Biological Psychiatry
Volume 66, Issue 10 , Pages 978-984 , 15 November 2009

An Autistic Endophenotype Results in Complex Immune Dysfunction in Healthy Siblings of Autistic Children

  • Marina Saresella

      Affiliations

    • Laboratory of Molecular Medicine and Biotechnology, Don C. Gnocchi ONLUS Foundation IRCCS-S.M. Nascente, Italy
    • Corresponding Author InformationAddress correspondence to Marina Saresella, Ph.D., Laboratory of Molecular Medicine and Biotechnology, Don C. Gnocchi ONLUS Foundation IRCCS, Via Capecelatro 66, Milan 20148, Italy
  • ,
  • Ivana Marventano

      Affiliations

    • Laboratory of Molecular Medicine and Biotechnology, Don C. Gnocchi ONLUS Foundation IRCCS-S.M. Nascente, Italy
  • ,
  • Franca Rosa Guerini

      Affiliations

    • Laboratory of Molecular Medicine and Biotechnology, Don C. Gnocchi ONLUS Foundation IRCCS-S.M. Nascente, Italy
  • ,
  • Roberta Mancuso

      Affiliations

    • Laboratory of Molecular Medicine and Biotechnology, Don C. Gnocchi ONLUS Foundation IRCCS-S.M. Nascente, Italy
  • ,
  • Lara Ceresa

      Affiliations

    • Laboratory of Molecular Medicine and Biotechnology, Don C. Gnocchi ONLUS Foundation IRCCS-S.M. Nascente, Italy
  • ,
  • Milena Zanzottera

      Affiliations

    • Laboratory of Molecular Medicine and Biotechnology, Don C. Gnocchi ONLUS Foundation IRCCS-S.M. Nascente, Italy
  • ,
  • Beatrice Rusconi

      Affiliations

    • Department of Neuropsychiatry, Sacra Famiglia Institute, University of Milano, Milano, Italy
  • ,
  • Emanuela Maggioni

      Affiliations

    • Department of Neuropsychiatry, Don C. Gnocchi ONLUS Foundation IRCCS-S.M. Nascente, Italy
  • ,
  • Carmine Tinelli

      Affiliations

    • Clinical Epidemiology and Biometric Unit, IRCCS Policlinico S. Matteo Foundation, Pavia, Italy
  • ,
  • Mario Clerici

      Affiliations

    • Laboratory of Molecular Medicine and Biotechnology, Don C. Gnocchi ONLUS Foundation IRCCS-S.M. Nascente, Italy
    • Chair of Immunology, Department of Biomedical Sciences and Technologies, University of Milano, Milano, Italy

Received 9 January 2009 ,Revised 25 June 2009 ,Accepted 26 June 2009.

References 

  1. Amaral DG, Schumann CM, Nordahl CW. Neuroanatomy of autism. Trends Neurosci. 2008;31:137–145
  2. Ashwood P, Van de Water J. Is autism an autoimmune disease?. Autoimmun Rev. 2004;3:557–562
  3. Krause I, He XS, Gershwin ME, Shoenfeld Y. Brief report: Immune factors in autism: A critical review. J Autism Dev Disord. 2002;32:337–345Review
  4. Singh VK, Warren R, Averett R, Ghaziuddin M. Circulating autoantibodies to neuronal and glial filament proteins in autism. Pediatr Neurol. 1997;17:88–90
  5. Plioplys AV, Greaves A, Kazemi K, Silverman E. Immunoglobulin reactivity in autism and Rett's syndrome. Dev Brain Dysfunct. 1994;7:12–16
  6. Bashina VM, Kozlova IA, Kliushnik TP, Simashkova NV, Danilovskaia EV, Gorbachevskaia NL, et al. An elevation in the level of autoantibodies to nerve-growth factor in the blood serum of schizophrenic children. Zh Nevropatol Psikhiatr Im S S Korsakova. 1997;97:47–51
  7. Todd RD, Ciaranello RD. Demonstration of inter- and intraspecies differences in serotonin binding sites by antibodies from an autistic child. Proc Natl Acad Sci U S A. 1985;82:612–616
  8. Yuwiler A, Shih JC, Chen CH, Ritvo ER, Hanna G, Ellison GW, et al. Hyperserotoninemia and antiserotonin antibodies in autism and other disorders. J Autism Dev Disord. 1992;22:33–45
  9. Ferrari P, Marescot MR, Moulias R, Bursztejn C, Deville Chabrolle A, Thiollet M, et al. Immune status in infantile autism (Correlation between the immune status, autistic symptoms and levels of serotonin). Encephale. 1988;14:339–344
  10. Croonenberghs J, Wauters A, Devreese K, Verkerk R, Scharpe S, Bosmans E, et al. Increased serum albumin, gamma globulin, immunoglobulin IgG, and IgG2 and IgG4 in autism. Psychol Med. 2002;32:1457–1463
  11. Stubbs EG, Crawford ML, Burger DR, Vandenbark AA. Depressed lymphocyte responsiveness in autistic children. J Autism Child Schizophr. 1977;7:49–55
  12. Plioplys AV, Greaves A, Kazemi K, Silverman E. Lymphocyte function in autism and Rett's syndrome. Neuropsicobiology. 1994;29:12–16
  13. Warren RP, Foster A, Mararetten NV, Pace NC. Immune abnormalities in patients with autism. J Autism Dev Disord. 1986;16:189–197
  14. Warren RP, Yonk LJ, Burger RA, Cole P, Odell JD, Warren WL, et al. Deficiency of suppressor-inducer (CD4+ CD45RA+) T cells in autism. Immunol Investig. 1990;19:245–251
  15. Yonk LJ, Warren RP, Burger RA, Cole P, Odell JD, Warren WL, et al. CD4+ helper T cell depression in autism. Immunol Lett. 1990;25:341–345
  16. Menage P, Thibault G, Barthelemy C, Lelord G, Bardos P. CD4+ CD45RA+ T lymphocyte deficiency in autistic children: Effect of a pyridoxine-Magnesium treatment. Brain Dysfunct. 1992;5:326–333
  17. Denney DR, Wood Frei B, Gaffney GR. Lymphocyte subsets and interleukin-2 receptors in autistic children. J Autism Dev Disord. 1996;26:87–97
  18. Ferrante P, Saresella M, Guerini FR, Marzorati M, Musetti MC, Cazzullo CL. Significant association of HLA A2-DR11 with CD4 naive decrease in autistic children. Biomed Pharmacother. 2003;57:372–374
  19. Warren RP, Foster A, Mararetten NC. Reduced natural killer cell activity in autism. J Am Acad Child Adolesc Psychiatry. 1987;26:333–335
  20. Gupta S, Aggarwal S, Rashanravan B, Lee T. Th1 and Th2-like cytokines in CD4+ and CD8+ T cells in autism. J Neuroimmunol. 1998;85:106–109
  21. Engstrom AH, Ohlson S, Stubbs EG, Maciulus A, Caldwell V, Odell JD, et al. Decreased expression of CD95 (FAS/APO-1) on CD4+ T-lymphocytes from participants with autism. J Dev Phys Disabil. 2003;15:155–163
  22. Constantino JN, Lajonchere C, Lutz M, Gray T, Abbacchi A, McKenna K, et al. Autistic social impairment in the siblings of children with pervasive developmental disorders. Am J Psychiatry. 2006;163:294–296
  23. Constantino JN, Todd RD. Intergenerational transmission of subthreshold autistic traits in the general population. Biol Psychiatry. 2005;57:655–660
  24. Alarcón M, Yonan AL, Gilliam TC, Cantor RM, Geschwind DH. Quantitative genome scan and ordered-subsets analysis of autism endophenotypes support language QTLs. Mol Psychiatry. 2005;10:747–757
  25. Yirmiya N, Ozonoff S. The very early autism phenotype. J Aut Dev Disord. 2007;37:1–11
  26. Torres AR, Maciulis A, Stubbs EG, Cutler A, Odell D. The transmission disequilibrium test suggests that HLA-DR4 and DR13 are linked to autism spectrum disorder. Hum Immunol. 2002;63:311–322
  27. Lee LC, Zachary AA, Leffell MS, Newschaffer CJ, Matteson KJ, Tyler JD, et al. HLA-DR4 in families with autism. Pediatr Neurol. 2006;35:303–316
  28. Guerini FR, Manca S, Sotgiu S, Tremolada S, Zanzottera M, Agliardi C, et al. A family based linkage analysis of HLA and 5-HTTLPR gene polymorphisms in Sardinian children with autism spectrum disorder. Hum Immunol. 2006;67:108–120
  29. Nemni R, Fazio R, Quattrini A, Lorenzetti I, Mamoli D, Canal N. Antibodies to sulfatide and to chondroitin sulfate C in patients with chronic sensory neuropathy. J Neuroimmunol. 1993;43:79–86
  30. Ashwood P, Wills S, Van de Water J. The immune response in autism: A new frontier for autism research. J Leukoc Biol. 2006;80:1–15
  31. Singh VK. Plasma increase of interleukin-12 and interferon-gamma (Pathologic significance in autism). J Neuroimmunol. 1996;66:143–145
  32. Jyonouchi H, Sun S, Le H. Proinflammatory and regulatory cytokine production associated with innate and adaptive immune responses in children with autism spectrum disorders and developmental regression. J Neuroimmunol. 2001;120:170–179
  33. Croonenberghs J, Bosmans E, Deboutte D, Kenis G, Maes M. Activation of the inflammatory response system in autism. Nueropsycobiology. 2002;45:1–6
  34. Chez MG, Dowling T, Patel PB, Khanna P, Kominsky M. Elevation of tumor necrosis factor-alpha in cerebrospinal fluid of autistic children. Pediatr Neurol. 2007;36:361–365
  35. Ashwood P, Wakefield AJ. Immune activation of peripheral blood and mucosal CD3+ lymphocyte cytokine profiles in children with autism and gastrointestinal symptoms. J Neuroimmunol. 2006;173:126–134
  36. Snider LA, Swedo SE. Post-streptococcal autoimmune disorders of the central nervous system. Curr Opin Neurol. 2003;16:359–365
  37. Morris CM, Pardo-Villamizar C, Gause CD, Singer HS. Serum autoantibodies measured by immunofluorescence confirm a failure to differentiate PANDAS and Tourette syndrome from controls. J Neurol Sci. 2009;276:45–48
  38. Dantzer R, Kelley KW. Twenty years of research on cytokine-induced sickness behavior. Brain Behav Immun. 2007;21:153–160
  39. Sallusto F, Langenkamp A, Geginat J, Lanzavecchia A. Functional subsets of memory T cells identified by CCR7 expression. Curr Top Microbiol Immunol. 2000;251:167–171
  40. Geginat J, Sallusto F, Lanzavecchia A. Cytokine-driven proliferation and differentiation of human naive, central memory, and effector memory CD4(+) T cells. J Exp Med. 2001;194:1711–1719
  41. Sacco R, Militerni R, Frolli A, Bravaccio C, Gritti A, Elia M, et al. Clinical, morphological, and biochemical correlates of head circumference in autism. Biol Psychiatry. 2007;62:1038–1047
  42. Beasley R, Crane J. Head circumference at birth and the development of allergic disease–more questions than answers. Clin Exp Allerg. 2001;31:1804–1805
  43. Katz KA, Pocock AJ, Strachan DP. Neonatal head circumference, neonatal weight, and risk of hayfever, asthma and eczema in a large cohort of adolescents from Sheffield, England. Clin Exp Allerg. 2003;33:737–745
  44. Bernsen RM, de Jongste JC, Koes BW, Aardoom HA, van der Wouden JC. Perinatal characteristics and obstetric complications as risk factors for asthma, allergy and eczema at the age of 6 years. Clin Exp Allerg. 2005;35:1135–1140

PII: S0006-3223(09)00825-7

doi: 10.1016/j.biopsych.2009.06.020

Biological Psychiatry
Volume 66, Issue 10 , Pages 978-984 , 15 November 2009