Immune abnormalities, mainly autoimmunity to brain tissue, may have a pathogenic role in autism [26–29]. Recently, vitamin D deficiency has been implicated as a potential environmental factor triggering some autoimmune disorders [5, 6].
In the present study, autistic children had significantly lower serum levels of 25-hydroxy vitamin D than healthy children, P < 0.001, with 40% and 48% being vitamin D deficient and insufficient, respectively.
Vitamin D deficiency is being associated with a number of psychiatric conditions with a developmental basis, such as autism and schizophrenia. Vitamin D deficiency in early life affects neuronal differentiation, axonal connectivity, dopamine ontogeny, and brain structure and function . Some investigators reported reduced serum 25-hydrox vitamin D in autistic children. These studies could classify them as being ‘vitamin D inadequate’, which lends support to the hypothesis that autism is a vitamin D deficiency disorder [31, 32].
Worldwide, the rate of autism has been steadily rising. There are several environmental factors in concert with genetic susceptibilities that are contributing to this rise. Genetic polymorphisms of cytochrome P450 enzymes have also been linked to autism, specifically CYP27B1 that is essential for proper vitamin D metabolism. Three novel structural variants of the vitamin D receptor were reported in psychiatric disease . Further study is required to clarify their role, if any, in autism.
In the present work, serum 25-hydroxy vitamin D levels had significant negative correlations with CARS (P < 0.001) which signifies the possible link between the extent of vitamin D deficiency and the degree of the severity of autism. Vitamin D receptors and vitamin D metabolizing enzymes are present in CNS. Calcitriol, the active vitamin D, affects numerous neurotransmitters and neurotrophic factors, relevant for mental disorders . In addition, vitamin D plays important roles in repairing DNA damage and protecting against oxidative stress which is a key cause of DNA damage. Thus, vitamin D deficiency may contribute to higher mutation rates and impaired repair of DNA  as a result of increased oxidative stress which was reported in some autistic children . In addition, Calcitriol may down-regulate the production of inflammatory cytokines in the brain that have been suggested to be associated with autism .
Maternal vitamin D deficiency may be a risk factor for autism, possibly by affecting fetal brain development as well as by affecting maternal immune system status during pregnancy [37, 38]. Autism was more common among children of the mothers who took antiepileptic drugs as these drugs are one of the few classes of drugs that consistently and significantly interfere with vitamin D metabolism . Unfortunately, the tiny 10 μg (400 IU) dose in prenatal vitamins is virtually irrelevant in preventing gestational vitamin D deficiency . For this reason, in 2007, the Canadian Paediatric Society recommended 2000 IU/day, or more, to prevent gestational vitamin D deficiency .
The current study revealed no significant difference between autistic children and healthy children in the duration of sun exposure/week (P = 0.49). In addition, serum 25-hydroxy vitamin D had no significant correlations with the duration of sun exposure/week in children with autism (P = 0.96). In addition, all subjects were studied during summer (April to September) to avoid the effect of seasonal variation on serum 25 hydroxy vitamin D levels. Thus, the results of our study did not signify the reduced duration of sun exposure as a causal factor of 25 hydroxy vitamin D deficiency in autistic children.
In this study, autistic children had significantly higher serum levels of anti-MAG auto-antibodies than healthy children, P < 0.001. Increased serum levels of anti-MAG auto-antibodies were found in 70% of autistic patients. A previous study conducted on 32 Egyptian children, aged between 3 and 8 years, reported anti-MAG seropositivity in 62.5% of autistic children . MAG is a minor myelin protein that is located in the most periaxonal oligodendrocytes processes. It controls neurofilament phosphorylation and hence, controls the axon caliber which is crucial for efficient impulse transmission. In contrast to mature CNS, MAG promotes regeneration of young neurons . Circulating anti-MAG antibodies may play an etiopathogenic role in some autoimmune disorders as autoimmune chronic demyelinating neuropathy . Autoimmune reaction to neurons might be initiated by environment triggers resulting in the release of neuronal antigens, which through the activation of inflammatory cells, may result in autoimmune reactions in genetically susceptible individuals [26, 27].
In the present work, patients with severe autism had significantly higher serum anti-MAG auto-antibodies than children with mild to moderate autism, P < 0.001. Also, serum anti-MAG auto-antibodies had significant positive correlations with CARS (P < 0.001). These results may indicate that the extent of the elevation of serum anti-MAG auto-antibodies was possibly linked to the degree of the disease severity assessed by CARS. Thus, anti-MAG auto-antibodies might be playing a role in the pathogenesis of brain damage, the extent of which may determine the clinical severity of autism.
Vitamin D deficiency has been implicated as a potential environmental factor triggering some autoimmune disorders suggesting that vitamin D might play a role in regulating auto-antibody production [5, 6]. In this study, we have tried to find a possible link between the reduced serum levels of 25-hydroxy vitamin D and the elevated serum levels of anti-MAG auto-antibodies in autism. Serum 25-hydroxy vitamin D levels had significant negative correlations with serum levels of anti-MAG auto-antibodies (P < 0.001). We could not trace data in the literature concerning the possible contributing role of 25-hydroxy vitamin D deficiency in the induction of the production of brain-specific auto-antibodies in some autistic children to compare our results. We are the first to study such a relationship.
In animal models, an increased Th2 response to vitamin D has been accompanied by increase in anti-inflammatory IL-10 response . Immunomodulatory effect of vitamin D may act not only through modulation of helper T cell function, but also through induction of CD4+CD25high regulatory T-cells (Tregs) . CD4+CD25high regulatory T-cells play an important role in the establishment of the immunological self tolerance and thereby, preventing autoimmunity . Tregs can suppress Th17 cells, the key players in the pathogenesis of autoimmune disorders, and autoimmunity . A recent study reported deficiency of Tregs in 73.3% of autistic children . Thus, vitamin D deficiency may be a contributing factor to the production of brain-specific auto-antibodies as a result of deficiency of Tregs in some autistic children.
The results of this study may indicate that 25-hydroxy vitamin D deficiency may be a possible contributing factor to the increased frequency of serum anti-MAG auto-antibodies in some autistic children. However, this is an initial report that warrants further research to determine the possible link between 25-hydroxy vitamin D deficiency and the increased frequency of brain-specific auto-antibodies in some children with autism.
The vitamin D theory of autism does not diminish genetic contributions to autism occurrence. Indeed, without the genetic tendency for autism, severe maternal or early childhood vitamin D deficiency may cause bone abnormalities with no evidence autism. Maternal and early childhood vitamin D deficiency may allow the genetic tendency for autism to express itself. If this theory is true, the path towards effective prevention and perhaps a treatment is so simple, so safe, so inexpensive, so readily available and so easy . Basic, genetic, and epidemiological studies indicate a potential role of vitamin D in the prevention of autoimmune diseases, but randomized and controlled trials are necessary to establish the clinical efficacy of vitamin D supplementation in ill or at-risk subjects . Three treatment modalities exist for vitamin D deficiency which include; sunlight, artificial ultraviolet B radiation, and vitamin D3 supplementation. Treatment of vitamin D deficiency in patients with 2,000 to 7,000 IU vitamin D per day should be sufficient to maintain year-round levels between 40 and 70 ng/mL . Children with chronic illnesses such as autism, diabetes, and/or frequent infections should be supplemented with higher doses of sunshine or vitamin D3 .