Autism and brain immunity storms

Autism Spectrum Disorders (ASD) are neurodevelopmental disorders characterized by varying deficits in social interactions, communication and learning, as well as stereotypic behaviors. Despite the significant increase in ASD, there are few if any clues for its pathogenesis, hampering early detection or treatment. Increasing evidence indicates that brain inflammation is involved in the pathogenesis of neuropsychiatric diseases. Premature babies appear to be at higher risk of developing ASD, and perinatal inflammation can be associated with adverse neurodevelopmental outcomes. The presence of circulating auto-antibodies against fetal brain proteins suggests either insufficient development or disruption of the blood-brain-barrier (BBB) that could permit exposure to potential neurotoxins that entered the circulation due to disrupted gut-blood barrier. This risk apparently increases considerably if parents had “allergic” or "autoimmune problems" during gestation, or if they had been exposed to stressors, mediated through corticotropin-releasing hormone (CRH). Recent evidence also indicates that many ASD children present with “allergic-like” symptoms that imply activation of a unique immune cell, the mast cell, which is activated by allergic, environmental, infectious, or stress-related triggers, to release pro-inflammatory and neurotoxic molecules. We recently showed that the peptide neurotensin (NT), present in the brain, gut and skin, is increased in the serum of children with ASD both (a) 3-year old with autistic disorder and (b) 4-10 years-old on the entire ASD spectrum. NT stimulates mast cells, responsible for allergic reactions, to secrete inflammatory mediators including IL-6 and TNF, which have been shown to be increased in the brain of patients with ASD. We also showed that during stimulation with NT, mast cell mitochondria, commonly known for their cellular energy production, undergo fission and translocation to the cell surface where they secrete some of their components outside the cell. These include DNA and ATP, which are misconstrued by the body as “innate pathogens” leading to an auto-inflammatory response affecting specific brain regions responsible for behavior and language. Both NT and mtDNA can further activate brain microglia and damage neurons leading to “Brain Immunity Storms” because they are not present all the same time, but may be provoked by environmental, immune, infectious and stress triggers thus contributing to the pathology and symptoms of ASD. Some of the key gene mutations that are associated with increased risk for autism, such as PTEN and mTOR, also increase mast cell proliferation and function. We have also shown that the natural flavonoid luteolin inhibits these processes, including mTOR activation, as well as activated T cells. Moreover, luteolin also inhibits microglia activation and is neuroprotective. Two recent clinical trials (4-6 months) using a unique formulation containing luteolin (NeuroProtek) reported significantly increased sociability in children with ASD. A double-blind, placebo-controlled, study using this formulation is now under way. Moreover, the advanced formulation BrainGain, has also been developed especially for older ASD patients and those with Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections (PANDAS).
Aspects of our work described above were funded by NIH grants NS38326 and AR47652, as well as the Autism Collaborative, the Autism Research Institute, National Autism Association, Safe Minds, the Jane Bostford Johnson Fnd and Theta Biomedical Consulting and Development Co., Inc. (Brookline, MA).

Learning objectives:
• Aberrant immunity during the perinatal period is critical for increased risk of developing ASD
• Brain inflammation can develop when the gut-blood and blood-brain-barrier are disrupted
• Neurotensin and mitochondrial components participate in brain inflammation
• Serum neurotensin and mitochondrial DNA may serve as objective markers for ASD
• The flavonone luteolin inhibits Neuroinflammation and is neuroprotective
• The luteolin-containing supplements NeuroProtek and BrainGain have significant benefit in ASD

References
1. Donelan J, Papadopoulou N, Marchand J, Kempuraj D, Lytinas M, Boucher W, Papaliodis D, Theoharides TC. Corticotropin-releasing hormone (CRH) induces skin vascular permeability through a neurotensin (NT)-dependent process. Proc Natl Acad Sci USA 103:7759-7764. 2006.
2. Angelidou A, Francis K, Vasiadi M, Alysandratos KD, Zhang B, Theoharides A, Lykouras L, Sideri K, Kalogeromitros D, Theoharides TC. Neurotensin is increased in serum of young children with autistic disorder. J Neuroinflammation 7:48, 2010.
3. Zhang BD, Angelidou A, Alysandratos KD, Vasiadi M, Francis K, Asadi. S, Theoharides A, Sideri K, Lykouras L, Kalogeromitros D, Theoharides TC, Mitochondrial DNA and anti-mitochondrial antibodies in serum of autistic children. J Neuroinflammation 7(1):80, 2010.
4. Theoharides TC, Zhang B, Kempuraj D, Tagen M, Vasiadi M, Angelidou A, Alysandratos KD, Kalogeromitros D, Asadi S, Stavrianeas N, Peterson E, Leeman S, Conti P. IL-33 augments substance P-induced VEGF secretion from human mast cells and is increased in psoriatic skin. Proc Natl Acad Sci USA 107(9):4448-53, 2010.
5. Zhang B, Alysandratos KD, Angelidou A, Asadi S, Sismanopoulos N, Delivanis D-A, Weng Z, Miniati A, Vasiadi M, Katsarou-Katsari A, Miao B, Leeman S, Kalogeromitros D, Theoharides TC. Human mast cell degranulation and granule-stored TNF secretion requires mitochondrial translocation to sites of exocytosis. J Allergy Clin Immunol 127(6):1522-1531.e8. 2011.
6. Asadi S, Theoharides TC. Corticotropin-releasing hormone and extracellular mitochondria augment IgE-stimulated human mast-cell vascular endothelial growth factor release, which is inhibited by luteolin. J Neuroinflammation 9(1):85, 2012.
7. Angelidou A, Alysandratos K-D, Asadi S, Karagkouni A, Kourembanas S, Theoharides TC. Perinatal stress, brain inflammation and risk for autism. BMC Pediatrics 12:89, 2012.
8. Vasiadi M, Therianou A, Sideri K, Smyrnioti M, Delivani D, Sismanopoulos N, Asadi S, Katsarou-Katsari A, Petrakopoulou D, Theoharides A, Antoniou C, Stavrianeas N, Kalogeromitros D, Theoharides TC. Increased serum CRH levels with decreased skin CRH-R1 gene expression in psoriasis and atopic dermatitis, J Allergy Clin Immunol 129(5):1410-3, 2012.
9. Zhang B, Asadi S , Weng Z, Sismanopoulos N, Theoharides TC. Stimulated human mast cells secrete mitochondrial components that have autocrine and paracrine inflammatory actions. PloS One 7(12):e49767, 2012.
10. Theoharides TC, Asadi S.Unwanted interactions among psychotropic drugs and other treatments for autism spectrum disorders. J Clin Psychopharmacol 32(4):437-40, 2012.
11. Theoharides TC, Asadi S, Panagiotidou S. A case series of a luteolin formulation (NeuroProtek®) in children with autism spectrum disorders. Int J Immunopathol Pharmacol 25(2):317-23, 2012.
12. Theoharides TC, Asadi S, Patel AB. Focal brain inflammation and autism. J Neuroinflammation 10:46, 2013.
13. Theoharides TC. Extracellular mitochondrial ATP, suramin, and autism? Clin Ther 35(9):1454-6, 2013.
14. Theoharides TC, Asadi S, Panagiotidou S, Weng Z. The "missing link" in autoimmunity and autism: extracellular mitochondrial components secreted from activated live mast cells. Autoimmun Rev 12(12):1136-42, 2013.
15. Theoharides TC. Is a subtype of autism an allergy of the brain? Clin Ther 35(5):584-91, 2013.
16. Taliou A, Zintzaras E, Lykouras L, Francis K. An open-label pilot study of a formulation containing the anti-inflammatory flavonoid luteolin and its effects on behavior in children with autism spectrum disorders. Clin Ther 35(5):592-602, 2013.
17. Theoharides TC, Conti P, Economu M. Brain inflammation, neuropsychiatric disorders, and immunoendocrine effects of luteolin. J Clin Psychopharmacol 34(2):187-9, 2014.

Theoharis C. Theoharides, BA, MS, MPhil, PhD, MD, FAAAAI

He received all his degrees from Yale University from where he was awarded the “Dean’s Research Award” and the “Winternitz Price in Pathology.” He trained in internal medicine at the New England Medical Center from which he received the “Oliver Smith Award “recognizing excellence, compassion and service.” He also received a Certificate in Global Leadership from the Fletcher School of Law and Diplomacy at Tufts University, and a J.F. Kennedy Fellowship at the Harvard Kennedy School of Government.

He is a member of 4 Academies and 17 scientific societies. He has published over 350 peer-reviewed research papers and 3 textbooks, with 17,500 citations. He has been placed in the top 1% of authors most cited in pharmacological and immunological journals. Dr. Theoharides was the first to show that certain immune cells, called mast cells and known because they cause allergic reactions, can be stimulated by non-allergic triggers, such as stress hormones, to secrete inflammatory mediators leading to neuro-inflammation. He was also the first to show that stimulated mast cells secrete mitochondrial components outside the cells where they are mistaken by the body as “innate pathogens” and lead to inflammation that may explain auto-immune diseases. Based on these discoveries, Dr. Theoharides proposed the novel concept that mast cells play a critical role in brain inflammation, especially in Alzheimer’s disease, autism, chronic fatigue syndrome, fibromyalgia, migraines, multiple sclerosis and psoriasis, all of which worsen with stress. He has been awarded 17 patents and 23 trademarks. He also developed the dietary supplements (www.algonot.com) ArthroSoft®, BrainGain®, CystoProtek®, FibroProtek®, MastoStop®, and NeuroProtek®. The latter was recently shown in two pilot clinical trials to significantly improve sociability in over 70% of children with autism in 6 months. In order to bring these discoveries to the patients, he developed two nonprofit organizations, shown above. For his efforts, he was made “Archon” of the Greek Patriarchate, the highest honor bestowed by the Greek Orthodox Church, was inducted into the “Rare Disease Hall of Fame,” was given an “Honorary Doctor of Medicine” from Athens University, Greece, was made a Fellow of the American Academy of Allergy, Asthma, Immunology, and the European Academy of Allergology and Immunology, and was nominated to the American Academy of Arts and Sciences.