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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