1History of Development Gut-Blood-Brain Barrier Disruption, Mast Cells and Brain Inflammation
In the majority of cases, the cause of autism is unknown. Although some possible autism susceptibility genes have been identified, no single or group of genes can explain the disturbing rise in the incidence of autism from 2 children out of every 100,000 only 20 years ago to 1 out of every 100 children presently. To date, research has focused on the behavioral and neurologic manifestations of autistic spectrum disorders instead of what led to them. Researchers hypothesized; autism starts when the protective gut-blood and blood-brain barriers break down either during pregnancy or early in life. Such a barrier disruption allows neurotoxic molecules to reach the brain ultimately resulting in inflammation and defective nerve processing. This premise is supported by the fact that at least 20% of autistic patients have antibodies against brain proteins, which implies that immune cells reached the brain through a leaky blood-brain-barrier. Recent research has also shown that mast cells (immune cells typically known for causing allergic reactions) can also be activated by environmental, infectious and stress triggers that lead to disruption of the blood-brain- barriers. One such mast cell trigger, neurotensin, was shown to be elevated in the serum of young children with autism. Mast cell activation during pregnancy or perinatally, in response to allergic or non-immune triggers, could disrupt the gut- blood-brain barriers and permit neurotoxic molecules to enter the brain and result in brain inflammation. Mast cell activation could be particularly critical during gestation, since mast cell- derived mediators might act epigenetically to alter the expression of autism susceptibility genes.
References
Theoharides TC, Spanos C, Pang X, Alferes L, Ligris K, Letourneau R, Rozniecki JJ, Webster E, Chrousos GP. Stress-induced intracranial mast cell degranulation: a corticotropin-releasing hormone-
mediated effect. Endocrinology. 1995 Dec;136(12):5745-50. Esposito P, Gheorghe D, Kandere K, Pang X, Connolly R, Jacobson S, Theoharides TC. Acute stress increases permeability of the blood-brain-barrier through activation of brain mast cells. Brain Res. 2001 Jan 5;888(1):117-127. Theoharides TC, Konstantinidou AD. Corticotropin-releasing hormone and the blood-brain-barrier. Front Biosci. 2007 Jan 1;12:1615-28. Theoharides TC, Doyle R. Autism, gut-blood-brain barrier, and mast cells. J Clin Psychopharmacol. 2008 Oct;28(5):479-83.
Mast Cells and Autism
The possible association between autism and mast cells was first investigated when research showed many symptoms that characterize patients with autism are also present in patients with mastocytosis, a spectrum of disorders that involve proliferation and activation of mast cells in the skin (urticaria pigmentosa, UP) and other organs. The Mastocytosis Society, Inc. (www.tmsforacure.org) together with the American Academy of Allergy, Asthma and Immunology recently produced a video, entitled “Mast Cell Activation Symptomatology” (available to physicians and patients), which highlights the fact that allergies may be only one aspect of mast cell activation. Preliminary research results indicate that the prevalence of autism in mastocytosis patients is 10- fold higher (1/10 children) than the general population.
References
Theoharides, TC. Autistic spectrum diseases and mastocytosis. Intl J Immunopathol Pharmacol. 2009 Oct-Dec;22(4):859-65.
Allergic Symptomatology and Autism
The observation that most children with autism have either a family or personal history of immune or allergic disorders prompted the proposal that autism may be a “neuroimmune” disorder. There have been numerous studies and papers that support this proposal. One study investigated infants born in California between 1995- 1999 and reported that maternal asthma and allergies during the second trimester of pregnancy were correlated with a greater than 2-fold elevated risk of autism in their children. In another study, 30% of autistic children had a family history of allergies as compared to 2.5% age-matched “neurologic controls.” A more recent study reported that immune allergic response, represented by the frequency of atopic dermatitis, asthma and rhinitis was increased in 70% of Asperger patients compared to 7% in age-matched healthy controls. A recent preliminary report of 362 children with autism in Italy also indicated that the strongest association of autism is with history of allergies. In a National Survey of Children’s Health, parents of autistic children reported symptoms of allergies more often than those of other children, with food allergies being the most prevalent complaint. Another study reported an increased prevalence of non-IgE mediated food allergy in the autism group compared to normal controls. It is also interesting that a recent study conducted in Germany reported an independent association between atopic eczema and Attention-Deficit Hyperactivity Disorder (ADHD), which has considerable phenotypic overlap with autism.
The link between allergic symptomotology and autism is also supported by the observation that in many cases, autistic symptoms worsen when a patient’s “allergic” symptoms flare-up. However, even in these symptomatic cases “allergy” tests, such as skin prick or RAST, are often negative. These circumstances suggest a non- allergic trigger of mast cells.
References
Theoharides TC, Doyle R, Francis K, Conti P, Kalogeromitros D. Novel therapeutic targets for autism. Trends Pharmacol Sci. 2008 Aug;29(8):375-82.
Theoharides TC, Kempuraj D, Redwood L. Autism: an emerging ‘neuroimmune disorder’ in search of therapy. Expert Opin Pharmacother. 2009 Sep;10(13):2127-43.
Environmental and Stress Mast Cell Triggers
Mast cells are critical for allergic reactions and important in regulating immunity and inflammation. Mast cells are located close to blood vessels both in the gut and in the brain. Functional mast cell-neuron interactions occur in these locations increasing both intestinal and brain permeability. This may help to explain the intestinal and neurologic complaints of autistic patients. Many substances originating in the environment, intestine or brain can trigger mast cell secretion. These triggers include: bacterial and viral antigens; environmental toxins such as
polychlorinated biphenyl (PCB) and mercury; neuropeptides such as neurotensin and corticotropin-releasing hormone (CRH). CRH is typically secreted under stress, which stimulates selective release of vascular endothelial growth factor (VEGF). The ability of viruses to trigger mast cell activation is an important consideration in their contribution to autism pathogenesis. A number of rotaviruses have been isolated from asymptomatic neonates and could activate mast cells at that age. Once activated, mast cells secrete numerous vasoactive, neurosensitizing and proinflammatory substances that are relevant to autism including interleukin-6 (IL-6). IL-6 can disrupt the gut-blood-brain barriers as well as promote the development of Th17 cells, which are critical for the development of autoimmune diseases. In this context, it is crucial to note that high IL-6 gene expression was found in autistic patients. This finding was also associated with increased levels of serum neurotensin, IL-6 and IL-17.
References
Theoharides TC, Kalogeromitros D. The critical role of mast cells in allergy and inflammation. Ann N Y Acad Sci. 2006 Nov;1088:78-99. Theoharides TC, Kempuraj D, Tagen M, Conti P, Kalogeromitros D. Differential release of
mast cell mediators and the pathogenesis of inflammation. Immunol Rev. 2007 Jun;217:65-78. Kempuraj D, Asadi S, Zhang B, Manola A, Hogan J, Peterson E, Theoharides Mercury induces inflammatory mediator release
from human mast cells. J Neuroinflamm. 2010 Mar 11;7:20.