably, OSP is an ana-
logue of the protein, contained in peripheral nerve tissues,
so-called peripheral myelin proteinPMP-22) [27].
Abnormal structure of myelin together with dege-
neration of axons, reduction in the activity of metabolic
processes in cells and decrease of axon diameter is ob-
served in mice with insufficient/lack of OSP [28]. When
exposed to the agents of autoimmune system, intra-lam-
ellar contacts (tight junctions) are exposed to severe
degradation. By virtue of this action, the integrity of my-
elin sheath is violated and restructuration of inter-cel-
lular matrix with consequent disruption of basic myelin
constituents occurs [29,30].
OSP is a relatively new protein, whose encephalito-
genic properties as well as its pathogenic role in MS are
still unclear. Nevertheless, chronic OSP-induced EAE in
C57BI/6J mice has a strong association with pathogenic
T cells, aimed at minor encephalitogenic regions OSP
199-207 and OSP22-46. Major OSP epitopes 55-80 and
179-207 are the leading pathogenic target for auto-reac-
tive T cells in SJL/L mice. In general, there are a number
of epitopes with strong encephalitogenic potential: 52-
71, 82-101, 102-121, 142-161, 182-201, and 192-207. In
vast majority of experimental data these sequences caused
severe relapse-remitting EAE and formation of mononu-
clear cell infiltrates. Infiltration of parenchymal organs is
a characteristic feature of every encephalitogenic OSP
except OSP142-161 and OSP182-201, including that ones,
which don’t lead to the clinical form of MS: OSP72-91
and OSP132-151 [31-34] (Figure 2).
2.6. Proteolipid Protein
Proteolipid protein (PLP), also known as lipophilin, is
the most abundant protein in the structure of myelin in
the CNS (50%). It is a hydrophobic and highly con-
servative molecule, represented in the human body with
2 basic transcripts: 276 full-length amino acid and
DM-20. The last isoform differs from the full-length
form by the absence of 35 amino acids, expressed
mainly in cerebrum and spinal cord prior to myelination
and in non-CNS tissues. Interestingly, the major ence-
phalittogenic and immunodominant PLP peptide (139-
154) is contained in full-length PLP but not in DM-20.
This observation is thought to account for the encepha-
litogenicity and immunodominance of the PLP (139-154)
peptide, since it is essentially not available for thy-
mus-related negative selection and consequently a high
pre-cursor frequency of PLP(139-154)-specific T cells
has been observed even in naive unprimed animals. The
autoimmune attack against such a conventional target as
PLP190-209 leads to multiple lesions of brainstem and
cerebellum [35].
At the same time, there is a significant correlation
between the enhanced activity of humoral and cell-me-
diated immunity towards PLP 184-209 with HLA-DR4,
HLA-DR7 or HLA-DR13 and progression of cerebral
lesions of demyelination. Additionally, more than a half
of MS patients with primary spinal cord and brain dam-
age show an enlarged reactivity of T cells against PLP
184-209. According to Greer JM et al., the presence of
HLA-DR4, DR7 or DR13 does not mean that they have
an increased propensity to the developing of brainstem
or cerebral lesions.
However, if the autoimmune attack really occurs, the
density of lesions in the myelin sheath will be much
higher in that case [36].
Ultimately, these data prove the theory that an enlarged
reactivity of T cell immunity towards PLP184-209 results
in the enhanced attack against brainstem and/or cerebellum.
It is important to point out that during the first attacks of
demyelination, autoreactive T cell clones can be detected
both in peripheral blood, and in CSF. The phase of remi-
ssion reveals the reduced reactivity of T cells, but prior to
the first clinical manifestation a substantial expansion of T
cells, directed against PLP184-190 and/or PLP190-209, is
observed [37,38].
2.7. Tubulin Polymerization Promoting
Protein (TPPP/P25)
Tubulin polymerization promoting protein (TPPP/
p25), localized in adult oligodendrocytes, takes part in
aggregation of cytoplasmic oligodendrocyte inclusions
in case of systemic atrophy of nerve tissues and can be a
valuable diagnostic and prognostic marker of MS. The
loss of TPPP/p25-positive OD in demyelinated lesions
of the CNS is a prospective biomarker for quantification
and quality characterization with a special view to esti-
mate physiological state of OD in different types and
stages of the disease. It is also possible to use this
method for testing the efficacy of applied therapy and
both allows to predict the very disease and to count the
possibilities for its transition into the complicated form.
When conducting a monitoring of average TPPP/p25
levels in CSF, Vinze et al. found that individuals with
clinically isolated syndrome and relapse-remitting type
of MS show a significant increase in concentrations of
TPPP/p25 (62.8 and 64.7 μg/l, correspondingly) com-
pared with the control group (27.9 μg/l) [39,40].
D. Kostyushev et al. / Open Journal of Immunology 1 (2011) **-**
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Figure 2. T cell proliferative recall responses to OSP peptides in SJL mice immunized with indi-
vidual OSP peptides. Spleen cell proliferation assays were performed on one mouse from each
group on days 30, 36, 42, and 48 post-injection. OSP peptides were added to a final concentration
in culture of 5, 20, and 40 µg/ml. The best SIs were obtained at 20 or 40 µg/ml. The PLP139-151
peptide was used at approximate molar equivalences. The highest SI obtained for each individual
mouse’s spleen cells cultured at 4 × 106 and 2 × 106 cells/ml is plotted of adjacent like-patterned
bars. The red/yellow/grey/orange part of each bar represents the smallest SI obtained from the
OSP peptide titration at 4 × 106 cells/ml or 2 × 106 cells/ml. The green part of bar submit how
much SI at 4 × 106 more than 2 × 106, or blue part when SI at 2 × 106 more than 4 × 106.
3. CONCLUSIONS valuable tool for detecting of dormant pathological
processes in the myelin sheath. Nonetheless, auto-Abs
are the key agents involved in the destruction and de-
generation of myelin in the CNS and expansion of
autoimmune responses, e.g. pro-inflammotary agression
and epitope spreading. As it can be inferred from above,
Abs by virtue of its peculiar properties, circulate in pe-
On the basis of the ample data in conventional Abs-
proteases and Abs with functional reserve in diagnosis of
minor lesions occurring in MS patients as well as dif-
ferentiated diagnosis, we discussed the crucial antigenic
targets for autoimmune attack and their prospects as a
Openly accessible at
D. Kostyushev et al. / Open Journal of Immunology 1 (2011) **-**
Copyright © 2011 SciRes. Openly accessible at http://www.scirp.org/journal/oji/
ripheral blood and CSF for years before clinical mani-
festation. Subsequently, using these biomarkers, we can
define prospectives for further progression of current
pre-morbid state to the stages of profound clinical sym-
pthoms and blockade it by time-lapse introducing of mo-
dern predictive and preventive therapeutic protocols. In
addition, determination of specific epitopes in different
constituents of myelin (BMP, MOG, PLP, MOBP, OSP)
in some cases allows to find predominant sites of autoa-
gression (e.g. cerebrum, spinal cord).
Serological assay based on the identification of speci-
fic immune biomarkers and monitoring of their spectra
are fundamental principles of Predictive and Preventive
Medicine. Further search for prospective biomolecules
and description of their potential role regarding the prin-
ciples of pre-clinical diagnosis is especially important
for their capable application and impact in clinical and
pre-clinical practice.
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