By A. Minocha MD, author: Guide to Alternative Medicine and the Digestive System
The
problem
Studies
indicate increasing incidence of autism spectrum disorders and ADHD. Lack of
a specific laboratory abnormality and reliance on symptom complex makes
diagnosis unclear/controversial in many cases. Likewise, one cannot
distinguish whether the clinical manifestations are as a result of different
diagnosis or symbolize diverse manifestations of a similar various
genetic and/or environmental factors underlying the diagnosis of neurodevelopmental and neuropsychiatric disorders like autism spectrum disorders and ADHD.
Genetics versus environment
While a
strong genetic predisposition is suspected, less than half of the variance can
be explained by genetic influences. The role of environmental influences is
being increasingly appreciated although the specific factors involved may be
very diverse and not yet clearly identified. Prenatal injury like an infection interacts with other environmental and genetic factors in shaping the risk of postnatal brain dysfunction.
Increased prevealnce of allergic disorders in autism/ADHD along with streptococcus-mediated neuropsychiatric disorders suggest that critical tole of the immune system in causing and/or perpetuating such disorders.
Perhaps, autism and ADHD occur as a result
of “perfect storm” when genetic or environmental imbalances conspire
together at any/many of the crucial steps involved in the development of
nervous system.
Gut at
the cross-roads on interplay between immune and nervous system
One factor
of “perfect storm” that may be involved is the immune system which develops as
a result of not just the genetic make-up but also the environmental factors
especially during its maturation. The gut and its trillions of
bacteria as they move from neonatal pattern to the adult bacterial pattern play
a critical role in the final make-up of the immune system.
Any
disturbances along in later life can still upset the proverbial apple-cart making
things worse. Conversely, modulation of gut bacteria has the potential to
module the immune system, the neuro-immune interactions along with multiple
diverse clinical manifestations of diseases like autism. Immune activation caused by bacterial components that may enter across leaky gut are known to impair attention.
Evidence that exclusion diets as well as use of probiotics is of benefit in many patients with autism and ADHD lends further support to the the hypothesis of critical role of gut.
Immune
alterations in neuropsychiatric disorders like autism/ADHD
Evidence suggests ongoing inflammation in brain specimens,
elevated pro-inflammatory cytokine profiles in brain and blood, increased
presence of brain-specific auto-antibodies and abnormal immune cell
function in neurodevelpopmental disorders. There is increased incidence of allergic sensitization and allergic rhinitis in ADHD.
According to Careaga and Ashwood, of University of California, Davis, CA, changes
have been documented in immune cell number,
cytokines, cellular function at rest and in response to
immunological challenge in autism. The worse the immune dysfunction,, the greater
the impairment in behaviors that are core features of autism
especially impaired social interactions and communication.
Maternal
versus fetus immune system
Pregnancy
contributes to an exponential increase in complexity of immune interactions
since mother's immune system has to be tolerant of both the fetus and its
antigens while at the same time maintaining a healthy immuneresponsive system that
can mount an effective defensive responses to real
pathogens.
Conversely, the fetus is constantly exposed to
“environmental aliens” made up of maternal components including maternal immune
system e.g. antibodies, cytokines and immune complexes.
Maternal
IgG antibodies during pregnancy and early infancy
Just
like the semi-permeable or exclusionary intestinal barrier, the placenta is
also a selective barrier allowing nutrition as well as
neuro-endocrine-immune signals to go through to the growing fetus while
blocking potentially harmful pathogens.
Among
the factors allowed passage to the fetus are protective maternal IgG antibodies
such that their levels in new born fetus are higher than even in the mother.
This allows the new born baby ready-made means of immunity while its own immune
system is immature and not up to speed.
Maternal
autoantibodies
Unanticipated
chaos may in fetus when mother has autoantibodies which are acting already
against her own tissues. These antibodies can also cross the placenta into the
growing fetus. Usually such harmful antibodies disappear by about 6 months
after birth.
However,
their presence in the fetus in-utero and early infancy which is a critical
period for neuro-immune developmental and gene expression processes has potential
to affect the growth and development of different organs including brain and as
such impact the life over short and long term.
Examples of such dysfunction
include transient myasthenia gravis (short term) and neonatal lupus causing
cardiac defects (long term).
Maternal
antibodies, blood-brain barrier and central nervous system
While
IgG antibodies cannot usually cross blood brain barrier and gain access to the
brain in adults, such is not the case in fetus because of immature barrier
structure and function. Genetic predisposition to delayed or dysfunctional or
nonselective barrier function may be involved in pathogenesis of autism.
Maternal antibodies and/or immune complexes mimicking targets in
fetal brain may sometimes occur as a result of a toxin or infectious exposure
leading to inflammation in the brain and long term damage.
Maternal
IgG and neurodevelopmental disorders
Comparison
of kids with autism and controls has shown the presence of fetal brain specific
antibodies targeting fetal brain proteins are found in kids with autism. Some
of these aberrant antibodies correlate with poor expressive language scores,
other antibodies appear to be involved with increased irritability
on the Aberrant Behavioral Checklist. Thus diverse patterns of abnormal
antibodies may be found leading to diverse manifestations.
Conclusion
of Immune dysfunction and neurodevelopmental disorders
Patients
with autism and their families display many immune abnormalities
including cytokines that are mediators of immune activities but are
also critical to development and function of the nervous
system.
There
is a dramatic change in immune cell pathways as well cytokines during an
infectious episode as well as during toxic exposures and as such may be at
crossroads between the interplay of genetic and immune factors underlying
autism. Potentially damaging pro-Inflammatory cytokines with potential to
interact with brain have been documented in autism
Alterations
in immune function are associated with increased behavioral problems in
patients with autism. Whether these changes represent a cause-effect
relationship or a mere association remains to be clearly established.
Potential
significance of research on immune system and autism
Greater
specificity of Identification of immune interactions with nervous system during
its early development would allow for development of specific targets for
therapeutic interventions.
References: 1. Careaga M and Ashwood P.
Autism spectrum disorders: from immunity to behavior. Methods Mol Biol. 2012. 2. Braunschweig et al. Behavioral correlates of
maternal antibody status among children with autism. J Autism Dev Disord. 2012. 3. Onore et al. The role of immune
dysfunction in the pathophysiology of autism. Brain Behav Immun. 2012.
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