Myelin-associated serological targets as applicable to diagnostic tools to be used at the preclinical and transient stages of multiple sclerosis progression

doi:10.4236/oji.2011.13010

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Vol.1, No.3, 80-86 (2011)

doi:10.4236/oji.2011.13010

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.

ABSTRACT

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

1. INTRODUCTION

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

disease.

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-speciﬁc

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) **-**

8181

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. CONSTITUENTS OF MYELIN:

INDUCERS OF MS AND PROVOKING

FACTORS

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

MS—the 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) **-**

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-

mary—demylination and secondary—MS requires pre-

cise differentiation and complete description of the next

criteria:

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

(OSP)/Claudin-11

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) **-**

8383

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 protein—PMP-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) **-**

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) **-**

8585

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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