431
Views
66
CrossRef citations to date
0
Altmetric
Reviews

Autism: an emerging ‘neuroimmune disorder’ in search of therapy

, MS MPhil PhD MD FAAAI, , MS MPhil PhD & , RN MSN
Pages 2127-2143 | Published online: 29 Jul 2009

Bibliography

  • Fombonne E, Zakarian R, Bennett A, et al. Pervasive developmental disorders in Montreal, Quebec, Canada: prevalence and links with immunizations. Pediatrics 2006;118(1):e139-50
  • Gerberding J. Prevalence of autism spectrum disorder–Autism and developmental disabilities monitoring network, six sites, United States, 2000 and 2002. MMWR Morb Mortal Wkly Rep 2007;56(1S):1-40
  • Newschaffer CJ, Croen LA, Daniels J, et al. The epidemiology of autism spectrum disorders. Annu Rev Public Health 2007;28:235-58
  • Yeargin-Allsopp M, Rice C, Karapurkar T, et al. Prevalence of autism in a US metropolitan area. JAMA 2003;289(1):49-55
  • Gurney JG, McPheeters ML, Davis MM. Parental report of health conditions and health care use among children with and without autism: National Survey of Children's Health. Arch Pediatr Adolesc Med 2006;160(8):825-30
  • Johnson CP, Myers SM. Identification and evaluation of children with autism spectrum disorders. Pediatrics 2007;120(5):1183-215
  • Center for disease control: prevalence of autism spectrum disorders -autism and developmental disabilities monitoring network, six sites, 2000. Morb Mortal Wkly Rep 2007;15:1-11
  • Kuehn BM. CDC: autism spectrum disorders common. JAMA 2007;297(9):940
  • Fombonne E. Epidemiology of pervasive developmental disorders. Pediatr Res 2009;65(6):591-8
  • Hertz-Picciotto I, Delwiche L. The rise in autism and the role of age at diagnosis. Epidemiology 2009;20(1):84-90
  • Stehr-Green P, Tull P, Stellfeld M, et al. Autism and thimerosal-containing vaccines: lack of consistent evidence for an association. Am J Prev Med 2003;25(2):101-6
  • D'Souza Y, Fombonne E, Ward BJ. No evidence of persisting measles virus in peripheral blood mononuclear cells from children with autism spectrum disorder. Pediatrics 2006;118(4):1664-75
  • Destefano F. Vaccines and autism: evidence does not support a causal association. Clin Pharmacol Ther 2007;82(6):756-9
  • Baker JP. Mercury, vaccines, and autism: one controversy, three histories. Am J Public Health 2008;98:244-53
  • Fombonne E. Thimerosal disappears but autism remains. Arch Gen Psychiatry 2008;65(1):15-6
  • Gallagher C, Goodman M. Hepatitis B triple series vaccine and developmental disability in US children aged 1-9 years. Toxicol Environ Chem 2008;90(5):997-1008
  • Geier DA, Geier MR. A meta-analysis epidemiological assessment of neurodevelopmental disorders following vaccines administered from 1994 through 2000 in the United States. Neuro Endocrinol Lett 2006;27(4):401-13
  • Woo EJ, Ball R, Landa R, et al. Developmental regression and autism reported to the Vaccine Adverse Event Reporting System. Autism 2007;11(4):301-10
  • Young HA, Geier DA, Geier MR. Thimerosal exposure in infants and neurodevelopmental disorders: an assessment of computerized medical records in the Vaccine Safety Datalink. J Neurol Sci 2008;271(1-2):110-8
  • Rapin I, Tuchman RF. What is new in autism? Curr Opin Neurol 2008;21(2):143-9
  • Caronna EB, Milunsky JM, Tager-Flusberg H. Autism spectrum disorders: clinical and research frontiers. Arch Dis Child 2008;93(6):518-23
  • Lintas C, Persico AM. Autistic phenotypes and genetic testing: state-of-the-art for the clinical geneticist. J Med Genet 2009;46:1-8
  • Palmieri L, Papaleo V, Porcelli V, et al. Altered calcium homeostasis in autism-spectrum disorders: evidence from biochemical and genetic studies of the mitochondrial aspartate/glutamate carrier AGC1. Mol Psychiatry 2008. [Epub ahead of print]
  • Garbett K, Ebert PJ, Mitchell A, et al. Immune transcriptome alterations in the temporal cortex of subjects with autism. Neurobiol Dis 2008;30(3):303-11
  • Lintas C, Sacco R, Garbett K, et al. Involvement of the PRKCB1 gene in autistic disorder: significant genetic association and reduced neocortical gene expression. Mol Psychiatry 2008;14(7):705-18
  • Persico AM, Bourgeron T. Searching for ways out of the autism maze: genetic, epigenetic and environmental clues. Trends Neurosci 2006;29(7):349-58
  • Cai G, Edelmann L, Goldsmith JE, et al. Multiplex ligation-dependent probe amplification for genetic screening in autism spectrum disorders: efficient identification of known microduplications and identification of a novel microduplication in ASMT. BMC Med Genomics 2008;1:50
  • Wang K, Zhang H, Ma D, et al. Common genetic variants on 5p14.1 associate with autism spectrum disorders. Nature 2009;459:528-33
  • Glessner JT, Wang K, Cai G, et al. Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature 2009;459:569-73
  • Strom SP, Stone JL, Ten B, et al. High-density SNP association study of the 17q21 chromosomal region linked to autism identifies CACNA1G as a novel candidate gene. Mol Psychiatry 2009. [Epub ahead of print]
  • James SJ, Melnyk S, Jernigan S, et al. Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism. Am J Med Genet B Neuropsychiatr Genet 2006;141(8):947-56
  • James SJ, Cutler P, Melnyk S, et al. Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. Am J Clin Nutr 2004;80(6):1611-7
  • Carvalho CM, Chew EH, Hashemy SI, et al. Inhibition of the human thioredoxin system. A molecular mechanism of mercury toxicity. J Biol Chem 2008;283(18):11913-23
  • James SJ, Rose S, Melnyk S, et al. Cellular and mitochondrial glutathione redox imbalance in lymphoblastoid cells derived from children with autism. FASEB 2009. [Epub ahead of print]
  • Geier DA, Kern JK, Garver CR, et al. A prospective study of transsulfuration biomarkers in autistic disorders. Neurochem Res 2009;34(2):386-93
  • Geier DA, Kern JK, Garver CR, et al. Biomarkers of environmental toxicity and susceptibility in autism. J Neurol Sci 2008;280(1-2):101-8
  • Sajdel-Sulkowska EM, Lipinski B, Windom H, et al. Oxidative stress in autism: elevated cerebellar 3-nitrotyrosine levels. AM J Biochem Biotechnol 2008;4:73-84
  • Yorbik O, Sayal A, Akay C, et al. Investigation of antioxidant enzymes in children with autistic disorder. Prostaglandins Leukot Essent Fatty Acids 2002;67(5):341-3
  • James JS, Melnyk S, Jernigan S, et al. Abnormal transmethylation/transsulfuration metabolism and DNA hypomethylation among parents of children with autism. J Autism Dev Disord 2008;38(10):1966-75
  • Chauhan A, Chauhan V, Brown WT, Cohen I. Oxidative stress in autism: increased lipid peroxidation and reduced serum levels of ceruloplasmin and transferrin–the antioxidant proteins. Life Sci 2004;75(21):2539-49
  • Yao Y, Walsh WJ, McGinnis WR, Pratico D. Altered vascular phenotype in autism: correlation with oxidative stress. Arch Neurol 2006;63(8):1161-4
  • Weissman JR, Kelley RI, Bauman ML, et al. Mitochondrial disease in autism spectrum disorder patients: A cohort analysis. PloS One 2008;3(11):e3815
  • Deth R, Muratore C, Benzecry J, et al. How environmental and genetic factors combine to cause autism: a redox/methylation hypothesis. Neurotoxicology 2008;29(1):190-201
  • Pardo CA, Vargas DL, Zimmerman AW. Immunity, neuroglia and neuroinflammation in autism. Int Rev Psychiatry 2005;17(6):485-95
  • Ashwood P, van de Water J. Is autism an autoimmune disease? Autoimmun Rev 2004;3(7-8):557-62
  • Ashwood P, Wills S, van de Water J. The immune response in autism: a new frontier for autism research. J Leukoc Biol 2006;80(1):1-15
  • Cohly HH, Panja A. Immunological findings in autism. Int Rev Neurobiol 2005;71:317-41
  • Gregg JP, Lit L, Baron CA, et al. Gene expression changes in children with autism. Genomics 2008;91(1):22-9
  • Enstrom AM, Lit L, Onore CE, et al. Altered gene expression and function of peripheral blood natural killer cells in children with autism. Brain Behav Immun 2009;23:124-33
  • Chez MG, Dowling T, Patel PB, et al. Elevation of tumor necrosis factor-alpha in cerebrospinal fluid of autistic children. Pediatr Neurol 2007;36(6):361-5
  • Zimmerman AW, Jyonouchi H, Comi AM, et al. Cerebrospinal fluid and serum markers of inflammation in autism. Pediatr Neurol 2005;33(3):195-201
  • Li X, Chauhan A, Sheikh AM, et al. Elevated immune response in the brain of autistic patients. J Neuroimmunol 2009;207(1-2):111-6
  • Reichenberg A, Yirmiya R, Schuld A, et al. Cytokine-associated emotional and cognitive disturbances in humans. Arch Gen Psychiatry 2001;58(5):445-52
  • Weizman A, Weizman R, Szekely GA, et al. Abnormal immune response to brain tissue antigen in the syndrome of autism. Am J Psychiatry 1982;139(11):1462-5
  • Ashwood P, Schauer J, Pessah IN, de Water JV. Preliminary evidence of the in vitro effects of BDE-47 on innate immune responses in children with autism spectrum disorders. J Neuroimmunol 2009;208:130-5
  • Grigorenko EL, Han SS, Yrigollen CM, et al. Macrophage migration inhibitory factor and autism spectrum disorders. Pediatrics 2008;122(2):e438-45
  • Vargas DL, Nascimbene C, Krishnan C, et al. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol 2005;57(1):67-81
  • Conti P, Pang X, Boucher W, et al. Impact of Rantes and MCP-1 chemokines on in vivo basophilic mast cell recruitment in rat skin injection model and their role in modifying the protein and mRNA levels for histidine decarboxylase. Blood 1997;89:4120-7
  • Ashwood P, Enstrom A, Krakowiak P, et al. Decreased transforming growth factor beta1 in autism: a potential link between immune dysregulation and impairment in clinical behavioral outcomes. J Neuroimmunol 2008;204:149-53
  • Gebhardt T, Lorentz A, Detmer F, et al. Growth, phenotype, and function of human intestinal mast cells are tightly regulated by transforming growth factor beta1. Gut 2005;54(7):928-34
  • Gomez G, Ramirez CD, Rivera J, et al. TGF-beta1 inhibits mast cell FcåRI expression. J Immunol 2005;174:5987-93
  • Dahlgren J, Samuelsson AM, Jansson T, Holmang A. Interleukin-6 in the maternal circulation reaches the rat fetus in mid-gestation. Pediatr Res 2006;60(2):147-51
  • Smith SE, Li J, Garbett K, et al. Maternal immune activation alters fetal brain development through interleukin-6. J Neurosci 2007;27(40):10695-702
  • Huang M, Pang X, Karalis K, Theoharides TC. Stress-induced interleukin-6 release in mice is mast cell-dependent and more pronounced in Apolipoprotein E knockout mice. Cardiovasc Res 2003;59(1):241-9
  • de Boer AG, Breimer DD. Cytokines and blood-brain barrier permeability. Prog Brain Res 1998;115:425-51
  • Abbott NJ. Inflammatory mediators and modulation of blood-brain barrier permeability. Cell Mol Neurobiol 2000;20:131-47
  • Vojdani A, Campbell AW, Anyanwu E, 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. J Neuroimmunol 2002;129(1-2):168-77
  • Wills S, Cabanlit M, Bennett J, et al. Detection of autoantibodies to neural cells of the cerebellum in the plasma of subjects with autism spectrum disorders. Brain Behav Immun 2008;23:64-74
  • Singer HS, Morris CM, Williams PN, et al. Antibrain antibodies in children with autism and their unaffected siblings. J Neuroimmunol 2006;178(1-2):149-55
  • Cabanlit M, Wills S, Goines P, et al. Brain-specific autoantibodies in the plasma of subjects with autistic spectrum disorder. Ann NY Acad Sci 2007;1107:92-103
  • Singer HS, Morris CM, Gause CD, et al. Antibodies against fetal brain in sera of mothers with autistic children. J Neuroimmunol 2008;194(1-2):165-72
  • Zimmerman AW, Connors SL, Matteson KJ, et al. Maternal antibrain antibodies in autism. Brain Behav Immun 2007;21(3):351-7
  • Braunschweig D, Ashwood P, Krakowiak P, et al. Autism: maternally derived antibodies specific for fetal brain proteins. Neurotoxicology 2008;29(2):226-31
  • Persico AM, Sacco R, Curatolo P, et al. Isolation of principal components in autistic disorder symptomatology and their association with biological endophenotypes. Proc Society for Neuroscience, Washington; 2008
  • Jyonouchi H, Geng L, Cushing-Ruby A, Quraishi H. Impact of innate immunity in a subset of children with autism spectrum disorders: a case control study. J Neuroinflamm 2008;5:52
  • Lucarelli S, Frediani T, Zingoni AM, et al. Food allergy and infantile autism. Panminerva Med 1995;37(3):137-41
  • Venter C, Pereira B, Voigt K, et al. Prevalence and cumulative incidence of food hypersensitivity in the first 3 years of life. Allergy 2008;63:354-9
  • Teufel M, Biedermann T, Rapps N, et al. Psychological burden of food allergy. World J Gastroenterol 2007;13(25):3456-65
  • Lack G. Food allergy. N Engl J Med 2008;359(12):1252-60
  • Ortolani C, Pastorello EA. Food allergies and food intolerances. Best Pract Res Clin Gastroenterol 2006;20(3):467-83
  • Farhadi A, Fields JZ, Keshavarzian A. Mucosal mast cells are pivotal elements in inflammatory bowel disease that connect the dots: stress, intestinal hyperpermeability and inflammation. World J Gastroenterol 2007;13(22):3027-30
  • Rijnierse A, Nijkamp FP, Kraneveld AD. Mast cells and nerves tickle in the tummy. Implications for inflammatory bowel disease and irritable bowel syndrome. Pharmacol Ther 2007;116:207-35
  • O'Sullivan M, Clayton N, Breslin NP, et al. Increased mast cells in the irritable bowel syndrome. Neurogastroenterol Motil 2000;12:449-57
  • Levy SE, Souders MC, Ittenbach RF, et al. Relationship of dietary intake to gastrointestinal symptoms in children with autistic spectrum disorders. Biol Psychiatry 2007;61(4):492-7
  • Valicenti-McDermott MD, McVicar K, Cohen HJ, et al. Gastrointestinal symptoms in children with an autism spectrum disorder and language regression. Pediatr Neurol 2008;39(6):392-8
  • Nikolov RN, Bearss KE, Lettinga J, et al. Gastrointestinal symptoms in a sample of children with pervasive developmental disorders. J Autism Dev Disord 2009;39(3):405-13
  • Jyonouchi H, Geng L, Ruby A, Zimmerman-Bier B. Dysregulated innate immune responses in young children with autism spectrum disorders: their relationship to gastrointestinal symptoms and dietary intervention. Neuropsychobiology 2005;51(2):77-85
  • Black C, Kaye JA, Jick H. Relation of childhood gastrointestinal disorders to autism: nested case-control study using data from the UK General Practice Research Database. BMJ 2002;325(7361):419-21
  • Wakefield AJ, Ashwood P, Limb K, Anthony A. The significance of ileo-colonic lymphoid nodular hyperplasia in children with autistic spectrum disorder. Eur J Gastroenterol Hepatol 2005;17(8):827-36
  • Krigsman A, Boris M, Goldblatt A, Scott C. Review of clinical presentation and histologic findings at ileocolonoscopy in children with autistic spectrum disorder and chronic gastrointestinal symtoms. Autism Res 2008. [Epub ahead of print]
  • Liu Z, Li N, Neu J. Tight junctions, leaky intestines, and pediatric diseases. Acta Paediatr 2005;94(4):386-93
  • Bode L, Salvestrini C, Park PW, et al. Heparan sulfate and syndecan-1 are essential in maintaining murine and human intestinal epithelial barrier function. J Clin Invest 2008;118(1):229-38
  • Lencer WI. Patching a leaky intestine. N Engl J Med 2008;359(5):526-8
  • Alberti A, Pirrone P, Elia M, et al. Sulphation deficit in ‘low-functioning’ autistic children: a pilot study. Biol Psychiatry 1999;46(3):420-4
  • Menage P, Thibault G, Martineau J, et al. An IgE mechanism in autistic hypersensitivity? Biol Psychiatry 1992;31(2):210-2
  • Bakkaloglu B, Anlar B, Anlar FY, et al. Atopic features in early childhood autism. Eur J Paediatr Neurol 2008;12:476-9
  • Castells M, Austen KF. Mastocytosis: mediator-related signs and symptoms. Int Arch Allergy Immunol 2002;127:147-52
  • Metcalfe DD, Akin C. Mastocytosis: molecular mechanisms and clinical disease heterogeneity. Leuk Res 2001;25:577-82
  • Valent P, Horny HP, Escribano L, et al. Diagnostic criteria and classification of mastocytosis: a consensus proposal. Leuk Res 2001;25:603-25
  • Available from: www.tmsforacure.org
  • Theoharides TC, Doyle R, Francis K, et al. Novel therapeutic targets for autism. Trends Pharmacol Sci 2008;29(8):375-82
  • Theoharides TC, Boucher W, Spear K. Serum interleukin-6 reflects disease severity and osteoporosis in mastocytosis patients. Int Arch Allergy Immunol 2002;128:344-50
  • Croen LA, Grether JK, Yoshida CK, et al. Maternal autoimmune diseases, asthma and allergies, and childhood autism spectrum disorders: a case-control study. Arch Pediatr Adolesc Med 2005;159(2):151-7
  • Comi AM, Zimmerman AW, Frye VH, et al. Familial clustering of autoimmune disorders and evaluation of medical risk factors in autism. J Child Neurol 1999;14(6):388-94
  • Theoharides TC, Kalogeromitros D. The critical role of mast cell in allergy and inflammation. Ann NY Acad Sci 2006;1088:78-99
  • Galli SJ, Kalesnikoff J, Grimbaldeston MA, et al. Mast cells as ‘tunable’ effector and immunoregulatory cells: recent advances. Annu Rev Immunol 2005;23:749-86
  • Bachelet I, Levi-Schaffer F. Mast cells as effector cells: a co-stimulating question. Trends Immunol 2007;28(8):360-5
  • Theoharides TC, Cochrane DE. Critical role of mast cells in inflammatory diseases and the effect of acute stress. J Neuroimmunol 2004;146:1-12
  • Dimitriadou V, Rouleau A, Trung Tuong MD, et al. Functional relationships between sensory nerve fibers and mast cells of dura mater in normal and inflammatory conditions. Neuroscience 1997;77:829-39
  • Rozniecki JJ, Dimitriadou V, Lambracht-Hall M, et al. Morphological and functional demonstration of rat dura mast cell-neuron interactions in vitro and in vivo. Brain Res 1999;849:1-15
  • Stead RH, Dixon MF, Bramwell NH, et al. Mast cells are closely apposed to nerves in the human gastrointestinal mucosa. Gastroenterology 1989;97:575-85
  • Blank U, Rivera J. The ins and outs of IgE-dependent mast-cell exocytosis. Trends Immunol 2004;25:266-73
  • Redegeld FA, Nijkamp FP. Immunoglobulin free light chains and mast cells: pivotal role in T-cell-mediated immune reactions? Trends Immunol 2005;24:181-5
  • Kempuraj D, Tagen M, Iliopoulou BP, et al. Luteolin inhibits myelin basic protein-induced human mast cell activation and mast cell dependent stimulation of Jurkat T cells. Br J Pharmacol 2008;155:1076-84
  • Carraway R, Cochrane DE, Lansman JB, et al. Neurotensin stimulates exocytotic histamine secretion from rat mast cells and elevates plasma histamine levels. J Physiol 1982;323:403-14
  • Janiszewski J, Bienenstock J, Blennerhassett MG. Picomolar doses of substance P trigger electrical responses in mast cells without degranulation. Am J Physiol 1994;267:C138-45
  • Kulka M, Sheen CH, Tancowny BP, et al. Neuropeptides activate human mast cell degranulation and chemokine production. Immunology 2008;123(3):398-410
  • Frossi B, de Carli M, Daniel KC, et al. Oxidative stress stimulates IL-4 and IL-6 production in mast cells by an APE/Ref-1-dependent pathway. Eur J Immunol 2003;33:2168-77
  • Kempuraj D, Hogan J, Zhang B, et al. Mercury chloride triggers human mast cells to release vascular endothelial growth factor (VEGF)-relevance to autism. 96th Annual Meeting, The Americal Association of Immunologisits, May 8-12. Immunology; 2009
  • Elferink JG. Thimerosal: a versatile sulfhydryl reagent, calcium mobilizer, and cell function-modulating agent. Gen Pharmacol 1999;33(1):1-6
  • Strenzke N, Grabbe J, Plath KE, et al. Mercuric chloride enhances immunoglobulin E-dependent mediator release from human basophils. Toxicol Appl Pharmacol 2001;174(3):257-63
  • Salamon P, Shoham NG, Gavrieli R, et al. Human mast cells release interleukin-8 and induce neutrophil chemotaxis on contact with activated T cells. Allergy 2005;60(10):1316-9
  • Nakae S, Suto H, Iikura M, et al. Mast cells enhance T cell activation: importance of mast cell costimulatory molecules and secreted TNF. J Immunol 2006;176(4):2238-48
  • Theoharides TC, Kempuraj D, Tagen M, et al. Differential release of mast cell mediators and the pathogenesis of inflammation. Immunol Rev 2007;217:65-78
  • Theoharides TC, Bondy PK, Tsakalos ND, Askenase PW. Differential release of serotonin and histamine from mast cells. Nature 1982;297:229-31
  • Okayama Y. Mast cell-derived cytokine expression induced via Fc receptors and Toll-like receptors. Chem Immunol Allergy 2005;87:101-10
  • Varadaradjalou S, Feger F, Thieblemont N, et al. Toll-like receptor 2 (TLR2) and TLR4 differentially activate human mast cells. Eur J Immunol 2003;33:899-906
  • McCurdy JD, Olynych TJ, Maher LH, Marshall JS. Cutting edge: distinct Toll-like receptor 2 activators selectively induce different classes of mediator production from human mast cells. J Immunol 2003;170:1625-9
  • Kulka M, Alexopoulou L, Flavell RA, Metcalfe DD. Activation of mast cells by double-stranded RNA: evidence for activation through Toll-like receptor 3. J Allergy Clin Immunol 2004;114(1):174-82
  • Ikeda RK, Miller M, Nayar J, et al. Accumulation of peribronchial mast cells in a mouse model of ovalbumin allergen induced chronic airway inflammation: modulation by immunostimulatory DNA sequences. J Immunol 2003;171(9):4860-7
  • Arvola T, Ruuska T, Keranen J, et al. Rectal bleeding in infancy: clinical, allergological, and microbiological examination. Pediatrics 2006;117(4):e760-8
  • Dunn SJ, Greenberg HB, Ward RL, et al. Serotypic and genotypic characterization of human serotype 10 rotaviruses from asymptomatic neonates. J Clin Microbiol 1993;31(1):165-9
  • Difazio MP, Braun L, Freedman S, Hickey P. Rotavirus-induced seizures in childhood. J Child Neurol 2007;22(12):1367-70
  • Oslejskova H, Dusek L, Makovska Z, et al. Complicated relationship between autism with regression and epilepsy. Neuro Endocrinol Lett 2008;29(4):558-70
  • Pehlivanidis C, Fotoulaki M, Boucher W, et al. Acute stress-induced seizures and loss of consciousness in a ten-year-old boy with cutaneous mastocytosis. J Clin Psychopharmacol 2002;22:221-4
  • Kandere-Grzybowska K, Letourneau R, Kempuraj D, et al. IL-1 induces vesicular secretion of IL-6 without degranulation from human mast cells. J Immunol 2003;171(9):4830-6
  • Cao J, Papadopoulou N, Kempuraj D, et al. Human mast cells express corticotropin-releasing hormone (CRH) receptors and CRH leads to selective secretion of vascular endothelial growth factor. J Immunol 2005;174:7665-75
  • Theoharides TC, Weinkauf C, Conti P. Brain cytokines and neuropsychiatric disorders. J Clin Psychopharmacol 2004;24:577-81
  • Theoharides TC, Konstantinidou A. Corticotropin-releasing hormone and the blood-brain-barrier. Front Biosci 2007;12:1615-28
  • White SW, Oswald D, Ollendick T, Scahill L. Anxiety in children and adolescents with autism spectrum disorders. Clin Psychol Rev 2009;29:216-29
  • Gillott A, Standen PJ. Levels of anxiety and sources of stress in adults with autism. J Intellect Disabil 2007;11(4):359-70
  • Jansen LM, Gispen-de Wied CC, van der Gaag RJ, van EH. Differentiation between autism and multiple complex developmental disorder in response to psychosocial stress. Neuropsychopharmacology 2003;28(3):582-90
  • Tani P, Lindberg N, Matto V, et al. Higher plasma ACTH levels in adults with Asperger syndrome. J Psychosom Res 2005;58(6):533-6
  • Geier DA, Geier MR. A clinical and laboratory evaluation of methionine cycle-transsulfuration and androgen pathway markers in children with autistic disorders. Horm Res 2006;66(4):182-8
  • Geier DA, Geier MR. A prospective assessment of androgen levels in patients with autistic spectrum disorders: biochemical underpinnings and suggested therapies. Neuro Endocrinol Lett 2007;28(5):565-73
  • Theoharides TC, Spanos CP, Pang X, et al. Stress-induced intracranial mast cell degranulation. A corticotropin releasing hormone-mediated effect. Endocrinology 1995;136:5745-50
  • Esposito P, Chandler N, Kandere-Grzybowska K, et al. Corticotropin-releasing hormone (CRH) and brain mast cells regulate blood-brain-barrier permeability induced by acute stress. J Pharmacol Exp Ther 2002;303:1061-6
  • Esposito P, Gheorghe D, Kandere K, et al. Acute stress increases permeability of the blood-brain-barrier through activation of brain mast cells. Brain Res 2001;888:117-27
  • Theoharides TC. Mast cells: the immune gate to the brain. Life Sci 1990;46:607-17
  • Silver R, Silverman A-J, Vitkovic L, Lederhendler II. Mast cells in the brain: evidence and functional significance. Trends Neurosci 1996;19:25-31
  • Theoharides TC, Singh LK, Boucher W, et al. Corticotropin-releasing hormone induces skin mast cell degranulation and increased vascular permeability, a possible explanation for its pro-inflammatory effects. Endocrinology 1998;139:403-13
  • Crompton R, Clifton VL, Bisits AT, et al. Corticotropin-releasing hormone causes vasodilation in human skin via mast cell-dependent pathways. J Clin Endocrinol Metab 2003;88:5427-32
  • Akin C, Valent P, Escribano L. Urticaria pigmentosa and mastocytosis: the role of immunophenotyping in diagnosis and determining response to treatment. Curr Allergy Asthma Rep 2006;6(4):282-8
  • Theoharides TC, Kempuraj D, Marchand J, et al. Urticaria pigmentosa associated with acute stress and lesional skin mast cell expression of CRF-R1. Clin Exp Dermatol 2009;34:e163-6
  • Theoharides TC, Letourneau R, Patra P, et al. Stress-induced rat intestinal mast cell intragranular activation and inhibitory effect of sulfated proteoglycans. Dig Dis Sci 1999;44:87S-93S
  • Castagliuolo I, Lamont JT, Qiu B, et al. Acute stress causes mucin release from rat colon: role of corticotropin releasing factor and mast cells. Am J Physiol 1996;271:884-92
  • Kokkotou E, Torres D, Moss AC, et al. Corticotropin-releasing hormone receptor 2-deficient mice have reduced intestinal inflammatory responses. J Immunol 2006;177(5):3355-61
  • La Fleur SE, Wick EC, Idumalla PS, et al. Role of peripheral corticotropin-releasing factor and urocortin II in intestinal inflammation and motility in terminal ileum. Proc Natl Acad Sci USA 2005;102(21):7647-52
  • Wallon C, Yang P, Keita AV, et al. Corticotropin releasing hormone (CRH) regulates macromolecular permeability via mast cells in normal human colonic biopsies in vitro. Gut 2008;57:50-8
  • Umathe SN, Bhutada PS, Jain NS, et al. Gonadotropin-releasing hormone agonist blocks anxiogenic-like and depressant-like effect of corticotrophin-releasing hormone in mice. Neuropeptides 2008;42(4):399-410
  • Umathe SN, Dixit PV, Wanjari MM, Ullewar MP. Leuprolide–a GnRH agonist–prevents restraint stress-induced immunosuppression via sex steroid-independent peripheral mechanism in mice. Int Immunopharmacol 2008;8(1):71-9
  • Barreau F, Cartier C, Leveque M, et al. Pathways involved in gut mucosal barrier dysfunction induced in adult rats by maternal deprivation: corticotrophin-releasing factor and nerve growth factor interplay. J Physiol 2007;580(Pt 1):347-56
  • Barreau F, Salvador-Cartier C, Houdeau E, et al. Long-term alterations of colonic nerve-mast cell interactions induced by neonatal maternal deprivation in rats. Gut 2008;57(5):582-90
  • Wright RJ, Finn P, Contreras JP, et al. Chronic caregiver stress and IgE expression, allergen-induced proliferation, and cytokine profiles in a birth cohort predisposed to atopy. J Allergy Clin Immunol 2004;113(6):1051-7
  • Theoharides TC, Doyle R. Autism, gut-blood-brain barrier and mast cells. J Clin Psychopharmacol 2008;28(5):479-83
  • Myers SM. The status of pharmacotherapy for autism spectrum disorders. Expert Opin Pharmacother 2007;8(11):1579-603
  • Broadstock M, Doughty C, Eggleston M. Systematic review of the effectiveness of pharmacological treatments for adolescents and adults with autism spectrum disorder. Autism 2007;11(4):335-48
  • Rogers SJ, Vismara LA. Evidence-based comprehensive treatments for early autism. J Clin Child Adolesc Psychol 2008;37(1):8-38
  • Findling RL. Pharmacologic treatment of behavioral symptoms in autism and pervasive developmental disorders. J Clin Psychiatry 2005;66(Suppl 10):26-31
  • Leskovec TJ, Rowles BM, Findling RL. Pharmacological treatment options for autism spectrum disorders in children and adolescents. Harv Rev Psychiatry 2008;16(2):97-112
  • West L, Waldrop J, Brunssen S. Pharmacologic treatment for the core deficits and associated symptoms of autism in children. J Pediatr Health Care 2009;23(2):75-89
  • Liptak GS, Stuart T, Auinger P. Health care utilization and expenditures for children with autism: data from U.S. national samples. J Autism Dev Disord 2006;36(7):871-9
  • Oswald DP, Sonenklar NA. Medication use among children with autism spectrum disorders. J Child Adolesc Psychopharmacol 2007;17(3):348-55
  • Gerhard T, Chavez B, Olfson M, Crystal S. National patterns in the outpatient pharmacological management of children and adolescents with autism spectrum disorder. J Clin Psychopharmacol 2009
  • Hollander E, Phillips A, Chaplin W, et al. A placebo controlled crossover trial of liquid fluoxetine on repetitive behaviors in childhood and adolescent autism. Neuropsychopharmacology 2005;30(3):582-9
  • Tandon M, Pruett JR Jr. An overview of the use of antidepressants in children and adolescents. Mo Med 2008;105(1):79-84
  • Posey DJ, Stigler KA, Erickson CA, McDougle CJ. Antipsychotics in the treatment of autism. J Clin Invest 2008;118(1):6-14
  • Morgan S, Taylor E. Antipsychotic drugs in children with autism. BMJ 2007;334(7603):1069-70
  • Chavez B, Chavez-Brown M, Sopko MA, et al. Atypical antipsychotics in children with pervasive developmental disorders. Paediatr Drugs 2007;9(4):249-66
  • McDougle CJ, Stigler KA, Erickson CA, Posey DJ. Atypical antipsychotics in children and adolescents with autistic and other pervasive developmental disorders. J Clin Psychiatry 2008;69(Suppl 4):15-20
  • Mandell DS, Morales KH, Marcus SC, et al. Psychotropic medication use among Medicaid-enrolled children with autism spectrum disorders. Pediatrics 2008;121(3):e441-8
  • Parikh MS, Kolevzon A, Hollander E. Psychopharmacology of aggression in children and adolescents with autism: a critical review of efficacy and tolerability. J Child Adolesc Psychopharmacol 2008;18(2):157-78
  • Research units on pediatric psychparmacology autism network. Randomized, controlled, crossover trial of methylphenidate in pervasive developmental disorders with hyperactivity. Arch Gen Psychiatry 2005;62(11):1266-74
  • McCracken JT, McGough J, Shah B, et al. Risperidone in children with autism and serious behavioral problems. N Engl J Med 2002;347(5):314-21
  • Scott LJ, Dhillon S. Risperidone: a review of its use in the treatment of irritability associated with autistic disorder in children and adolescents. Paediatr Drugs 2007;9(5):343-54
  • Peachell PT, Pearce FL. Divalent cation dependence of the inhibition by phenothiazines of mediator release from mast cells. Br J Pharmacol 1989;97(2):547-55
  • Akhondzadeh S, Erfani S, Mohammadi MR, et al. Cyproheptadine in the treatment of autistic disorder: a double-blind placebo-controlled trial. J Clin Pharm Ther 2004;29(2):145-50
  • Hranilovic D, Bujas-Petkovic Z, Vragovic R, et al. Hyperserotonemia in adults with autistic disorder. J Autism Dev Disord 2007;37(10):1934-40
  • de Giorgio R, Barbara G, Furness JB, Tonini M. Novel therapeutic targets for enteric nervous system disorders. Trends Pharmacol Sci 2007;28(9):473-81
  • Curtis LT, Patel K. Nutritional and environmental approaches to preventing and treating autism and attention deficit hyperactivity disorder (ADHD): a review. J Altern Complement Med 2008;14(1):79-85
  • Adams JB. Summary of biomedical treatments for autism. Autism Research Institute (ARI) Publication 2008;40:1-27
  • Weber W, Newmark S. Complementary and alternative medical therapies for attention-deficit/hyperactivity disorder and autism. Pediatr Clin North Am 2007;4(6):983-1006
  • James SJ, Melnyk S, Fuchs G, et al. Efficacy of methylcobalamin and folinic acid treatment on glutathione redox status in children with autism. Am J Clin Nutr 2009;89(1):425-30
  • Middleton E Jr, Kandaswami C, Theoharides TC. The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease and cancer. Pharmacol Rev 2000;52:673-751
  • Beretz A, Cazenave JP, Anton R. Inhibition of aggregation and secretion of human platelets by quercetin and other flavonoids: structure-activity relationships. Agents Actions 1982;12:382-7
  • Jang S, Kelley KW, Johnson RW. Luteolin reduces IL-6 production in microglia by inhibiting JNK phosphorylation and activation of AP-1. Proc Natl Acad Sci USA 2008;105(21):7534-9
  • Sharma V, Mishra M, Ghosh S, et al. Modulation of interleukin-1beta mediated inflammatory response in human astrocytes by flavonoids: implications in neuroprotection. Brain Res Bull 2007;73(1-3):55-63
  • Kumar A, Goyal R. Quercetin protects against acute immobilization stress-induced behaviors and biochemical alterations in mice. J Med Food 2008;11(3):469-73
  • Kimata M, Shichijo M, Miura T, et al. Effects of luteolin, quercetin and baicalein on immunoglobulin E-mediated mediator release from human cultured mast cells. Clin Exp Allergy 2000;30:501-8
  • Kempuraj D, Madhappan B, Christodoulou S, et al. Flavonols inhibit proinflammatory mediator release, intracellular calcium ion levels and protein kinase C theta phosphorylation in human mast cells. Br J Pharmacol 2005;145:934-44
  • Kandere-Grzybowska K, Kempuraj D, Cao J, et al. Regulation of IL-1-induced selective IL-6 release from human mast cells and inhibition by quercetin.Br J Pharmacol 2006;148:208-15
  • Harwood M, Nielewska-Nikiel B, Borzelleca JF, et al. A critical review of the data related to the safety of quercetin and lack of evidence of in vivo toxicity, including lack of genotoxic/carcinogenic properties. Food Chem Toxicol 2007;45(11):2179-205
  • Manach C, Donovan JL. Pharmacokinetics and metabolism of dietary flavonoids in humans. Free Radic Res 2004;38(8):771-85
  • Erlund I, Kosonen T, Alfthan G, et al. Pharmacokinetics of quercetin from quercetin aglycone and rutin in healthy volunteers. Eur J Clin Pharmacol 2000;56(8):545-53
  • Theoharides TC, Patra P, Boucher W, et al. Chondroitin sulfate inhibits connective tissue mast cells. Br J Pharmacol 2000;131:1039-49
  • Vasiadi M, Kalogeromitros K, Kempuraj D, et al. Rupatadine inhibits pro-inflammatory mediator secretion from human mast cells. Clin Exp Allergy 2009. In press
  • Elchaar GM, Maisch NM, Augusto LM, Wehring HJ. Efficacy and safety of naltrexone use in pediatric patients with autistic disorder. Ann Pharmacother 2006;40(6):1086-95
  • Barke KE, Hough LB. Opiates, mast cells and histamine release. Life Sci 1993;53:1391-9
  • Bertoglio K, Hendren RL. New developments in autism. Psychiatr Clin North Am 2009;32(1):1-14
  • Theoharides TC, Wang L, Pang X, et al. Cloning and cellular localization of the rat mast cell 78kD protein phosphorylated in response to the mast cell ‘stabilizer’ cromolyn. J Pharmacol Exp Ther 2000;294:810-21
  • Tagen M, Elorza A, Boucher W, et al. The mitochondrial uncoupling protein 2 (UCP2) inhibits mast cell activation and reduces histamine content. J Immunol 2009. In press
  • Kamide R, Niimura M, Ueda H, et al. Clinical evaluation of ketotifen for chronic urticaria: multicenter double-blind comparative study with clemastine.Ann Allergy 1989;62:322-5
  • Weissman JR, Kelley RI, Bauman ML, et al. Mitochondrial disease in autism spectrum disorder patients: a cohort analysis. PLoS One 2008;3(11):e3815
  • King BH, Hollander E, Sikich L, et al. Lack of efficacy of citalopram in children with autism spectrum disorders and high levels of repetitive behavior: citalopram ineffective in children with autism. Arch Gen Psychiatry 2009;66(6):583-90
  • Volkmar FR. Citalopram treatment in children with autism spectrum disorders and high levels of repetitive behavior. Arch Gen Psychiatry 2009;66(6):581-2

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.