This document discusses adaptive maternal immune deviations as a potential ground for autism spectrum disorders (ASD) development in children. It proposes that one of the most likely mechanisms inducing ASD may be maternal immune imprinting, where maternal antibodies cross the placenta and epigenetically 'tune' the fetus's immune system. While this mechanism provides early infection resistance, it can also cause inborn pathologies like ASD in some cases. The document examines how different maternal autoantibody repertoires, influenced by microbes or environmental toxins, may impact fetal development and argues that immune changes are generally adaptive for the mother but potentially pathogenic for the fetus in some situations.

1. Folia Medica 2014; 56(2): 5-10
Copyright © 2014 Medical University, Plovdiv
doi: 10.2478/folmed-2014-0001
( Invited Lectu res )
ADAPTIVE МAТERNAL IММUNE DEVIATIONS AS А GROUND FOR AUTISM SPECTRUМ
DISORDERS DEVELOPМENТ IN CНILDREN
Alexander В. Poletaev 1, AlinaA. Poletaeva 1, Alexander 1.Pukhalenko 1, Roza S. Zamaleeva2, NataliaA.
Свегерапома', Dmitry У. FrizinЗ
1РК Anokhin Institute 0/Normal Physiology, Russian Academy 0/Medical Sciences, The MedicaZ Research
Center "Тттипсшиз", Moscow, Russia, 2Kazan' MedicaZ State Academy, Kazan, Tatarstan, Russia, 3Volgsk'
Central Hospital, Volgsk, Mary-EZ, Russia с
АДAIIТИВПЫЕ ИММУППЫЕ РЕАКЦИ.Ц МАТЕРИ КАК ФАКТОР, ВЕДУЩИЙ К
ФОРМИРОВAНИIO РАССТРОЙСТВ АУТИСТИЧЕСКОГО СПЕКТРА У ЕЕ РЕБЕНКА
Александр Б. Полетаев ', Алина А. Полетаева', Александр И. Пухаленко ', Роза С. Замалеева/,
Наталия А. Черепановв ', Дмитрий В. Фризин!
'нии нормальной физиологии им. П.КАнохина РАМН, Медицинский исследовательский центр
"Иммункулус", Москва; 2Казанская государственная медицинская академия, Казань,
Татарстан, ЗВолжская центральная городская больница, Волжск, Мари-Эл, Россия,
AВSTRACT
Autism is а vexed problem today. Оуегай, there is а high frequency of birth children (1 :80 - 1:150) with late
diagnosed autism spectrum disorders (ASD) and this trend is getting progressively stronger. Тhe causes for the
currently increased frequency of ASD and the pathogenesis of ASD аге not fully understood yet. Опе of the
most likely mechanisms inducing ASD тау Ье а matemal immune imprinting. Тhis рЬепотепоп is based оп
transplacental translocation of matemal antibodies of IgG class and, as а consequence, оп the epigenetic ''tun-
ing" of immune system of the fetus and child. Тhis mechanism provides development of child's anti-infection
resistance before meeting with microorganisms, but it сап Ье also а cause of inЬоm pathology including the ASD
appearance. Тhe quantitative changes in matemal blood serum autoantibodies depend оп а specific microbial
population, ог are induced Ьу environmental chemical pollutants in association with some individual features of
the matemal metabolism. Тhese immune changes аге adaptive in most cases for the matemal organism, but сan
Ье pathogenic for the fetus in some cases. We discuss in the present рарег the possibilities to predict the risk from
abnormal development of nervous system in fetus and early diagnosis of ASD in high-risk group of children.
Keywords: аийзт, diagnosis, ASD, CNS path%gy, immune imprinting, autoantibodies, cytokines
Folia Medica 2014; 56(1): 5-9
Copyright © 2014 Medical University, Plovdiv
РЕЗЮМЕ
Частота случаев рождения детей, страдающих расстройствами аутисгического спектра (РАС) с каждым
roдом растет и сеroдня составляет 1:80 - 1:150 в глобальном масштабе. Причины этого, как и собственно
патогенез РАС остаются не вполне понятными, Одним из наиболее вероятных механизмов, запускающих
формирование РАС, во многих случаях, является феномен материнскоro иммунноro импринтинга,
основанный на трансплацентарном поступлении антител матери класса IgG к плоду и эпигенетической
«настройке» иммунной системы будущеro ребенка. Иммунный импринтинг обеспечивает формирование
противоинфекционной резистентности у ребенка еще во внутрнутробном периоде (до встречи с инфектами),
но, в некоторых случаях, он может быть причиной ряда варушений и, в частности, формирования РАС.
Особенности репертуаров аутоантител Са-АТ) матери могут зависеть от превалирования у нее тех или
иных бактериально-вирусных ассоциатов, а также от индивидуальных особенностей организма женщины.
Соответствующие иммунные изменения как правило являются адаптивныии для матери, однако, для
будущеro ребенка могут являтъся патогенными. Обсуждаются возможности прогнозирования риска
развития плода и новорожденного с патологией нервной системы у женщин с аномалиями репертуаров
а-АТ, а также ранней диагности:ки РАС у детей группы риска, начиная с первых месяцев жизни.
Ключевые слова: аутuзм, диагностика, РАС, патология ЦНС, иммунный импринтинг, аутоантитела,
цитокины
Folia Medica 2014; 56(2): 5-9
© 2014 Все права защнщены. Медицинский университет, Пловдив
Articles history: Received: 7 March 2014; Received in revised form: 2 April 2014; Accepted: 3 April2014
*Correspondence and reprint request to: А. PoleLaev, 1РК Anokhin [пэипае 0/ Norтal Physiology, Russian Acadeтy 0/ Medical
Sciences, The Medical Research Сетеп "Тттипсшия", Moscow, Russia; E-тail: a-Ь-ро/еLаеv@уаndех.гu; МоЬ.: +7 .
I
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5

2. А. Poletaev et al
AUТISM (ASD). GENERAL PROVISIONS
Fonning а clear view оп pathogenesis is necessary
for the most effective prevention, diagnostics, and
treatment of апу disease. This statement is quite
valid for autism cases ог autism spectrum disor-
ders (ASD). Nowadays, we do not Ьауе objective
laboratory methods to diagnose ASD and usuaIly
autism diagnosis is based оп behavioural deviations
(impairments in communication and social interac-
tions, stereotypic behaviour, deviations of sensory
perception and emotional state, етс.).
Analysing in detail relevant pubIications that
appeared in some highly rated medical journals
(1971-2010), Rossignol and Ргуе! concluded that:
1. ASD ате directly related to gene defects in
only 6-15% of cases.
2. Different epigenetic factors ате the reasons
for 85-95% of ASD.
3. 1mmunity deviations, inflammation, toxic
influences, oxidative stress ог mitochondrial dys-
function ргоЬаЫу play the most important role in
the ASD development.
4. ТЬе most significant research defines immune
abnormality and inflammation related deviations as
the basis for ASD development.
ТЬе term autism spectrum disorders (ASD) is
used to designate а heterogeneous group of disorders
with соттоп features but different pathogenesis
and expressed behavioural disorders. А relatively
small part of these disorders is evidently caused
Ьу аЬепаtiопs of particular genes, but autism is
predominantly а multifactor disease. These disorders
тау арреат only if some epigenetic (environmental)
factors influence them. 1t does not теап that most
fonns of ASD ате totally independent from genetic
peculiarities of the suffering individual. Genetic
features тау contribute to the risk of ASD and
dozens ог hundreds of genes associated with this
disease will Ье evidently ргевеш-, however, this
dependence will Ье сотратаЫе to genetically соп-
ditioned resistance/sensitivity to influenza. Different
combinations of multiple genes тау Ье а ground
for multiple minor metabolic changes declining ог
elevating the general stability of the organism to
the different environmental factors. According to
genome-wide association studies (GWAS), some
factors associated with ап increased risk of ASD
сan Ье геvеаlеdЗ (as well as factors leading to
an increased risk of catching а cold ог suffering
myocardial infarction), however such data would
Ье of little predictive value for medical practice.
Most of ASD cases аге associated with the ef-
fect of multiple environmental (epigenetic) factors,
6
for example, Ьеауу metal chronic action, pesticides
(тегситу, lead, polychlorinated biphenyls, toluene,
етс.), immune deviations, inflammatory processes,
acute infection diseases during pregnancy, chronic
oxidative stresses, etc. А simple enumeration of
different factors that induce ASD allows us to
make some inferences.
Firstly, уегу different epigenetically conditioned
ASD fonns сап Ье ргоЬаЫу considered as а kind
of equifinal pathophysiological phenomena. Гп
other words, тanу different influences that touch
different organs and tissues and affect different
metabolic cycles сan result in the same clinical
consequences if the organism of а pregnant woman
ог the newborn is affected.
Secondly, ASD should Ье ргоЬаЫу considered
not as а neurological disorder, but as а fonn of
pathology that affects а wide range of organs and
systems: the digestive system (stomach, intestine,
colon, pancreas), the endocrine system (thyroid,
adrenals), and probably some other organs and
systems that consistently reflect multisystemic
disorders for ASD.
Thirdly, шшпше and inflammatory deviations,
toxic environmental influences, chronic oxidative
stresses, mitochondrial dysfunctions сan Ье related
not only to ASD but also to the development of
тапу nervous system disorders, including schizo-
phrenia, Alzheimer disease, bipolar disease, and
several other disorders.I,4,5 That is, попе of noted
factors сап Ье defined as specific ASD-inducing
factor. ТЬе question is: why is it that the same type
of influence тау Ьесоте а base for development of
ASD ог in other cases - schizophrenia, ог bipolar
disease? Unlike other mental diseases, ASD сan
Ье diagnosed among small children only (emerges
during intrauterine development, but not in puberty
period ог in adults). It сan Ье suggested that the
vector of pathological development depends to а
great extent оп the ontogenetic period in which
the inducing factors Ьауе Ьееп active. With respect
to ASD such а period is the stage of primordial
systems (nervous and other) differentiation and
maturation.
ТНЕ IMMUNE SYSTEM: AN INTERFACE ВЕ-
TWEEN AN ORGANISM AND ENVIRONМENT
ТЬе major function of the nervous system (as well
as the immune system) is providing safety in the
contacts between ап organism and its environ-
ment.6 Both system components ате presented in
organs and tissues, and evolutionary intended for
reception, integration, storing and retrieving of the
Folia Medica 2014; 56(2): 5-10
© 2014 Medical University, Plovdiv

3. Adaptive Mateтa1 Immune Deviations as а Ground [ог Autism Spectrum Disorders Development in Children
incoming infonnation and for fonning an individual
(non-inheritable) living experience providing the
most adequate reaction to the repeating situation.6
ТЬе nervous system is specialized in reception and
reaction to physical stimuli (vision, hearing, tactile
stimuli, and thennal stimuli). ТЬе specialization
of the imшunе system is reception and reaction to
chemical stimuli. Some authors suggest that the цп-
типе system appeared during evolution to receive
and integrate chemical infonnation unregistered Ьу
the nervous system.7,8
А multitude of external and internal environ-
ment chemical stimuli and pathogenic microbes сап
induce ап iштипе system adaptive reaction that
manifests Ьу the changes in the levels of cytokines,
chemokines, antibodies and autoantibodies. These
immune changes manifest (at the organismallevel)
Ьу inflammation, clearance enhancement, activation
ofregeneration, etc. Respective immunophysiologic
changes in essence are adaptive and sanogenic.
However, it сап Ье transfonned into pathogenic
ones in some conditions.
Speaking about functionality, the шшшпе sys-
tem сan Ье considered as ап interface between the
chemistry of the organism and the chemistry of
the environment. Therefore, anу chemically active
substances entering into the system will inevitably
induce some changes in the state of individual цп-
типе system, including production and secretion
Ьу lymphocytes, macrophages, and dendritic cells
of тапу biologically active molecules. ТЬе latter
in their turn will affect the state of the pregnant
woman and fetus. Regarding ASD, the next ques-
tion сап Ье: аге the effects of different toxins and
infection agents related to pathogenesis of the
disorder, primarily realized Ьу iшmипе deviations
in а pregnant woman? Ог induced iшmunе devia-
tions should Ье considered as an important but
relatively small part of whole organism changes
which leads to ASD development. ТЬе question is
crucial, because if immune changes are the basic
condition for development of autism, the preventive
and сопесtivе measures сan Ье mostly directed to
the state of the immune system. Otherwise, it will
Ье principally impossible to manage prevention
and сопесtiоп of ASD without widely complex
measures in addition to the immune correction
ones. We suppose that available information does
not pennit to solve this question. We will consider
some of immunopathological aspects of ASD below,
because, in anу case, iштипе deviations play ап
important role in the disorder development.
Folia Medica 2014; 56(2): 5-10
© 2014 Medical University, PIQvdiv
CYTOК1NES AS FACTORS RELATED ТО AВNOR-
МALIТY OF FETOGENESIS
Cytokines, pro-inflammatory as well as сопна-
inflammatory (interleukins, interferons, chemokines,
growth factors, етс.), аге the most biologically ас-
tive products expressed and secreted Ьу cells of
the immune system. It should Ье noted, that most
of the immune-derived cytokines also possess а
neurotropic activity and аге involved in the regula-
tion of the growth, maturation and functional dif-
ferentiation of neurons and glial cells.6 It was noted
that a-interferon сап Ье an inducer of catatonia and
depression in aniшаl models, and С3 - а component
of the complement, has ап anorexogenic аспмпу.?
It was demonstrated that interleukin-6 had ап anti-
amnestic activity,which prevents binding ofneuronal
antagonistic ligands with ш-спойпогесерюгв.!? А lot
of data (fragmentary to some extent) is related to
neurotropic, behavioural and psychotropic activity
of different cytokines has Ьееп accumulated during
the last 30 years. These рЬепотепа Ьесате а base
for the hypothesis about cytokines as "main conduc-
tors of the пешо-шшише orchestra".9 We accept
ап idea of cytokines participation in neuro-immune
functional co-tuning, but suppose more complicate
situation with the mechanisms of co-tuning, and
Ьаме some doubts about the leading role exactly
of cytokines in mutual coordination of the nervous
and immune systems activity in еасЬ case.
МATERNAL ANTIВODIES AND ТНЕ PHENOM-
ENON OF EPIGENEТIC IММUNE IМPRINTING
ТЬе notable biological ability is ап important
characteristic of the cytokines (blood half-life of
the most is just а few dozen шшшез!'). These
molecules сап Ье effectively used for regulation
of different short-term physiological processes but
hardly for regulating long-term ones. For example,
such event as prolonged, high-ordered and high-
protected transfonnation of the fetal nervous tube
into anatomically and functionally matured nervous
system of the newborn сan Ье affected rather some
long-acting (i.e. stable) and omnipresent regulatory
molecules. From this point of view natural (physi-
ological) matemal autoantibodies (auto-Abs) ofIgG
class could Ье most suitable candidates.
Мanу different auto-Abs (аЫе to interact with
апу self-antigens) are synthesized in еасЬ person
during his individual life-span.12,13 Serum content
auto-Abs of the еасЬ antigen specificity is nearly
the same in аН healthy adults, and changes in the
auto-Abs production and content Ьауе Ьееп соп-
7

4. А. Poletaev ет al
sidered as а marker signs of pathology in defined
organs and tissues, ог тау Ье induced Ьу different
chemicals and infection agents.12 Ап averaged IgG
molecules Ьауе а bIood half-Iife of nearly 3 weeks
and actively transferred to the fetus Ьу means of
а specialized mechanisms of active cross-placental
transport (in contrast to auto-Abs of IgM, IgA,
IgE, IgD classes that аге not transported through
placental barrier).14 IgG molecules аге the main
instrument for realization maternal epigenetic im-
mune imprinting.12 ТЬе latter is probabIy related
with cross binding the specific membrane antigen
receptors of the fetal B-Iymphocytes Ьу maternal
anti-idiotypic auto-Abs of the respective specific-
ity. Such binding usually leads to the long-Iasting
specific inhibition ог stimulation B-cells clones
of the defined specificity and accordingly steady
changes in the rate of production of the respective
antibodies in а child.15,16
Maternal immune imprinting is impressing
Ьу the child's шшшпе system of а peculiar fea-
tures maternal immune state (takes place during
pregnancy), but поп paternal imшunе state. As а
result, the child's imшunе state has acquired (for
years sоmеtiшеs) the main features of maternal
immunity.12,16,17 ТЬе biological meaning of the
phenomenon is evident and is clearly iIIustrated Ьу
the next example. Yellow fever virus is endemic in
tropical countries of Africa and Ашеriса. Among
native inhabitants, children were infected shortly
after birth and this infection, in the presence of
maternal antibodies, generally developed without
symptoms, but induced lifelong immunity. As а
consequence, the disease was almost exclusively
observed when foreigners newly arrived in those
countries. Ап especially striking example is the
epidemics during the building of the Рапата Сапаl
when about 100000 foreign workers, but not natives,
died of yellow fever.16 This example indicates ап
imprinting meaning for а priory (before meeting
with microbes) acquiring Ьу the child of specific
resistance against infection agents.
However, maternal imprinting тау influence the
child's health state not only positively. Negative
influence тау Ье also seen in cases when mothers
Ьауе steady changes in their autoantibodies level
during pregnancy.
PНYSIOLOGIC (SANOGENIC) МATERNAL AU-
TOIММUNITY AND PATHOLOGY OF ТНЕ FETUS
In the past, molecules of auto-Abs and аutоimшu-
nity in general Ьауе been associated exclusively
with the state of pathology (autoimmune diseases).
8
However, nowadays it is widely accepted, that ашо-
Abs аге permanently and obligatorily produced in
аll healthy individuals. No longer is the presence of
auto-Abs automatically associated with pathological
processes; we now know that stabIe anomalies in
their production and serum concentration occur not
in relation to failures in imшuпоrеgulаtоry mесЬа-
nisms. Multitudes of natural auto-Abs of IgG and
IgM classes Ьауе been permanently synthesized,
secreted and presented in the bIood serum of аll
healthy persons. These data were clearly and ге-
peatedly demonstrated in several laboratories.12,18
Оп the опе hand, serum concentrations of ашо-
Abs with the same specificity in healthy individu-
als (having по tissue ог organ damage to express
corresponding antigens) is rough1y equal; оп the
other hand, several diseases аге accompanied Ьу
notabIe deviations in serum content of particular
auto-Abs (against specific antigens of certain cells).
This secondary rise in ("danger signal"-induced)
production and secretion of auto-Abs against ап-
tigens of damaged cells should not Ье considered
as а side effect but rather а reflection of опе of
the major roles of the ADS, namely its ability to
execute the function of autoclearance.12,13,18 Еу-
ery day, in various compartments of ап organism,
clearance of hundreds of billions of apoptotically
dying cells (efferocytosis) is required for normal
tissue homeostasis and prevention of iпflаmша-
tion.13 Obviously, the homeostatic importance of
local activation of autoclearance mechanisms in-
creases dramatically in case of tissue damage (of
any etiology). This primary tissue damage then
induces ап evolutionarily fixed phenomenon of а
secondary increase in the production of auto-Abs
against tissue-specific antigens (and сап Ье reflected
Ьу "mirror" of auto-Abs).
ТЬе idea of auto-Abs participation in the clear-
апсе was hypothesized Ьу Pierre Grabar19 and
was developed Ьу Kovalioff IE in his conception
of immunochemical homeostasis.20 ln accordance
with the basic statements of the immunochemi-
саl homeostasis concept, rates of natural auto-Ab
production are regulated Ьу quantity/availability of
respective antigens via а feedback principle. ТЬе
rates of production, secretion and/or release of
anу cytoplasmic, membranous, or nuclear antigen
into the intercellular space are nearly equivalent in
аll healthy individuals (or differ insufficiently to
effect real differences); therefore, sеruш levels of
respective auto-Abs should also demonstrate only
slight individual variability. This picture changes
dramatically in nearly аll cases of pathology. Мanу
Folia Medica 2014; 56(2): 5-10
© 2014 Medical University. Plovdiv

5. Adaptive Matemal Immune Deviations as а Gгоuпd for Autism Spectrum Disorders Development in Children
disorders, especially those of а chronic nature,
are directly associated with either сеll necrosis ог
apoptosis in the involved organ ог deviations in
the production and/or excretion of certain antigens.
It is typical for some isofonns of insulin гесер-
tors to Ье elevated in skeletal muscle fibers at the
pre-disease and early stages of diabetes mellitus
(probabIy as compensation for deteriorating receptor
functionality). Accordingly, тanу patients with рге-
clinical diabetes mellitus demonstrate аЬпоrшаllу
increased serum levels of auto-Abs against insulin
receptors. In most cases, this increase did not relate
directly to the pathogenesis of diabetes but instead
reflects abnormally increased expression of гесер-
tors in accordance with Kovalioff's rule: elevated
quantity of antigen leading to rise of production
of corresponding auto-Ab. Malignancy-associated
increases in auto-Abs against the phosphoprotein
р53, а regulator of apoptosis, тау Ье attributabIe to
the same principle. It is known that р53 alterations
(missense mutations) арреаг to Ье present in 40 to
45% of patients with different fonns of malignant
diseases. Frequently, these alterations are ассот-
panied Ьу compensatory elevations in р53 expres-
sion and, secondarily, Ьу а rise in corresponding
auto-Abs. Lubin and co-authors especially noted
that extensive accumulation of р53 is the cause
of "self-immunization", i.e. арреагапсе of excess
anti-p53 Abs in the patient's вегшп.Ч
In accordance with the general logic of liv-
ing systems, quantitative changes in physiologic
parameters аге usually aimed at correcting ог
compensating for ап abnormal situation in the
body. For example, а tremendous physical effort
is accompanied Ьу elevation of bIood pressure,
tachycardia, rise of bIood glucose level, and other
abnormalities that are аН untypical of the resting
state. Such reactions provide additional resources
for "fight or flight" reaction and are physiologi-
саllу and evolutionarily justified. Principally, the
same physiological (sanogenic) autoimmune reac-
tions тау Ье observed, for example, in patients
suffering from ischemic stroke. lt was shown that
prominent temporary elevation of "neurotropic"
IgG auto-Abs in the serum, if observed soon after
stroke and for а few weeks thereafter, is а favorabIe
prognostic sign. Conversely, the lack of а notabIe
stroke-induced secondary autoimmune reaction -
that is, preservation of поnnаl or low levels of
"neurotropic" auto-Abs during the few days fol-
lowing а stroke - is а bad prognostic sign that is
typical of non-survivors and of survivors suffering
prominent motor and/or cognitive deterioration.
Folia Medica 2014; 56(2): 5-10
© 2014 Medical University, Plovdiv
As опе тау suppose, stroke-induced sharp and
relatively prolonged (ир to 1-2 months) elevation
of auto-Abs against proteins of the injured brain
cells (GFAP, S100, МВР, and others) is а deeply
rational autoirnmune sanogenic рЬепотепоп aimed
at increasing clearance of damaged neural structures
and functional гезтогапоп.Ч Besides auto-Abs тау
revealed trophic activity and stimulate the processes
of regeneration.22
From а practical point of view, it is crucial to
distinguish primary (pathogenic) and secondary
(physiological) autoimmune processes. Primary
autoimmune reactions (for example, virus-induced,
ог heavy metals induced, etc.) тау Ье observed
relatively гаге and аге usually pathogenic in es-
sence; these events тау еуеп cause systemic ог
organ-specific autoimmune diseases. lп contrast,
secondary and transitory (physiological) activation
of natural autoimmunity, following the primary
(injury-associated) events in organs, often seems
to Ье positive in essence Ьу aiming for increased
clearance of antigens in the involved organ and
recovery of the disturbed physiological functions.
Matemal auto-Abs with anу specificity, sano-
genic in relation to own organism, тау Ьесоте а
patbogenic for fetus if transferred through placenta
in excess: а) because direct cytotoxic effects оп а
target cells23, Ь) because аЬпоnnаl tuning of the
immune system of future child Ьу the mechanism
of matemal immune imprinting. As examples there
сan Ье considered the cases of а thyroid dysfunc-
tion in newborns and children from mothers with
thyroid gland24; newborn' lupus тау Ье transferred
from mother with SLE to ber child, and the typical
symptoms тау arise in child at 4-6 months only,
that is after complete elirnination of matemal auto-
Abs.25 Elevated synthesis of anti-insulin auto-Abs
(prognostic sign of diabetes type 1) is typical for
some children from diabetic mothers.26 Matemal
immune imprinting тау Ье ground for not infre-
quent cases of pathology related to same organs
in the mother and child (kidney, heart, endocrine
organs).27 In апу case far from optimal intrauterine
development, conditioned Ьу the changes from
different matemal auto-Abs production, will lead
not obIigatorily to miscarriages and stil1birth, but
nearly always results in some negative changes in
child health state.28
EXCESS OF ТНЕ МATERNAL "NEUROTROPIC"
AUTO-ABS AS REASON FOR PAmOLOGY OFTНE
NERVOUS SYSTEM IN ТНЕ FETUS AND CНILD
Мапу infective agents тау induce abnormal activa-
9

6. .11. сшеше» еь Ш
tion of Т- and B-lymphocytes, that is elevating of
the production of different cytokines and auto-Abs.
Both, in their turn, сап influence negatively fetal
development. In accordance with Patterson, viral
infection of pregnant woman does affect а fetal
nervous tube development indirectly, Ьу means of
deviated cytokines ргоёцспоп.З? We support an idea
of immune-mediated effects of viral agents ироп
fetal development, but we suppose, besides cyto-
kines, auto-Abs deviations as а factors influenced
оп пеша] tube development, should Ье also taken in
mind. Мапу representatives ofherpesviridae (Herpes
sirnplex, Cytomegalovirus, Epstein-Bar virus etc.)
play а role of costirnulators-inductors and activate
different clones of the СО4+ Т lymphocytes. ТЬе
latter, in their tum, do induce the polyclonal ас-
tivation of B-cells and rise of production of the
different auto-АЬs.ЗО,Зl
Furthermore, [от diminishing of antirnicrobial
immune activity, тапу infection agents use а
"camouflage" tactic (molecular mimicryI2). For
these purposes ап antigenic structures, similar to
some antigens of the host-organism, ате expressed
оп the surface. Nonetheless, the immune system
reacts to microbe antigens, though not so actively.
For example, different forms of Ьитап рарШота
viruses (ИРУ) express viral proteins partly similar
to the human S100 proteins. It is а reason for
excessive production of auto-Abs against S100 Ьу
most persons with иру infection.12 But excess of
auto-Abs against S100 тау lead to deviations of
the general morphogenesis and tissue differentiation
in embryo. Могеоуег, S 1ОО proteins participate
in morphology and functional differentiation of
neuroblasts of the fetal neural tube. Thus, excess
of auto-Abs against S1ОО тау cause deviation of
the nervous system foтmation. Therefore the иру
infection in pregnant women тау lead to frequent
miscarriages, stillbirths от malformation of the
fetus' nervous system. In апу case, newborns and
children from mothers with ИРУ-iпduсеd excess
of auto-Abs against S 1ОО characterized sharply
elevated (Ьу 10-12 times) frequency of different
anomalies in the nervous system and mentallneu-
rology problems.12
Specificity of changes in the repertoires of maternal
serum auto-Abs тау depend оп prevailing bacterial
and virus associates, as well as оп the matemal
genetic background and expression of defined МНС
alleles. Тhe character of the fetal reaction/changes
inducing Ьу matemal auto-Abs excessively enter-
ing to fetus will Ьесоте fonned depending оп the
antigenic specificity of auto-Abs transferred, and the
10
ресиliаг stage offetogenesis influenced Ьу auto-Abs.
МATERNAL AUTO-AВS AND ASD
If some ideas proposed Ьете will Ье additionally
confirmed in experiments and clinical observations
this тау give а serious impetus for elaboration
of medical and organizational measures aimed at
prominent decreasing frequency of ASD and other
developmental (intrauterine formed) pathology.
Because high prevalence of ASD (опе case рег 80
to 150 пеwЬоrnsЗ2,зз) wide screening of women
prepared to pregnancy seems to Ье justified, ев-
pecially if it includes women in the risk group.
Besides screening the newborns of mothers with
complicated disease history, mothers with signs of
иру infection, ог mothers suffering of infectious
disease during pregnancy, от those that Ьауе had
апу kind of toxic exposure, etc., will Ье quite jus-
tified also. Testing for the marker auto-Abs in the
mother's blood serum samples as well as in the
child's could Ье probably quite infonnative, simple,
available and inexpensive.
А very preliminary data about some auto-Abs that
probably сап Ье useful for prognosis ате presented
below. ТЬе presented data were obtained Ьу using
ELI-Test mеthоdsЗ4 between 2012 and 2013 and
based оп analysis of profiles of the specific serum'
цппшпе reactivity. It should Ье specialIy noted, in
accordance with ош experience as well as conclu-
sion of professor PL Мегопу and соllеаguеsЗ4,З5
that profiles of immune reactivity, reflecting оп
changes in partial content of different auto-Abs
аге а тоте sensitive and infonnative characteristic
in comparison with the quantitative evaluation of
апу single auto-Abs.
Serum samples from children with diagnosed
ASD (п = 152; age ranging йош 1.5 to 4.5 years)
were investigated. These results were compared
with serum samples of clinically healthy children
(n = 124; age 2-5 years)
ТЬе most typical features revealed in 40% of
ASD cases от тоге and unrevealed от rarely revealed
(по тоте than 2-3%) in healthy children were:
1. Anomalous peaks ofthe serum iшmипе reactivity
conditioned Ьу auto-Abs of IgG class and directed
to next antigens of the nervous tissue:
• Glial fibrillar acidic protein; specific [от astro-
cytes)
• S100-b (Ca2+-binding protein ofthe nervous tis-
sue; similar antigens аге expressed Ьу different
viruses of рарillоmа)
• Myelin basic protein
• Dopamine receptors type О2
Folia Medica 2014; 56(2): 5-10
© 2014 Medical University, Plovdiv

7. Adaptive Maternallmmune Deviations as а Ground for Autism Spectrum Disorders Development in Children
• Dopamine receptors type D3
• Serotonine receptors type Н-2А
• N-Acetylcholinoreceptors
• PPRIB (ог DARPP-32; Dopamine- and сАМР-
regulated neuronal phosphoprotein).
2. Anomalous peaks ofthe serum imтипе reactivity
conditioned Ьу auto-Abs of IgG class, and directed
to next antigens of digestive system organs:
• Stomach wall antigen Gas
• Stomach wall antigen Gam
• Intestine wall antigen Itm-07
• Colon wall antigen SCM-O 1
• Insulin
3. Anomalous peaks of the serum immune геас-
tivity conditioned Ьу auto-Abs of IgG class, and
directed to antigens of other organs:
• Spermal-prostatic antigen SPR-06 (elevated цп-
тunе reactivity to SPR-06 тау Ье induced Ьу
some intracellular bacteria Ьу mechanisms of
molecular mimicry)
ТЬе presented data should Ье considered as
preliminary. The detailed and widening data will
Ье presented in а following publication.
CONCLUSIONS
ТЬе term "autism" (ASD) is used for the designation
of similar neurologic symptoms and affected organs
heterogenic group of disorders of gastro-intestinal
tract and some others in addition to the nervous
system.
А small part of ASD is based оп genetic aberra-
tions, and тау Ье probably attended to monogenic
disorders.
ТЬе greater part of ASD cases characterized the
weak genetic association only, and сan Ье attended
to the peculiar form of intrauterine malformation,
induced Ьу different infectious agents and chemi-
са! influences.
Immune changes in the pregnant woman, includ-
ing deviated production of тапу autoantibodies and
proinflammatory cytokines, mediates pathogenic
effects of the substantial part of infectious and
chemical factors оп the development of fetus.
Some serum IgG class auto-Abs сan Ье generally
used as perspective bio-markers for ASD prediction.
Mass-scale women screening before their planned
pregnancy, especially ones belonging to the risk
group, and their correction in necessity before
pregnancy, тау Ьесоте an effective measure for
significant decreasing ofthe frequency of ASD cases.
Revealing serum profiles characteristic of the
immune reactivity, typical for children in ASD risk
group during first months of their life and early
Folia Medica 2014; 56(2): 5-10
© 20/4 Medical University, Plovdiv
conducting of corrective measures could Ье most
etfective for diminishing ofthe disease manifestation.
ACКNOWLEDGEМENT
This work was supported Ьу the non-profit Founda-
tion "VYКНОD", Moscow, Russia.
Authors express their sincere gratitude to Dr.
Еlепа Chachanidze (Non-profit Foundation "VYК-
HOD", St-Petersburg Branch) for the invaluable
help in the manuscript preparation.
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