25
«NEVROLOGIYA»—3(83), 2020
ВОПРОСЫ ДЕТСКОЙ НЕВРОЛОГИИ
HIV does not directly infect neurons, but it damages neurons
and glial cells indirectly through the pro-inflammatory mediators
and by the mechanism of excitotoxicity (the phenomenon of dam-
age and death of nerve cells due to excessive activation of re-
ceptors by neurotransmitters) [1,2]. The HIV enters central ner-
vous system (CNS) in the early phase of infection by breaking the
blood-brain barrier with infected monocytes and lymphocytes - a
pathway called the Trojan Horse [2]. Infected monocytes in the
central nervous system differentiate into resident macrophages
and by maintaining a low level of replication of viral particles, in-
fect the surrounding microglia. Astrocytes are also prone to infec-
tion, but they do not produce HIV replication. Viral proteins (Tat),
released from the infected monocyte derivatives, can directly
damage neurons [3,4]. At the same time, an increase in the per-
meability of the intestinal membrane for bacteria increases the
lipopolysaccharide mechanism of activation of systemic inflam-
matory response and activation of monocytes [5,6]. Activated
monocytes and macrophages produce cytokines and chemo-
kines, which increase the migration of inflammatory effector cells,
and also express an increased number of excitotoxic neurotrans-
mitters [1,2]. Elevation of excitotoxic amino acids and excessive
activation of NMDA receptors leads to an increase in the internal
neuronal concentration of calcium to a toxic level, which is ac-
companied by an increase in lipid peroxidation (LPO) activity and
dysregulation of the normal autophagy process [7,8,9]. However,
in addition to the described mechanisms, an autoimmune reac-
tion plays a role in the damage to the central nervous system
against the background of HIV infection, which is confirmed by
an increase in the concentration of antibodies to myelin in pa-
tients with HIV encephalopathy. One of the mechanisms of dam-
age is CNS vasculitis, which has an autoimmune pathogenesis
and is associated with cerebrovascular complications of HIV [10-
UDC: 616.8.578.828.6
FEATURES OF AUTOIMMUNE REACTIONS ACTIVATION
ASSOCIATED WITH PEDIATRIC HIV-ENCEPHALOPATHY
Saidkhodjaeva S.N., Madjidova Y.N.
Tashkent pediatric medical institute
Keywords: pediatric HIV encephalopathy, autoimmunity, antibodies to myelin, antibodies to 1 and 2 stranded DNA, adolescents,
neurocognitive disorder.
ОСОБЕННОСТИ АКТИВАЦИИ АУТОИММУННЫХ РЕАКЦИЙ, АССОЦИИРОВАННЫХ С ПЕДИАТРИЧЕСКОЙ
ВИЧ-ЭНЦЕФАЛОПАТИЕЙ
Саидходжаева С.Н., Маджидова Я.Н.
Ключевые слова: педиатрическая ВИЧ-энцефалопатия, аутоиммунитет, антитела к миелину, антитела к 1-но и 2-х цепо-
чечной ДНК, подростки, нейрокогнитивное расстройство
В настоящем исследовании оценивается активность аутоиммунных реакций у детей подросткового возраста с ВИЧ-
энцефалопатией различной выраженности. По результатам проведенного исследования обнаружено, что у детей с ВИЧ - эн-
цефалопатией симптомные нейрокогнитивные нарушения ассоциируются с активацией клеточного и гуморального иммуни-
тета – преимущественно натуральных киллеров, маркеров апоптоза, антителопродуцирующих и реактивных лимфоцитов. В
связи с этим была выдвинута гипотеза о роли аутоиммунных реакций в формировании ВИЧ-энцефалопатией. Вероятными
путями повреждения ЦНС могут быть как васкулит, так и аутоиммунное повреждение собственно нервной ткани. Исходя из
этой гипотезы в ходе исследования было проведено изучение концентрации аутоантител - Ат к миелину, АФА (индукция ва-
скулита), Ат к клеточным ядрам (АНА) и их компонентам – 1-но и 2-х цепочечной ДНК.
ПЕДИАТРИК ОИВ ЭНЦЕФАЛОПАТИЯ БИЛАН БОҒЛИҚ АУТОИММУН РЕАКЦИЯЛАРНИ ФАОЛЛАШТИРИШ
ХУСУСИЯТЛАРИ
Саидходжаева С.Н., Маджидова Я.Н.
Калит сўзлар: педиатрик ОИВ энцефалопатия, аутоиммунитет, миелин антикорлари, 1-ва 2-занжир ДНК антикорлари,
ўсмирлар, нейрокогнитив бузилиши
Ушбу тадқиқот турли зўравонлик ОИВ энцефалопатияси бўлган ўсмир болаларда аутоиммун реакцияларнинг фаоллиги-
ни баҳолайди. Тадқиқот натижаларига кўра, ОИВ энцефалопатия бўлган болаларда симптоматик нейрокогнитив бузилишлар
уяли ва гуморал иммунитетни фаоллаштириш билан боғлиқ - асосан табиий қотиллар, апоптоз маркерлари, антикоришлаб
чиқарувчи ва реактив лимфоцитлар еканлиги аниқланди. Шу муносабат билан ОИВ энцефалопатиясининг ҳосил бўлишида
аутоиммун реакцияларнинг роли ҳақида гипотеза илгари сурилди. Марказий асаб тизимига зарар етказишнинг еҳтимолий
усуллари асаб тўқимасининг ўзига васкулит ва аутоиммун зарар етказиши мумкин. Бу гипотезага асосланиб ишда аутоанти-
кодларнинг концентрацияси – Ат- га миелин, АФА (васкулит индуксияси), Ат га ҳужайра ядролари (АНА) ва уларнинг таркибий
қисмлари – 1-лекин ва 2-занжирли ДНК ўрганилган.
14].
Study aim - to evaluate the activity of autoimmune reactions
in children with HIV encephalopathy of various severity.
Material and research methods.
The study included 260 children (153 boys - 58.85%) with
HIV-positive status and taking ART according to an individually
selected scheme for at least 6 months. All children at the time of
inclusion in the study were in inpatient treatment regime in a spe-
cialized clinic of the Republican AIDS Center. The average age
was 14.53 ± 1.58 years (12-18 years), the duration of HIV history
was 7.05 ± 3.36 years (1-13 years), the duration of ART therapy
was 6.41 ± 3.47 years (1-13 years). 35 children were diagnosed
with (13.46%) the vertical route of infection, and their mothers did
not take ART during pregnancy, the therapy was started from the
moment of birth.
Children who didn’t receive ART therapy and who had signs
of active OI of the central nervous system, active tuberculous
process of any localization, children with hyperthermia of more
than 370C degrees and central nervous system tumors wasn’t
included into the study. Neuro-AIDS was also a criterion for ex-
clusion from the study.
The HIV diagnosis was verified by anamnesis and according
to the results of laboratory data of ELISA and PCR of the periph-
eral blood.
All children included in the study were examined for signs of
HIVE. For this purpose, a standard neurological examination was
carried out, including an assessment of consciousness and some
mental functions, speech, praxis, gnosis, functions of the cranial
nerves, the state of the motor and sensory spheres, the auto-
nomic nervous system, and the use of special scales and ques-
tionnaires. The study revealed the components of HIVE, back-
ground neurological disorders associated with HIV (for example,
«NEVROLOGIYA»—3(83), 2020
26
ВОПРОСЫ ДЕТСКОЙ НЕВРОЛОГИИ
cerebrovascular diseases and their complications) and associat-
ed neurological syndromes (convulsive syndrome, enuresis, lo-
goneurosis, insomnia and parasomnia).
All children included in the study showed signs of HIVE. Dur-
ing the study, it was decided to classify HIVE according to the
Frascatti criteria proposed for the classification of VAND accord-
ing to the stages: asymptomatic neurocognitive disorders (AND),
moderate ND (MND) and HIV-associated dementia (HAD). at the
same time, asymptomatic neurocognitive disorder (AND) was di-
agnosed in 116 (44.62%), moderate neurocognitive disorder
(MND) in 88 (33.85%), and HIV-associated dementia in 56 chil-
dren (21.54%) (HAD).
Virology investigation included a PCR study to determine the
number of copies of HIV RNA in plasma and peripheral blood
monocytes. Activation of autoimmunity was evaluated by the
concentration of antibodies to the components of myelin, lupus
anticoagulant and antibodies to 1 and 2-stranded DNA.
Statistical analysis. All data obtained during the investigation
process was entered into the summary tables of the table editor
Excell and grouped according to the criteria formulated in the
study protocol. For each indicator in the groups, the arithmetic
mean value and its standard deviation were calculated. The reli-
ability of intergroup differences was evaluated using the Student
test. The statistical hypothesis was considered reliable with a co-
incidence probability of 95% or more. In the case of multiple com-
parisons, the Student criterion adjusted by the Bonferroni correc-
tion was used. To compare the frequency of occurrence of the
sign, a tabular Chi-square criterion was used, the reliability of
which was determined from the tables depending on the number
of degrees of freedom. Correlation analysis was carried out using
the Pearson criterion with an assessment of its reliability accord-
ing to the tables depending on the number of correlated pairs of
signs (with the number of degrees of freedom 200-300, for a
probability of 95% - r> 0.138, 99% - r> 0.181).
Study results and discussion. The pathogenetic characteris-
tic of HIV is the existence of violation of anti-infective immunity. At
the same time, this study found that in children with HIVE, symp-
tomatic neurocognitive impairment is associated with activation
of cellular and humoral immunity - mainly natural killers, markers
of apoptosis, antidiv-producing and reactive lymphocytes. In
this regard, a hypothesis was put forward on the role of autoim-
mune reactions in the formation of HIVE. The likely ways of dam-
age to the central nervous system can be both vasculitis and au-
toimmune damage to the nervous tissue itself. Based on this
hypothesis, the study examined the concentration of autoanti-
bodies - Ab to myelin, AFA (vasculitis induction), Ab to cell nuclei
(ANA) and their components - 1 and 2 stranded DNA.
In general it was found that children cohort group included
into the study, had the extending normative range diapason of
the concentration of all the antibodies studied: for example, the
concentration of Ab to myelin was 16.77 ± 0.99 U/ml with a
normative range less than 10 U/ml, the AFA confirmation test was
1.35 ± 0.03 rel. units with a normative range less than 1.2 rel.
units, Ab for 1-stranded DNA - 47.65 ± 3.77 units/ml, 2-stranded
DNA - 54.38 ± 3.80 units/ml with a normative range less than 25
units/ml, ANA - 13.38 ± 1.78 units/ml with a normative range less
than 1 unit/ml. The duration of coagulation in children with HIVE
in the test to reveal the AFA was increased to 67.33 ± 1.50 sec
(AFA1) and 53.61 ± 1.04 sec (AFA2) with a reference norm of 31-
44 sec and 30-38 sec, respectively.
Analysis of changes in antidiv concentration depending on
the stage of HIVE (Table 1) revealed significant increase in the
concentration of antibodies to myelin, AFA and Ab to DNA in
patients with symptomatic HIVE compared with patients with
AND (significance of the difference between AND and MND
groups for Ab to myelin , AFA and Ab to 2 stranded DNA - p
<0.001, for Ab to 1 stranded DNA - p <0,01; between the AND -
HAD groups for all the indicated Ab - p <0,001). The concentration
of ANA did not differ in children with AND -MND and significantly
increased in children with HAD (the significance of the difference
between the groups of AND -HAD and the groups of MND - HAD
was p <0.05).
Table 1
Autoantidiv concentration in children with HIV
Indicator
Groups
Reliability of intergroup
differences
AND
(n=116)
MND (n=88) HAD
(n=56)
AND/
MND
AND/
HAD
MND/
HAD
Ab to myelin,
Units/ml
9,60±0,88
19,93±1,68 26,63±2,65 P<0,001 P<0,001 n/a
AFA1, sec
50,10±1,21 81,60±2,39 80,57±2,93 P<0,001 P<0,001 n/a
AFA2, sec
50,28±1,46 55,43±1,81 57,64±2,32 n/a
P<0,05
n/a
AFA1/AFA2,
standard units
1,09±0,04
1,60±0,06
1,49±0,07
P<0,001 P<0,001 n/a
Ab to 1 stranded
DNA, Units/ml
28,24±2,85 61,80±9,31 65,63±5,85 P<0,01
P<0,001 n/a
Ab to 2 stranded
DNA,
Units/ml
33,25±2,87 69,96±9,32 73,68±5,82 P<0,001 P<0,001 n/a
ANA, Units/ml
9,47±2,23
10,64±2,72 25,79±5,11 n/a
P<0,05
P<0,05
During the course of study, we deduced the integral index of
autoimmunity activity (IIAA) = Ab to myelin + AFA confirmation
test *10 + (Ab to 1-stranded DNA + Ab to 2-stranded
DNA)/5+ANA*10.
Formula is made taking into account the difference in refer-
ence concentrations of antibodies. In general, in the entire cohort
of patients IIAA was 184.44 ± 60.43 standard units, the inter-
group analysis showed the comparability of IIAA in the groups of
AND-MND and a significant increase in the group of HAD (Fig. 1).
During the course of study the predictor effectiveness of the
concentration of autoantibodies in the aspect of the development
of symptomatic HIVE was examined. It was determined that an
increase in the concentration of Ab to myelin above the median
(13 units/ml) increases the risk of symptomatic HIVE by 2.27
times (chi square = 48.83, p <0.001), an increase in the confirma-
tory indicator of the presence of AFA by more than 1.29 - 2.10
times (chi square = 40.68, p <0.001), an increase in the concen-
tration of Ab to 1 and 2 stranded DNA above 26.5 units/ml and 35
units/ml, respectively 2.69 times (chi square = 67 , 82, p <0.001).
For the concentration of ANA, the predictor significance in the as-
pect of the development of symptomatic HIVE was unreliable.
The increase in IIAA above 60.43 associated with an increase of
risk of symptomatic HIVE by 2.03 times (chi square = 37.91, p
<0.001).
Table 3.13
Predictor effectiveness of autoimmunity indicators in HIV-infected
children in the aspect of the development of symptomatic HIVE
Indicator
Median
AND (n=166)
MND+HAD
(n=144)
The
incidence of
symptomatic
HIVE if there
is a criterion
The
incidence of
symptomatic
HIVE in the
absence of
a criterion
Relative
risk,%
increase
in risk
Ab to myelin,
Units/ml
>=13
9,60±0,88
22,53±1,47***
100/130
(76,92%)
44/130
(33,85%)^^^
2,27
(56,00%)
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«NEVROLOGIYA»—3(83), 2020
ВОПРОСЫ ДЕТСКОЙ НЕВРОЛОГИИ
AFA1/AFA2,
standard
units
>1,29
1,09±0,04
1,56±0,05***
97/129
(75,19%)
47/131
(35,88%)^^^
2,10
(52,29%)
Ab to 1
stranded
DNA, Units/
ml
>26,5
28,24±2,8563,
28±6,11***
105/130
(80,77%)
39/130
(30,00%)^^^
2,69
(62,86%)
Ab to 2
stranded
DNA, Units/
ml
>35
33,25±2,87
71,40±6,11***
105/130
(80,77%)
39/130
(30,00%)^^^
2,69
(62,86%)
ANA, Units/
ml
>0
9,47±2,23
16,53±2,65*
60/98
(61,22%)
84/162
(51,85%)
1,18
(15,30%)
IIAA,
standard
units
>60,43 127,51±22,37
230,31±27,31**
95/127
(74,80%)
49/133
(36,84%)
2,03
(50,75%)
Note: * - reliability between indicators among groups of as-
ymptomatic and symptomatic HIVE, ^ - reliability of the frequency
difference in the occurrence of symptomatic HIVE in children with
the presence of the studied criterion and with no criterion. One
character is p <0.05, two characters are p <0.01, three charac-
ters are p <0.001.
Conclusion.
Thus, the present study found the relations of HIVE severity
in HIV infected children with an increase of the autoimmunity ac-
tivity. The risk of developing symptomatic HIV is associated with
an increase in the concentration of antibodies to myelin and
DNA.
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