Skip to main content
SpringerLink
Log in

Brief Report: Immune Factors in Autism: A Critical Review

  • Published:
Journal of Autism and Developmental Disorders Aims and scope Submit manuscript

Abstract

Pervasive developmental disorders represent a group of neurodevelopmental disorders that affect children early in their development. Autistic disorder is the best described of these disorders, yet even this term covers a broad group of clinical presentations. Various immune system abnormalities, including autoimmunity and defects in different subsets of immune cells, have been reported in children with autistic disorder, suggesting that immune factors may play a role in the development of autism. Based on anecdotal observation, vaccination was proposed to cause autism in some children, but several controlled studies have failed to support this claim. Intravenous immunoglobulin infusions has been tested as immunotherapy for autism, although the preliminary results are inconclusive and there is a risk of potentially fatal transmission of blood-borne pathogens. To examine this issue, intensive well-controlled epidemiological and bench studies need to be carried out in defined and carefully controlled study subjects to establish the cellular and molecular basis of autism, against which the effects of each proposed immune factor can be examined.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

REFERENCES

  • Abedi-Valugerdi, M., Hu, H., & Moller, G. (1997). Mercury-induced renal immune complex deposits in young (NZB × NZW)F1 mice: Characterization of antibodies/autoantibodies. Clinical and Experimental Immunology, 110, 86–91.

    Google Scholar 

  • Afzal, M. A., Minor, P. D., Ghosh, S., & Jin, L. (2001). Measles virus persistence in specimens of inflammatory bowel disease and autism cases. Digestive Diseases Science, 46, 658–660.

    Google Scholar 

  • Akashi, K., Nagasawa, K., Mayumi, T., Yokota, E., Oochi, N., & Kusaba, T. (1990). Successful treatment of refractory systemic lupus erythematosus with intravenous immunoglobulins. Journal of Rheumatology 17, 375–379.

    Google Scholar 

  • Ando, T., & Dunn, A. J. (1999). Mouse tumor necrosis factor-alpha increases brain tryptophan concentrations and norepinephrine metabolism while activating the HPA axis in mice. Neuroimmunomodulation, 6, 319–329.

    Google Scholar 

  • Arsura, E. L., Bick, A., Brunner, N. G., & Grob, D. (1988). Effects of repeated doses of intravenous immunoglobulin in myasthenia gravis. American Journal of Medicine and Science, 295, 438–443.

    Google Scholar 

  • Bagenstose, L. M., Salgame, P., & Monestier, M. (1999). Cytokine regulation of a rodent model of mercuric chloride-induced autoimmunity. Environmental Health Perspective, 107 Suppl 5, 807–810.

    Google Scholar 

  • Bagentose, L. M., Salgame, P., & Monestier, M. (1999). Murinemercury-induced autoimmunity: a model of chemically related autoimmunity in humans. Immunology Research, 20, 67–78.

    Google Scholar 

  • Berkman, S. A., Lee, M. L., & Gale, R. P. (1988). Clinical uses of intravenous immunoglobulins. Seminars in Hematology, 25, 140–158.

    Google Scholar 

  • Binstock, T. (2001). Intra-monocyte pathogens delineate autism subgroups. Medical Hypotheses, 56, 523–531.

    Google Scholar 

  • Bronstein, J. M., DeSalles, A., & DeLong, M. R. (1999). Stereotactic pallidotomy in the treatment of Parkinson disease: An expert opinion. Archives of Neurology, 56, 1064–1069.

    Google Scholar 

  • Carper, R. A., & Courchesne, E. (2000). Inverse correlation between frontal lobe and cerebellum sizes in children with autism. Brain, 123, 836–844.

    Google Scholar 

  • Chadwick, N., Bruce, I. J., Schepelmann, S., Pounder, R. E., & Wakefield, A. J. (1998). Measles virus RNA is not detected in inflammatory bowel disease using hybrid capture and reverse transcription followed by the polymerase chain reaction. Journal of Medical Virology, 55, 305–311.

    Google Scholar 

  • Cohen, A. D., & Shoenfeld, Y. (1996). Vaccine-induced autoimmunity. Journal Autoimmunology, 9, 699–703.

    Google Scholar 

  • Comi, A. M., Zimmerman, A. W., Frye, V. H., Law, P. A., & Peeden, J. N. (1999). Familial clustering of autoimmune disorders and evaluation of medical risk factors in autism. Journal of Child Neurology, 14, 388–394.

    Google Scholar 

  • Connolly, A. M., Chez, M. G., Pestronk, A., Arnold, S. T., Mehta, S., & Deuel, R. K. (1999). Serum autoantibodies to brain in Landau-Kleffner variant, autism, and other neurologic disorders. Journal of Pediatrics, 134, 607–613.

    Google Scholar 

  • Cook, E. H., Jr., Perry, B. D., Dawson, G., Wainwright, M. S., & Leventhal, B. L. (1993). Receptor inhibition by immunoglobulins: Specific inhibition by autistic children, their relatives, and control subjects. Journal of Autism and Developmental Disorders, 23, 67–78.

    Google Scholar 

  • Deb, S., & Thompson, B. (1998). Neuroimaging in autism. British Journal of Psychiatry, 173, 299–302.

    Google Scholar 

  • DelGiudice-Asch, G., Simon, L., Schmeidler, J., Cunningham-Rundles, C., & Hollander, E. (1999). Brief report: A pilot open clinical trial of intravenous immunoglobulin in childhood autism. Journal of Autism and Developmental Disorders, 29, 157–160.

    Google Scholar 

  • Dunn, A. J., Wang, J., & Ando, T. (1999). Effects of cytokines on cerebral neurotransmission: Comparison with the effects of stress. Advances in Experimental Medicine and Biology, 461, 117–127.

    Google Scholar 

  • Field, E. J., Caspary, E. A., & Carnegie, P. R. (1971). Lymphocyte sensitization to basic protein of brain in malignant neoplasia: Experiments with serotonin and related compounds. Nature, 233, 284–286.

    Google Scholar 

  • Goto, M., Tanimoto, K., Chihara, T., & Horiuchi, Y. (1981). Natural cell-mediated cytotoxicity in Sjogren's syndrome and rheumatoid arthritis. Arthritis and Rheumatology, 24, 1377–1382.

    Google Scholar 

  • Goto, M., Tanimoto, K., & Horiuchi, Y. (1980). Natural cell mediated cytotoxicity in systemic lupus erythematosus: suppression by antilymphocyte antibody. Arthritis and Rheumatology, 23, 1274–1281.

    Google Scholar 

  • Gross, K., Combe, C., Kruger, K., & Schattenkirchner, M. (1995). Arthritis after hepatitis B vaccination. Report of three cases. Scandinavian Journal of Rheumatology, 24, 50–52.

    Google Scholar 

  • Gupta, S., Aggarwal, S., & Heads, C. (1996). Dysregulated immune system in children with autism: Beneficial effects of intravenous immune globulin on autistic characteristics. Journal of Autism and Developmental Disorders, 26, 439–452.

    Google Scholar 

  • Gupta, S., Aggarwal, S., Rashanravan, B., & Lee, T. (1998). Th1-and Th2-like cytokines in CD4+ and CD8+ T cells in autism. Journal of Neuroimmunology, 85, 106–109.

    Google Scholar 

  • Haraoui, B., Strand, V., & Keystone, E. (2000). Biologic agents in the treatment of rheumatoid arthritis. Current Pharmacology and Biotechnology, 1, 217–233.

    Google Scholar 

  • Hardan, A. Y., Minshew, N. J., Mallikarjuhn, M., & Keshavan, M. S.(2001). Brain volume in autism. Journal of Child Neurology, 16, 421–424.

    Google Scholar 

  • Hemmerich, P., Neu, E., Macht, M., Peter, H. H., Krawinkel, U., & von Mikecz, A. (1998). Correlation between chlamydial infection and autoimmune response: Molecular mimicry between RNA polymerase major sigma subunit from Chlamydia trachomatis and human L7. European Journal of Immunology, 28, 3857–3866.

    Google Scholar 

  • Horwitz, D. A., Gray, J. D., Ohtsuka, K., Hirokawa, M., & Takahashi, T. (1997). The immunoregulatory effects of NK cells: the role of TGF-beta and implications for autoimmunity. Immunology Today, 18, 538–542.

    Google Scholar 

  • Hu, H., Abedi-Valugerdi, M., & Moller, G. (1997). Pretreatment of lymphocytes with mercury in vitro induces a response in T cells from genetically determined low-responders and a shift of the interleukin profile. Immunology, 90, 198–204.

    Google Scholar 

  • Hultman, P., Lindh, U., & Horsted-Bindslev, P. (1998). Activation of the immune system and systemic immune-complex deposits in Brown Norway rats with dental amalgam restorations. Journal of Dental Research, 77, 1415–1425.

    Google Scholar 

  • Ilback, N. G. (1991). Effects of methyl mercury exposure on spleen and blood natural killer (NK) cell activity in the mouse. Toxicology, 67, 117–124.

    Google Scholar 

  • Jayne, D. R., Davies, M. J., Fox, C. J., Black, C. M., & Lockwood, C. M. (1991). Treatment of systemic vasculitis with pooled intravenous immunoglobulin. Lancet, 337, 1137–1139.

    Google Scholar 

  • Johansson, U., Hansson-Georgiadis, H., & Hultman, P. (1998). The genotype determines the B cell response in mercury-treated mice. International Archives of Allergy and Immunology, 116, 295–305.

    Google Scholar 

  • Kawashima, H., Mori, T., Kashiwagi, Y., Takekuma, K., Hoshika, A., & Wakefield, A. (2000). Detection and sequencing of measles virus from peripheral mononuclear cells from patients with inflammatory bowel disease and autism. Digestive Diseases Science, 45, 723–729.

    Google Scholar 

  • Kaye, J. A., del Mar Melero-Montes, M., & Jick, H. (2001). Mumps, measles, and rubella vaccine and the incidence of autism recorded by general practitioners: A time trend analysis. British Medical Journal, 322, 460–463.

    Google Scholar 

  • Kowal, C., Weinstein, A., & Diamond, B. (1999). Molecular mimicry between bacterial and self antigen in a patient with systemic lupus erythematosus. European Journal of Immunology, 29, 1901–1911.

    Google Scholar 

  • Krause, I., Hacham, S., Gilburd, B., Damianovitch, M., Blank, M., & Shoenfeld, Y. (1995). Absence of anti-idiotypic antibodies in IVIG preparations to autoantibodies of rare autoimmune diseases. Clinical Immunology Immunopathology, 77, 229–235.

    Google Scholar 

  • Levy, Y., Sherer, Y., Ahmed, A., Langevitz, P., George, J., Fabbrizzi, F., Terryberry, J., Meissner, M., Lorber, M., Peter, J. B., & Shoenfeld, Y. (1999). A study of 20 SLE patients with intravenous immunoglobulin—clinical and serologic response. Lupus, 8, 705–712.

    Google Scholar 

  • Lilic, D., & Ghosh, S. K. (1994). Liver dysfunction and DNA antibodies after hepatitis B vaccination. Lancet, 344, 1292–1293.

    Google Scholar 

  • Mackay, I. R., Van de Water, J., & Gershwin, M. E. (2000). Autoimmunity. Thoughts for the millennium. Clinical Reviews of Allergy and Immunology, 18, 87–117.

    Google Scholar 

  • Matthys, P., Vermeire, K., & Billiau, A. (2001). Mac-1(+) myelopoiesis induced by CFA: a clue to the paradoxical effects of IFN-gamma in autoimmune disease models. Trends in Immunology, 22, 367–371.

    Google Scholar 

  • Nicoll, A., Elliman, D., & Ross, E. (1998). MMR vaccination and autism 1998. British Medical Journal, 316, 715–716.

    Google Scholar 

  • Nieminen, U., Peltola, H., Syrjala, M. T., Makipernaa, A., & Kekomaki, R. (1993). Acute thrombocytopenic purpura following measles, mumps and rubella vaccination. A report on 23 patients. Acta Paediatrics, 82, 267–270.

    Google Scholar 

  • Parke, A. (1992). The role of IVIG in the management of patients with antiphospholipid antibodies and recurrent pregnancy losses. Clinical Review of Allergy, 10, 105–118.

    Google Scholar 

  • Peltola, H., Patja, A., Leinikki, P., Valle, M., Davidkin, I., & Paunio, M. (1998). No evidence for measles, mumps, and rubella vaccine-associated inflammatory bowel disease or autism in a 14-year prospective study. Lancet, 351, 1327–1328.

    Google Scholar 

  • Plioplys, A. V. (1998). Intravenous immunoglobulin treatment of children with autism. Journal of Children Neurology, 13, 79–82.

    Google Scholar 

  • Plioplys, A. V., Greaves, A., Kazemi, K., & Silverman, E. (1994). Lymphocyte function in autism and Rett syndrome. Neuropsychobiology, 29, 12–16.

    Google Scholar 

  • Plioplys, A. V., Greaves, A., & Yoshida, W. (1989). Anti-CNS antibodies in childhood neurologic diseases. Neuropediatrics, 20, 93–102.

    Google Scholar 

  • Rapin, I. (1997). Autism. New England Journal of Medicine, 337, 97–104.

    Google Scholar 

  • Risch, N., Spiker, D., Lotspeich, L., Nouri, N., Hinds, D., Hallmayer, J., Kalaydjieva, L., McCague, P., Dimiceli, S., Pitts, T., Nguyen, L., Yang, J., Harper, C., Thorpe, D., Vermeer, S., Young, H., Hebert, J., Lin, A., Ferguson, J., Chiotti, C., Wiese-Slater, S., Rogers, T., Salmon, B., Nicholas, P., Petersen, P. B., Pingree, C., McMahon, W., Wong, D. L., Cavalli-Sforza, L. L., Kraemer, H. C., & Myers, R. M. (1999). A genomic screen of autism: Evidence for a multilocus etiology. American Journal of Human Genetics, 65, 493–507.

    Google Scholar 

  • Romagnani, S. (1995). Biology of human TH1 and TH2 cells. Journal of Clinical Immunology, 15, 121–129.

    Google Scholar 

  • Rose, N. R., & Bona, C. (1993). Defining criteria for autoimmune diseases (Witebsky's postulates revisited). Immunology Today, 14, 426–430.

    Google Scholar 

  • Rossi, F., & Legras, J. F. (2000). [Viral safety: European and French directives]. Annales Medecine Interne (Paris), 151 Suppl 1, S55–S61.

    Google Scholar 

  • Rumsey, J. M., & Ernst, M. (2000). Functional neuroimaging of autistic disorders. Mentally Retarded Developmental Disabilities Research and Review, 6, 171–179.

    Google Scholar 

  • Shoenfeld, Y. (1994). Idiotypic induction of autoimmunity: a new aspect of the idiotypic network. FASEB Journal, 8, 1296–1301.

    Google Scholar 

  • Shoenfeld, Y., & Aron-Maor, A. (2000). Vaccination and autoimmunity-'vaccinosis': a dangerous liaison? Journal of Autoimmunity, 14, 1–10.

    Google Scholar 

  • Singh, V. K., Fudenberg, H. H., Emerson, D., & Coleman, M. (1988). Immunodiagnosis and immunotherapy in autistic children. Annals of New York Academy of Science, 540, 602–604.

    Google Scholar 

  • Singh, V. K., Lin, S. X., & Yang, V. C. (1998). Serological association of measles virus and human herpesvirus-6 with brain autoantibodies in autism. Clinical Immunology Immunopathology, 89, 105–108.

    Google Scholar 

  • Singh, V. K., Singh, E. A., & Warren, R. P. (1997). Hyperserotoninemia and serotonin receptor antibodies in children with autism but not mental retardation. Biological Psychiatry, 41,753–755.

    Google Scholar 

  • Singh, V. K., Warren, R. P., Odell, J. D., Warren, W. L., & Cole, P. (1993). Antibodies to myelin basic protein in children with autistic behavior. Brain Behavioral Immunology, 7, 97–103.

    Google Scholar 

  • Smeeth, L., Hall, A. J., Fombonne, E., Rodrigues, L. C., Huang, X., & Smith, P. G. (2001). A case-control study of autism and mumps-measles-rubella vaccination using the general practice research database: design and methodology. BMC Public Health, 1, 2.

    Google Scholar 

  • Strauss, B., & Bigham, M. (2001). Does measles-mumps-rubella (MMR) vaccination cause inflammatory bowel disease and autism? Can Commun Dis Rep, 27, 65–72.

    Google Scholar 

  • Stubbs, E. G. (1976). Autistic children exhibit undetectable hemagglutination-inhibition antibody titers despite previous rubella vaccination. Journal of Autism and Childhood Schizophrenia, 6, 269–274.

    Google Scholar 

  • Stubbs, E. G., & Crawford, M. L. (1977). Depressed lymphocyte responsiveness in autistic children. Journal of Autism and Childhood Schizophrenia, 7, 49–55.

    Google Scholar 

  • Taylor, B., Miller, E., Farrington, C. P., Petropoulos, M. C., Favot-Mayaud, I., Li, J., & Waight, P. A. (1999). Autism and measles, mumps, and rubella vaccine: no epidemiological evidence for a causal association. Lancet, 353, 2026–2029.

    Google Scholar 

  • Todd, R. D., & Ciaranello, R. D. (1985). Demonstration of inter-and intraspecies differences in serotonin binding sites by antibodies from an autistic child. Proceedings of National Academy of Science of the United States of America, 82, 612–616.

    Google Scholar 

  • Tomer, Y., & Shoenfeld, Y. (1992). Successful treatment of psychosis secondary to SLE with high dose intravenous immunoglobulin. Clinical Experimental Rheumatology, 10, 391–393.

    Google Scholar 

  • Trottier, G., Srivastava, L., & Walker, C. D. (1999). Etiology of infantile autism: a review of recent advances in genetic and neurobiological research. Journal of Psychiatry and Neuroscience, 24, 103–115.

    Google Scholar 

  • Tudela, P., Marti, S., & Bonal, J. (1992). Systemic lupus erythematosus and vaccination against hepatitis B. Nephron, 62, 236.

    Google Scholar 

  • Wakefield, A. J., Anthony, A., Murch, S. H., Thomson, M., Montgomery, S. M., Davies, S., O'Leary, J. J., Berelowitz, M., & Walker-Smith, J. A. (2000). Enterocolitis in children with developmental disorders. American Journal of Gastroenterology, 95, 2285–2295.

    Google Scholar 

  • Wakefield, A. J., Murch, S. H., Anthony, A., Linnell, J., Casson, D. M., Malik, M., Berelowitz, M., Dhillon, A. P., Thomson, M. A., Harvey, P., Valentine, A., Davies, S. E., & Walker-Smith, J. A. (1998). Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. Lancet, 351, 637–641.

    Google Scholar 

  • Wakefield, A. J., Pittilo, R. M., Sim, R., Cosby, S. L., Stephenson, J. R., Dhillon, A. P., & Pounder, R. E. (1993). Evidence of persistent measles virus infection in Crohn's disease. Journal of Medical Virology, 39, 345–353.

    Google Scholar 

  • Warren, R. P., Foster, A., & Margaretten, N. C. (1987). Reduced natural killer cell activity in autism. Journal of the American Academy of Child and Adolescent Psychiatry, 26, 333–335.

    Google Scholar 

  • Warren, R. P., Margaretten, N. C., Pace, N. C., & Foster, A. (1986). Immune abnormalities in patients with autism. Journal of Autism and Developmental Disorders, 16, 189–197.

    Google Scholar 

  • Warren, R. P., Odell, J. D., Warren, W. L., Burger, R. A., Maciulis, A., Daniels, W. W., & Torres, A. R. (1996). Strong association of the third hypervariable region of HLA-DR beta 1 with autism. Journal of Neuroimmunology, 67, 97–102.

    Google Scholar 

  • Warren, R. P., & Singh, V. K. (1996). Elevated serotonin levels in autism: association with the major histocompatibility complex. Neuropsychobiology, 34, 72–75.

    Google Scholar 

  • Warren, R. P., Singh, V. K., Averett, R. E., Odell, J. D., Maciulis, A., Burger, R. A., Daniels, W. W., & Warren, W. L. (1996). Immunogenetic studies in autism and related disorders. Molecular and Chemical Neuropathology, 28, 77–81.

    Google Scholar 

  • Warren, R. P., Yonk, J., Burger, R. W., Odell, D., & Warren, W. L. (1995). DR-positive T cells in autism: association with decreased plasma levels of the complement C4B protein. Neuropsychobiology, 31, 53–57.

    Google Scholar 

  • Warren, R. P., Yonk, L. J., Burger, R. A., Cole, P., Odell, J. D., Warren, W. L., White, E., & Singh, V. K. (1990). Deficiency of suppressor-inducer (CD4+CD45RA+) T cells in autism. Immunological Investigations, 19, 245–251.

    Google Scholar 

  • Westall, F. C., & Root-Bernstein, R. S. (1983). Suggested connection between autism, serotonin, and myelin basic protein. American Journal of Psychiatry, 140, 1260–1261.

    Google Scholar 

  • Yuwiler, A., Shih, J. C., Chen, C. H., Ritvo, E. R., Hanna, G., Ellison, G. W., & King, B. H. (1992). Hyperserotoninemia and antiserotonin antibodies in autism and other disorders. Journal of Autism and Developmental Disorders, 22, 33–45.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Research Unit of Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, and the Sackler Faculty of Medicine, Tel-Aviv University, Israel

    Ilan Krause & Yehuda Shoenfeld

  2. The Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, Davis, CA, 95616

    Xiao-Song He & M. Eric Gershwin

Authors
  1. Ilan Krause
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiao-Song He
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. Eric Gershwin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yehuda Shoenfeld
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yehuda Shoenfeld.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Krause, I., He, XS., Gershwin, M.E. et al. Brief Report: Immune Factors in Autism: A Critical Review. J Autism Dev Disord 32, 337–345 (2002). https://doi.org/10.1023/A:1016391121003

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1016391121003

Search

Navigation