Investigation of autoantibodies directed against tissue-specific myocardial antigens in dilated cardiomyopathy
The autoantibodies directed against actin and tnyosine have been detected in the blood sera of patients with dilated cardiomyopathy (DCMP) at the level that was sufficiently higher than in healthy donors. While comparing of the immunogeneicity of these proteins we have stated that myosine from affec...
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Інститут молекулярної біології і генетики НАН України
1995
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| Cite this: | Investigation of autoantibodies directed against tissue-specific myocardial antigens in dilated cardiomyopathy / L.L. Sidorik, N.V. Rodnin, V.I. Bobyk, D.V. Ryabenko, A.V. Veberov, T.Yu. Tkachenko, G.Kh. Matsuka // Биополимеры и клетка. — 1995. — Т. 11, № 1. — С. 81-86. — Бібліогр.: 22 назв. — англ. |
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nasplib_isofts_kiev_ua-123456789-1556552025-02-23T17:12:17Z Investigation of autoantibodies directed against tissue-specific myocardial antigens in dilated cardiomyopathy Дослідження аутоантитіл до тканиноспецифічних антигенів міокарда при дилятаційній кардюмюпатії Исследование аутоантител к тканеспецифическим антигенам миокарда при дилятационной кардиомиопатии Sidorik, L.L. Rodnin, N.V. Bobyk, V.I. Ryabenko, D.V. Veberov, A.V. Tkachenko, T.Yu. Matsuka, G.Kh. The autoantibodies directed against actin and tnyosine have been detected in the blood sera of patients with dilated cardiomyopathy (DCMP) at the level that was sufficiently higher than in healthy donors. While comparing of the immunogeneicity of these proteins we have stated that myosine from affected by DCMP myocardium have been more immunogenic then from normal one. In the case of actin the immunogeneicity have been higher for the protein from normal myocard. The investigations of actin by limited proteolysis may suggest that the differencies in immune properties are not connected with primary structure but with structures of higher levels. У роботі досліджено аутоантитіла проти тканиноспецифічних антигенів міокарда людини – актина і міозина. Методом твердофазного імуноферментного аналізу (ELISA) показано, що імунореактивність сироваток крові пацієнтів з дилятаційною кардіоміопатією (ДКМП) проти досліджених антигенів суттєво вища, ніж у здорових донорів. При порівнянні імунореактивності однакових сироваток проти антигенів, виділених із нормального і ураженого ДКМП міокарда, виявлено наступну закономірність: імунна відповідь на міозин із нормального міокарда була слабшою, ніж на той же білок із міокарда, ураженого ДКМП. Для актина спостерігалася зворотна залежність. Аналіз актина із нормального і ураженого ДКМП міокарда за допомогою методу обмеженого протеолізу дозволяє вважати, що з розвитком ДКМП цей білок підда ється субмолекулярним (скоріш за все, конформаційним) модифікаціям, які призводять до змін його імунореактивності. Отримані результати обговорюються з позиції функціонування скорочувального апарату кардіоміоцитів. В работе исследованы аутоантитела против тканеспецифических антигенов миокарда человека – актина и миозина. Методом твердофазного иммунофермеитиого анализа (ELISA) показано, что иммунореактивность сывороток крови пациентов с дилятационной кардиомиопатней (ДКМП) против исследованных антигенов существенно выше, чем у здоровых доноров. При сравнении иммунореактивности одних и тех же сывороток против антигенов, выделенных из нормального и пораженного ДКМП миокарда, обнаружена следующая закономерность: иммунный ответ на миозин из нормального миокарда был слабее, чем на тот же белок из миокарда, пораженного ДКМП. Для актина наблюдалась обратная зависимость. Анализ актина из нормального и пораженного ДКМП миокарда с помощью метода ограниченного протеолиза дает основание полагать, что при развитии ДКМП данный белок претерпевает субмолскулярные (вероятнее всего, конформационные) модификации, ведущие к изменениям его иммунореактивности. Полученные результаты обсуждаются с позиции функционирования сократительного аппарата кардиомиоцитов. 1995 Article Investigation of autoantibodies directed against tissue-specific myocardial antigens in dilated cardiomyopathy / L.L. Sidorik, N.V. Rodnin, V.I. Bobyk, D.V. Ryabenko, A.V. Veberov, T.Yu. Tkachenko, G.Kh. Matsuka // Биополимеры и клетка. — 1995. — Т. 11, № 1. — С. 81-86. — Бібліогр.: 22 назв. — англ. 0233-7657 DOI: http://dx.doi.org/10.7124/bc.0003D7 https://nasplib.isofts.kiev.ua/handle/123456789/155655 577.152 en Биополимеры и клетка application/pdf Інститут молекулярної біології і генетики НАН України |
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Digital Library of Periodicals of National Academy of Sciences of Ukraine |
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| description |
The autoantibodies directed against actin and tnyosine have been detected in the blood sera of patients with dilated cardiomyopathy (DCMP) at the level that was sufficiently higher than in healthy donors. While comparing of the immunogeneicity of these proteins we have stated that myosine from affected by DCMP myocardium have been more immunogenic then from normal one. In the case of actin the immunogeneicity have been higher for the protein from normal myocard. The investigations of actin by limited proteolysis may suggest that the differencies in immune properties are not connected with primary structure but with structures of higher levels. |
| format |
Article |
| author |
Sidorik, L.L. Rodnin, N.V. Bobyk, V.I. Ryabenko, D.V. Veberov, A.V. Tkachenko, T.Yu. Matsuka, G.Kh. |
| spellingShingle |
Sidorik, L.L. Rodnin, N.V. Bobyk, V.I. Ryabenko, D.V. Veberov, A.V. Tkachenko, T.Yu. Matsuka, G.Kh. Investigation of autoantibodies directed against tissue-specific myocardial antigens in dilated cardiomyopathy Биополимеры и клетка |
| author_facet |
Sidorik, L.L. Rodnin, N.V. Bobyk, V.I. Ryabenko, D.V. Veberov, A.V. Tkachenko, T.Yu. Matsuka, G.Kh. |
| author_sort |
Sidorik, L.L. |
| title |
Investigation of autoantibodies directed against tissue-specific myocardial antigens in dilated cardiomyopathy |
| title_short |
Investigation of autoantibodies directed against tissue-specific myocardial antigens in dilated cardiomyopathy |
| title_full |
Investigation of autoantibodies directed against tissue-specific myocardial antigens in dilated cardiomyopathy |
| title_fullStr |
Investigation of autoantibodies directed against tissue-specific myocardial antigens in dilated cardiomyopathy |
| title_full_unstemmed |
Investigation of autoantibodies directed against tissue-specific myocardial antigens in dilated cardiomyopathy |
| title_sort |
investigation of autoantibodies directed against tissue-specific myocardial antigens in dilated cardiomyopathy |
| publisher |
Інститут молекулярної біології і генетики НАН України |
| publishDate |
1995 |
| url |
https://nasplib.isofts.kiev.ua/handle/123456789/155655 |
| citation_txt |
Investigation of autoantibodies directed against tissue-specific myocardial antigens in dilated cardiomyopathy / L.L. Sidorik, N.V. Rodnin, V.I. Bobyk, D.V. Ryabenko, A.V. Veberov, T.Yu. Tkachenko, G.Kh. Matsuka // Биополимеры и клетка. — 1995. — Т. 11, № 1. — С. 81-86. — Бібліогр.: 22 назв. — англ. |
| series |
Биополимеры и клетка |
| work_keys_str_mv |
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2025-11-24T02:42:56Z |
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| fulltext |
УДК 577.152
L. L. Sidorik, N. V. Rodnin, V. I. Bobyk, D. V. Ryabenko,
A. V. Veberov, T. Yu. Tkachenko, G. Kh. Matsuka
INVESTIGATION OF AUTOANTIBODIES DIRECTED
AGAINST TISSUE-SPECIFIC MYOCARDIAL ANTIGENS
IN DILATED CARDIOMYOPATHY
The autoantibodies directed against actin and myosine have been detected in the blood
sera of patients with dilated cardiomyopathy (DCMP) at the level that was sufficiently
higher than in healthy donors. While comparing of the immunogeneicity of these pro
teins we have stated that myosine from affected by DCMP myocardium have been more
immunogenic then from normal one. In the case of actin the immunogeneicity have been
higher for the protein from normal myocard. The investigations of actin by limited
proteolysis may suggest that the differencies in immune properties are not connected
with primary structure but with structures of higher levels.
Introduction. Nowadays the presence of autoimmune processes during
the development of various pathologies including heart diseases is obvi
ous. At the same time the functional activity of autoAbs wasn't exami
ned enough. The investigation of structural and functional properties of
autoantibodies (aAbs) directed against antigens from heart and vessels,
the establishment of their role while the origin and development of heart
diseases is necessary not only for theoretical but for practical aims also,
in the context of developing of novel therapeutic and diagnostic prepa
rations [1].
The aim of our investigation was to study the molecular mechanisms
of autoantibodygenesis directed against the most important tissue-speci
fic antigens — actin and myosin, during development of dilated cardio
myopathy (DCMP). In recent studies the aAbs directed against adenine
nucleotide translocator (ANT) [2], the mitochondrial enzyme from myo
cytes were detected; the aAbs directed against another mitochondrial en
zyme, branched chain keto acid dehydrogenase (BCKD) [3] were also
described at DCMP and myocarditis. The laboratory of Limas (USA)
during recent years studied the structure and properties of aAbs directed
against p-adrenoreceptor [4—8]; these aAbs were detected in 30—40 %
of patients with DCMP. The presence of aAbs directed against myosin,
tropomyosin, vimentin, laminin at some heart diseases such as postmyo-
cardial infarction syndrome, dilated cardiomyopathy, infectious myocar
ditis, and doxorubicin (Adriamycin) cardiotoxicity [9]' is occasionally
accompanied by the deposition of antibodies within the myocardium, par
ticularly on the sarcolemma.
The present paper is a first stage of study of aAbs, their properties
and role at DCMP progressing, which are directed against the most
abundant heart antigens — actin and myosin.
The method described [10] for purifing of preparative quantities of
antigens from human myocardium (pathomorphological material) enabled
us to obtain the mentioned above antigens as from normal myocardium
as from myocardium, affected by DCMP.
The presence of aAbs in the sera of patients with DCMP was not
unexpected because many facts suggested the presence of cellular and
humoral immunity in the development of DCMP {4]. These data concern
© L. L. Sidorik, N. V. Rodnin, V. I. Bobyk, D. V. Ryabenko, A. V, Veberov, T. Yu. Tkachenko
G. Kh. Matsuka, 1996
ISSN 0233-7667. БИОПОЛИМЕРЫ И КЛЕТКА. 1995. Т. 11. № 1 б ' / г - 4 ' 9 3 5
81
the introduction of Igs (in the form of immune complexes) in affected
myocardium, the abnormalities in relative proportion and function of pe
ripheric lymphocytes, the occurrence of cytokines and existance of vari
ous aAbs directed against surface and intracellular components of myo
cytes. Meanwhile the correlation of mentioned processes with the clinical
manifestation of diseases wasn't identified yet.
Materials and methods. The sera from DCMP patients were kindly
provided by Strazesko Institute for Cardiology. The 45 sera from pati
ents with DCMP and 38 sera from healthy donors were examined. The
*
Fig 1 The immunoreactivity of sera of patients with DCMP directed against myosin
purified from normal (light columns) and DCMP myocardium (dark columns). The im
munoreactivity was detected as described in Materials and methods
Fig 2 The immunoreactivity of sera of patients with DCMP directed against actin pu
rified from normal (light columns) and DCMP myocardium (dark columns), ihe immu
noreactivity was detected as described in Materials and methods
diagnosis was provided according to the World Health Organization
criteria. ,
P u r i f i c a t i o n of a c t i n a n d m у о s і n. The preparations of
actin and myosin (90 % purity) were obtained from healthy and affected
by DCMP myocardium as described [1]. The purity of preparations was
controlled by the electrophoresis according Laemmly [11].
E L I S A. The immunoreactivity of the patients sera was detected
by the ELISA method [13] with modifications. The antigens were immo
bilized overnight at 4 °С in 0.1 M carbonate buffer, pH 8.0. The concen
trations of antigens were 5 pig per ml. Tubulin, DNA from salmon sperm,
trinitrophenol (TNP, «Sigma») and total preparation of human IgG from
healthy donors obtained by method [12] were used as control antigens.
The human anti-IgG conjugated with peroxidase was purchased
from DiaGen, Moscow. The results of ELISA were calculated as descri
bed in [14].
D e t e c t i o n of IgG a n d IgM in t h e s e r a of p a t i
e n t s . The concentrations of IgG and IgM in the sera investigated were
determined by ELISA method [13] with standard human sera from «Bo-
ehringer» (Germany) as control.
L i m i t e d p r o t e o l y s i s . The limited proteolysis of actin prepa
rations from normal and affected by DCMP myocardium was provided
as described [15] with several modifications: pH 8.0, temperature 20 °С,
enzyme-substrate ratio 1 : 100, TPCK-treated trypsin from «Sigma»
(USA) The proteolysis time was from 15 to 60 min. The results of hyd
rolysis were detected by SDS-gel electrophoresis [11]. The gels were
scanned by Ultroscan (LKB, Sweden).
82 ISSN 0233-7657. БИОПОЛИМЕРЫ И КЛЕТКА. 1995. Т. 11. № 1
Results and discussion. Table shows the concentrations of IgG and
IgM in the investigated sera of patients with DCMP and healthy donors.
It is obvious that Ig concentrations are different and don't depend on
kind and stage of disease.
The immunoreactivity of sera from DCMP patients against actin and
myosin from normal and affected by DCMP myocardium. Fig. 1 shows
the immunoreactivity of DCMP patients sera against myosin from nor
mal and affected by DCMP myocardium. It's obvious that immunoreac
tivity of sera against DCMP-myosin is higher then in the case of myosin
from normal heart. In the case
of actin it was vice versa (Fig. М^Ґт v
2). As it was shown by us ear
lier [10] myosin and actin pre
parations from normal and
Fig. 3. The densitogramm of proteo
lytic cleavage of myosine preparations
from normal (solid line) and DCMP
myocardium (dotted line). The positi
on of molecular mass markers are in
dicated by arrows. A — position of
undigested actin. The proteolysis was
conducted as described in Materials
and methods
DCMP-myocardium possess the same Mr and isoelectric point these
results suggest that the structure peculiarities aren't connected with the
primary structure of the molecules. We believe that the differencies in
the immunogeneicity are connected with certain conformational changes.
It's well known that protein folding is sufficient for their immunological
properties [16, 17]. The protein conformation depends on posttranslation
modifications and intracellular media, that is especially sufficient for ac
tin and myosin molecules, that form «molecular motor» among and with
a help of many other proteins: besides tropomyosin and family of tropo-
nines, nowadays at least 8 proteins are known to take part in functio
ning of this system [18].
We proceeded our work in the field of search of possible reasons in
the changes of immunogeneicity of myocardial tissue-specific antigens at
DCMP progressing on the conformational level of mentioned proteins.
Concentrations of IgG and IgM in the sera of patients with DCMP (1—22) and sera
of healthy donors (23—32) (the most immunoreactive sera are presented);
33 — control serum
Serum N
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
IgM, mg/ml
,1.18
3,6
1.7
3.02
2.48
1.9
1.2
0.9
0.5
0.8
1.97
0.95
1.02
0.9
0.95
1.3
2.23
IgQ. mg/ml
26.43
23.47
30.35
14.63
14.12
7.7
18.77
14.82
14.5
14.08
11.2
19.5
13.2
26.42
6.7
19.5
25.6
Serum N
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
IgM, mg/ml
0.9
0.92
1.33
2.29
0.98
1.33
1.1
2.1
0.94
2.23
0.5
1.26
0.96
2.01
1.05
0.58
IgG, mg/ml
13.5
13.7
14.65
18.61
20.48
19,92
22.53
18.17
15.17
17.07
15 22
16.56
13.89
11.2
23.5
12.24
ISSN 0233-7657. БИОПОЛИМЕРЫ И КЛЕТКА. 1995. Т. П. №. 16* 83
The first stage of these investigations was the study of the limited pro
teolysis of actin molecule.
The results of actin limited proteolysis are shown at Fig. 3. From
the densitogramm it's obvious that the spectrum of the fragments obta
ined is alike for both preparations. At the same time the intensivity of
digestion of actin from myocardium affected by DCMP is higher then
in the case of normal tissue that is expressed in higher concentrations
of low molecular weight fragments (14 and 23 % for fragment with Mr
12.000, respectively). The mentioned differencies in the intensivity of ac
tin preparations digestion may suggest the presence of certain confor
mational differencies in actin molecules in the preparations that leads
to the better digestion of actin preparations from myocardium affected
by DCMP. At the same time the absence of differencies in the spectrum
of proteolytic fragments suggests the absence of changes in the primary
structure of proteins.
In the present paper we had shown the presence of aAbs directed
against two tissue-specific myocardial proteins — actin and myosin.
In the recent investigations the aAbs directed against ANT and
BCKD from myocyte mitochondria as well as p-adrenoreceptor [4—8]
was described. The aAbs directed against myosin were detected only at
experimentally induced myocarditis in mice [19]. The investigations of
autoantibodygenesis against actin and myosin put forward several im
portant questions. First, myosin and actin represent the intracellular an
tigens. The origin of aAbs against them as well as aAbs against any
other intracellular is unclear [20].
It seems possible that aAbs directed against intracellular antigens
may be induced by viral infection, for example, Coxaki CB3, that may
induce myocarditis in mice [1, 21].
The overlapping peptides from myosin were synthesied and with a
help of them the autoimmune epitope of the heavy chain of a-isoform of
myosin had been localized. It was also shown that myocarditogenic forms
do not possess crossreactivity with myosin [1, 9]. Kanningham had shown
the immunological crossreactivity among several a-spiralic proteins in
cluding myosin, tropomyosin, vimentin, M-protein from streptococcus and
laminin, the surface protein from cardiomyocytes with a help of monoclo
nal antibodies [1]. The peptides from Лі-protein had shown the high struc
tural homology with myosin and laminin.
It's likely that in humans the progression of disease is more compli
cated then in mice. Kandolf had shown during the last stages of myocar
ditis and DCMP the limited replication of viral RNA, and Weiss had not
detected CB3 by PCR method [1]. So we can consider autoimmune me
chanisms sufficient in the origin of DCMP pathogenesis.
One of the possible explanations of the origin of autoimmune disea
ses is that viral infection [20, 21] leads to the secretion of antigen which
are identified by «professional» antigen-presenting dendrite cells in car
dial matrix. Moreover, in humans the degree of cellular inflammation and
rigidity of myocyte destruction doesn't correlate exactly with cardial dis
function that is in order with suggestion of aAbs directed against
myocyte antigen participation in the pathogenesis of myocarditis
and DCMP.
It seems reasonable to focuse our investigations on the heavy myo
sin chain as the most immunogenic part of the molecule. It's a problem
of special interest because in mice the immunization by myosin heavy
chain induced the myocarditis that was similar to that caused by Coxaki
virus CB3. At the same time it's well known that in many cases myocar
ditis leads to the progression of severe DCMP forms and aAbs spectra
are very similar at these pathologies. Moreover, the investigation of this
myosin epitope is sufficient not only from the point of view of search of
target antigen while cardiomyopathy development but also helps in un
derstanding of the functional role of aAbs directed against tissue-speci
fic myocardial antigens at DCMP. Even in the case of described auto-
84 ISSN 0233-7657. БИОПОЛИМЕРЫ И КЛЕТКА. 1995. Т. П. № 1
antigens at DCMP (as ANT or p-adrenoreceptor) the function of aAbs
in the origin and pathogenesis of disease is unclear yet.
It's obvious that the study of structure and properties of autoanti-
gens and their possible modifications must be conducted simultaneously.
This may help us in the understanding of the other aspect of autoimmune
disease development: what leads to the immunogeneicity of autoantigen
leading to the absence of tolerance to «own» antigens? We consider im
portant the further investigation of antigens from normal and affected
by DCMP myocardium, and the same antigens from skeletal and smooth
muscle by conformational methods such as spectrofluorimetry, circular
dichroism, electronic paramagnetic resonance and so on.
The further investigation of autoantibodygenesis against the compo
nents of contractile apparatus of myocytes may help to obtain the new
information about actin and myosin functioning because aAbs are often
directed against another epitopes of the same antigen that are evolutio
nary conserved and possess functional importance [22]. The data of our
investigations may help not only to understand the mechanisms of DCMP
development but other heart diseases as well.
Л. Л. Сидорик, М. В. Роднін, В. І. Бобик,
Д. В. Рябенко, О. В. Веберов, Т. Ю. Ткаченко, Г. X. Мацука
ДОСЛІДЖЕННЯ АУТОАНТИТІЛ ДО ТКАНИНОСПЕЦИФІЧНИХ
АНТИГЕНІВ МІОКАРДА ПРИ ДИЛЯТАЦІЙНІИ КАРДЮМЮПАТИ
Р е з ю м е
У роботі досліджено аутоантитіла проти тканиноспецифічних антигенів міокарда лю
дини— актина і міозина. Методом твердофазного імуноферментного аналізу (ELISA)
показано, що імунореактивність сироваток крові пацієнтів з дилятаційною кардіоміо-
патією (ДКМП) проти досліджених антигенів суттєво вища, ніж у здорових донорів.
При порівнянні імунореактивності однакових сироваток проти антигенів, виділених
із нормального і ураженого ДКМП міокарда, виявлено наступну закономірність:
імунна відповідь на міозин із нормального міокарда була слабшою, ніж на той же
білок із міокарда, ураженого ДКМП. Для актина спостерігалася зворотна залежність.
Аналіз актина із нормального і ураженого ДКМП міокарда за допомогою методу
обмеженого протеолізу дозволяє вважати, що з розвитком ДКМП цей білок підда
ється субмолекулярним (скоріш за все, конформаційним) модифікаціям, які призво
дять до змін його імунореактивності. Отримані результати обговорюються з позиції
функціонування скорочувального апарату кардіоміоцитів.
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