Novel therapeutic targets for autism.

Autism spectrum disorders (ASDs) are pervasive neurodevelopmental disorders, diagnosed in early childhood when acquired skills are lost or the acquisition of new skills becomes delayed. ASDs are associated with varying degrees of dysfunctional communication and social skills, in addition to repetitive and stereotypic behaviors. The diagnosis has increased considerably to approximately one in 180 people, but it is not clear whether this is because of a higher prevalence of the disorder, improved awareness by clinicians or a combination of both. There are no defined mechanisms of pathogenesis or curative therapy presently available. Oxidative stress, overactivation of the hypothalamic-pituitary-adrenal axis and increased gut-blood-brain-barrier permeability might be involved. The scope of this article is to integrate these findings and present the opinion that non-allergic activation of gastrointestinal and brain mast cells could contribute to many of the pathologic findings and provide unique targets for ASD therapy. We make suggestions for new research directives and possible novel therapies from readily available molecules.

[1]  J. Lipozenčić,et al.  ADVERSE REACTIONS TO FOOD , 1984, The Lancet.

[2]  A. Wakefield Autistic enterocolitis: is it a histopathological entity?—reply , 2007 .

[3]  A. Kraneveld,et al.  Mast cells and nerves tickle in the tummy: implications for inflammatory bowel disease and irritable bowel syndrome. , 2007, Pharmacology & therapeutics.

[4]  C. Cetrulo,et al.  Flavonols inhibit proinflammatory mediator release, intracellular calcium ion levels and protein kinase C theta phosphorylation in human mast cells , 2005, British journal of pharmacology.

[5]  T. Aikawa,et al.  Brain Mast Cells Act as an Immune Gate to the Hypothalamic-Pituitary-Adrenal Axis in Dogs , 2001, The Journal of experimental medicine.

[6]  Roger Smith,et al.  Corticotropin-releasing hormone causes vasodilation in human skin via mast cell-dependent pathways. , 2003, The Journal of clinical endocrinology and metabolism.

[7]  E. Pastorello,et al.  Food allergies and food intolerances. , 2006, Best practice & research. Clinical gastroenterology.

[8]  J. Keränen,et al.  Rectal Bleeding in Infancy: Clinical, Allergological, and Microbiological Examination , 2006, Pediatrics.

[9]  J. Neu,et al.  Tight junctions, leaky intestines, and pediatric diseases , 2005, Acta paediatrica.

[10]  P. Conti,et al.  Differential release of mast cell mediators and the pathogenesis of inflammation , 2007, Immunological reviews.

[11]  Melissa L McPheeters,et al.  Parental report of health conditions and health care use among children with and without autism: National Survey of Children's Health. , 2006, Archives of pediatrics & adolescent medicine.

[12]  H. Jyonouchi,et al.  Dysregulated Innate Immune Responses in Young Children with Autism Spectrum Disorders: Their Relationship to Gastrointestinal Symptoms and Dietary Intervention , 2005, Neuropsychobiology.

[13]  Stepan Melnyk,et al.  Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism , 2006, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[14]  Alinda Gillott,et al.  Levels of anxiety and sources of stress in adults with autism , 2007, Journal of intellectual disabilities : JOID.

[15]  M. Hadjivassiliou,et al.  The immunology of gluten sensitivity: beyond the gut. , 2004, Trends in immunology.

[16]  I. Bachelet,et al.  Mast cells as effector cells: a co-stimulating question. , 2007, Trends in immunology.

[17]  T. Macdonald,et al.  Autistic enterocolitis; is it a histopathological entity? , 2007, Histopathology.

[18]  Y. Taché,et al.  CRF1 receptors as a therapeutic target for irritable bowel syndrome. , 2006, Current pharmaceutical design.

[19]  Nathan Chandler,et al.  Corticotropin-Releasing Hormone and Brain Mast Cells Regulate Blood-Brain-Barrier Permeability Induced by Acute Stress , 2002, Journal of Pharmacology and Experimental Therapeutics.

[20]  Raja' M. Abdel-Majid,et al.  Prostaglandin E2 Induces Degranulation-Independent Production of Vascular Endothelial Growth Factor by Human Mast Cells1 , 2004, The Journal of Immunology.

[21]  D. Theriaque,et al.  The Gluten-Free, Casein-Free Diet In Autism: Results of A Preliminary Double Blind Clinical Trial , 2006, Journal of autism and developmental disorders.

[22]  D. Metcalfe,et al.  The role of reactive oxygen species and nitric oxide in mast cell‐dependent inflammatory processes , 2007, Immunological reviews.

[23]  An IgE mechanism in autistic hypersensitivity? , 1992, Biological Psychiatry.

[24]  A. Margioris,et al.  The corticotropin-releasing factor (CRF) family of neuropeptides in inflammation: potential therapeutic applications. , 2005, Current medicinal chemistry.

[25]  C. Rice,et al.  Prevalence of autism in a US metropolitan area. , 2003, JAMA.

[26]  K. Kandere-Grzybowska,et al.  IL-1 Induces Vesicular Secretion of IL-6 without Degranulation from Human Mast Cells1 , 2003, The Journal of Immunology.

[27]  C. Black,et al.  Relation of childhood gastrointestinal disorders to autism: nested case-control study using data from the UK General Practice Research Database , 2002, BMJ : British Medical Journal.

[28]  M. Daëron,et al.  The mast cell IgG receptors and their roles in tissue inflammation , 2007, Immunological reviews.

[29]  E. Fombonne Thimerosal disappears but autism remains. , 2008, Archives of general psychiatry.

[30]  M. Broadstock,et al.  Systematic review of the effectiveness of pharmacological treatments for adolescents and adults with autism spectrum disorder , 2007, Autism : the international journal of research and practice.

[31]  M R Mohammadi,et al.  Cyproheptadine in the treatment of autistic disorder: a double‐blind placebo‐controlled trial , 2004, Journal of clinical pharmacy and therapeutics.

[32]  T. Macdonald,et al.  Autistic enterocolitis; is it a histopathological entity? Commentary , 2007 .

[33]  T. Pollmächer,et al.  Cytokine-associated emotional and cognitive disturbances in humans. , 2001, Archives of general psychiatry.

[34]  Å. Keita,et al.  Corticotropin-releasing hormone (CRH) regulates macromolecular permeability via mast cells in normal human colonic biopsies in vitro , 2007, Gut.

[35]  T. Theoharides,et al.  Critical role of mast cells in inflammatory diseases and the effect of acute stress , 2004, Journal of Neuroimmunology.

[36]  K. Austen,et al.  Mastocytosis: Mediator-Related Signs and Symptoms , 2002, International Archives of Allergy and Immunology.

[37]  J. Marshall,et al.  Cutting Edge: Distinct Toll-Like Receptor 2 Activators Selectively Induce Different Classes of Mediator Production from Human Mast Cells 12 , 2003, The Journal of Immunology.

[38]  Cathleen K. Yoshida,et al.  Maternal autoimmune diseases, asthma and allergies, and childhood autism spectrum disorders: a case-control study. , 2005, Archives of pediatrics & adolescent medicine.

[39]  R. Cherian,et al.  Case Report: Adenocarcinoid of Ileum and Appendix, Incidentally Discovered During Exploratory Laparotomy for Gastric MALT Lymphoma, with Subsequent Diffuse Prostatic Metastases (Report of a Case with Light, Immunohistochemical, and Electron Microscopic Studies) , 2004, Digestive Diseases and Sciences.

[40]  J. Pléau,et al.  Toll‐like receptor 2 (TLR2) and TLR4 differentially activate human mast cells , 2003, European journal of immunology.

[41]  M. Chez,et al.  Elevation of tumor necrosis factor-alpha in cerebrospinal fluid of autistic children. , 2007, Pediatric neurology.

[42]  C. Johnson,et al.  Identification and Evaluation of Children With Autism Spectrum Disorders , 2007, Pediatrics.

[43]  T. Theoharides,et al.  Corticotropin-releasing hormone and the blood-brain-barrier. , 2007, Frontiers in bioscience : a journal and virtual library.

[44]  A. Keshavarzian,et al.  Mucosal mast cells are pivotal elements in inflammatory bowel disease that connect the dots: stress, intestinal hyperpermeability and inflammation. , 2007, World journal of gastroenterology.

[45]  S. H. Arshad,et al.  Original article: Prevalence and cumulative incidence of food hypersensitivity in the first 3 years of life , 2007, Allergy.

[46]  Paul Law,et al.  Familial Clustering of Autoimmune Disorders and Evaluation of Medical Risk Factors in Autism , 1999, Journal of child neurology.

[47]  H. Engeland,et al.  Differentiation between Autism and Multiple Complex Developmental Disorder in Response to Psychosocial Stress , 2003, Neuropsychopharmacology.

[48]  P. Arck,et al.  Neuroimmunoendocrine circuitry of the 'brain-skin connection'. , 2006, Trends in immunology.

[49]  P. Conti,et al.  Brain cytokines and neuropsychiatric disorders. , 2004, Journal of clinical psychopharmacology.

[50]  T. Porkka-Heiskanen,et al.  Higher plasma ACTH levels in adults with Asperger syndrome. , 2005, Journal of psychosomatic research.

[51]  William J Walsh,et al.  Altered vascular phenotype in autism: correlation with oxidative stress. , 2006, Archives of neurology.

[52]  David W Gaylor,et al.  Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. , 2004, The American journal of clinical nutrition.

[53]  E. Anyanwu,et al.  Antibodies to neuron-specific antigens in children with autism: possible cross-reaction with encephalitogenic proteins from milk, Chlamydia pneumoniae and Streptococcus group A , 2002, Journal of Neuroimmunology.

[54]  N. Abbott Inflammatory Mediators and Modulation of Blood–Brain Barrier Permeability , 2000, Cellular and Molecular Neurobiology.

[55]  M. Tsai,et al.  Mast cells as "tunable" effector and immunoregulatory cells: recent advances. , 2005, Annual review of immunology.

[56]  T. Theoharides,et al.  The Critical Role of Mast Cells in Allergy and Inflammation , 2006, Annals of the New York Academy of Sciences.

[57]  L. Hesse,et al.  Stress-induced rat intestinal mast cell intragranular activation and inhibitory effect of sulfated proteoglycans. , 1999, Digestive diseases and sciences.

[58]  P. Valent,et al.  Urticaria pigmentosa and mastocytosis: The role of immunophenotyping in diagnosis and determining response to treatment , 2006, Current allergy and asthma reports.

[59]  S. Levy,et al.  Relationship of Dietary Intake to Gastrointestinal Symptoms in Children with Autistic Spectrum Disorders , 2007, Biological Psychiatry.

[60]  A. Vojdani Antibodies as Predictors of Complex Autoimmune Diseases , 2008, International journal of immunopathology and pharmacology.

[61]  P. Henningsen,et al.  Psychological burden of food allergy. , 2007, World journal of gastroenterology.

[62]  T. Theoharides,et al.  Chondroitin sulphate inhibits connective tissue mast cells , 2000, British journal of pharmacology.

[63]  J. Baker Mercury, vaccines, and autism: one controversy, three histories. , 2008, American journal of public health.

[64]  P. Conti,et al.  Mast cells as targets of corticotropin-releasing factor and related peptides. , 2004, Trends in pharmacological sciences.

[65]  Richard A Flavell,et al.  Activation of mast cells by double-stranded RNA: evidence for activation through Toll-like receptor 3. , 2004, The Journal of allergy and clinical immunology.

[66]  P. Domizio,et al.  Autistic enterocolitis: is it a histopathological entity? , 2007, Histopathology.

[67]  J. Furness,et al.  Novel therapeutic targets for enteric nervous system disorders. , 2007, Trends in pharmacological sciences.

[68]  C. Cetrulo,et al.  Human Mast Cells Express Corticotropin-Releasing Hormone (CRH) Receptors and CRH Leads to Selective Secretion of Vascular Endothelial Growth Factor1 , 2005, The Journal of Immunology.

[69]  C. Kornetsky,et al.  Acute stress causes mucin release from rat colon: role of corticotropin releasing factor and mast cells. , 1996, The American journal of physiology.

[70]  K. Hock,et al.  Hyperserotonemia in Adults with Autistic Disorder , 2007, Journal of autism and developmental disorders.

[71]  E. Middleton,et al.  The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer. , 2000, Pharmacological reviews.

[72]  B. Anlar,et al.  Atopic features in early childhood autism. , 2008, European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society.

[73]  P. D'eufemia,et al.  Food allergy and infantile autism. , 1995, Panminerva medica.