Is a Subtype of Autism an Allergy of the Brain?
Molecular Immunopharmacology and Drug Discovery Laboratory, Department of Molecular Physiology and Pharmacology, Tufts University School of Medicine, Boston
Autism spectrum disorders (ASDs) are characterized by deficits in social communication and language and the presence of repetitive behaviors that affect as many as 1 in 50 US children. Perinatal stress and environmental factors appear to play a significant role in increasing the risk for ASDs. There is no definitive pathogenesis, which therefore significantly hinders the development of a cure.
We aimed to identify publications using basic or clinical data that suggest a possible association between atopic symptoms and ASDs, as well as evidence of how such an association could lead to brain disease, that may explain the pathogenesis of ASD.
PubMed was searched for articles published since 1995 that reported any association between autism and/or ASDs and any one of the following terms: allergy, atopy, brain, corticotropin-releasing hormone, cytokines, eczema, food allergy, food intolerance, gene mutation, inflammation, mast cells, mitochondria, neurotensin, phenotype, stress, subtype, or treatment.
Children with ASD respond disproportionally to stress and also present with food and skin allergies that involve mast cells.
Brain mast cells are found primarily in the hypothalamus, which participates in the regulation of behavior and language.
Corticotropin-releasing hormone is secreted from the hypothalamus under stress and, together with neurotensin, stimulates brain mast cells that could result in focal brain allergy and neurotoxicity.
Neurotensin is significantly increased in serum of children with ASD and stimulates mast cell secretion of mitochondrial adenosine triphosphate and DNA, which is increased in these children; these mitochondrial components are misconstrued as innate pathogens, triggering an autoallergic response in the brain.
Gene mutations associated with higher risk of ASD have been linked to reduction of the phosphatase and tensin homolog, which inhibits the mammalian target of rapamycin (mTOR). These same mutations also lead to mast cell activation and proliferation.
Corticotropin-releasing hormone, neurotensin, and environmental toxins could further trigger the already activated mTOR, leading to superstimulation of brain mast cells in those areas responsible for ASD symptoms.
Preliminary evidence indicates that the flavonoid luteolin is a stronger inhibitor of mTOR than rapamycin and is a potent mast cell blocker.
Activation of brain mast cells by allergic, environmental, immune, neurohormonal, stress, and toxic triggers, especially in those areas associated with behavior and language, lead to focal brain allergies and subsequent focal encephalitis. This possibility is more likely in the subgroup of patients with ASD susceptibility genes that also involve mast cell activation.
Further Readings of Interest
Open Label Pilot Study – Luteolin – ASD Children
Luteolin is a yellow crystalline compound. It is a flavonoid; to be specific, it is one of the more common flavones. From preliminary research, it is thought to play a role in the human body possibly as an antioxidant, a free radical scavenger, a promoter of carbohydrate metabolism, or an immune system modulator. If applicable to the human condition, these characteristics may inhibit cancer mechanisms. Basic research results indicate luteolin as an anti-inflammatory agent with other potential effects on septic shock. It has been suggested for multiple sclerosis on the basis of in vitro work.
Luteolin acts as a monoamine transporter activator, and is one of the few chemicals demonstrated to possess this property
Monoamine transporters (MATs) are protein structures that function as integral plasma membrane transporters to regulate concentrations of extracellular monoamine neurotransmitters. Three major classes of MATs (SERT, DAT, NET) are responsible for the reuptake of their associated amine neurotransmitters (serotonin, dopamine, norepinephrine). MATs are located just outside the synaptic cleft (peri-synaptically), transporting monoamine transmitter overflow from the synaptic cleft back to the cytoplasm of the pre-synaptic neuron. MAT regulation generally occurs through phosphorylation and posttranslational modification. Due to their significance in neuronal signaling, MATs are commonly associated with drugs used to treat mental disorders as well as recreational drugs, a line that can become quite blurred in many cases. Compounds targeting MATs range from medications such as the wide variety of tricyclic antidepressants, selective serotonin reuptake inhibitors such as fluoxetine (Prozac) to stimulant medications such as methylphenidate (Ritalin) and amphetamine in its many forms (Adderall, Dexedrine)) and derivatives methamphetamine (Desoxyn) and lisdexamfetamine (Vyvanse). Furthermore drugs such as MDMA (“ecstasy”, “molly”) natural alkaloids like cocaine exert their effects in a large part by their interaction with MATs.