[go: up one dir, main page]
Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Passive transfer of streptococcus-induced antibodies reproduces behavioral disturbances in a mouse model of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection

Molecular Psychiatry volume 15, pages 712–726 (2010)Cite this article

Abstract

Streptococcal infections can induce obsessive-compulsive and tic disorders. In children, this syndrome, frequently associated with disturbances in attention, learning and mood, has been designated pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS). Autoantibodies recognizing central nervous system (CNS) epitopes are found in sera of most PANDAS subjects, but may not be unique to this neuropsychiatric subset. In support of a humoral immune mechanism, clinical improvement often follows plasmapheresis or intravenous immunoglobulin. We recently described a PANDAS mouse model wherein repetitive behaviors correlate with peripheral anti-CNS antibodies and immune deposits in brain following streptococcal immunization. These antibodies are directed against group A β-hemolytic streptococcus matrix (M) protein and cross-react with molecular targets complement C4 protein and α-2-macroglobulin in brain. Here we show additional deficits in motor coordination, learning/memory and social interaction in PANDAS mice, replicating more complex aspects of human disease. Furthermore, we demonstrate for the first time that humoral immunity is necessary and sufficient to induce the syndrome through experiments wherein naive mice are transfused with immunoglobulin G (IgG) from PANDAS mice. Depletion of IgG from donor sera abrogates behavior changes. These functional disturbances link to the autoimmunity-related IgG1 subclass but are not attributable to differences in cytokine profiles. The mode of disrupting blood–brain barrier integrity differentially affects the ultimate CNS distribution of these antibodies and is shown to be an additional important determinant of neuropsychiatric outcomes. This work provides insights into PANDAS pathogenesis and may lead to new strategies for identification and treatment of children at risk for autoimmune brain disorders.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9

Similar content being viewed by others

References

  1. Trifiletti RR, Packard AM . Immune mechanisms in pediatric neuropsychiatric disorders. Tourette's syndrome, OCD, and PANDAS. Child Adolesc Psychiatr Clin N Am 1999; 8: 767–775.

    Article  CAS  PubMed  Google Scholar 

  2. da Rocha FF, Correa H, Teixeira AL . Obsessive-compulsive disorder and immunology: a review. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32: 1139–1146.

    Article  CAS  PubMed  Google Scholar 

  3. Pavone P, Parano E, Rizzo R, Trifiletti RR . Autoimmune neuropsychiatric disorders associated with streptococcal infection: Sydenham chorea, PANDAS, and PANDAS variants. J Child Neurol 2006; 21: 727–736.

    Article  PubMed  Google Scholar 

  4. Hoekstra PJ, Minderaa RB . Tic disorders and obsessive-compulsive disorder: is autoimmunity involved? Int Rev Psychiatry 2005; 17: 497–502.

    Article  PubMed  Google Scholar 

  5. Hornig M, Lipkin WI . Infectious and immune factors in the pathogenesis of neurodevelopmental disorders: epidemiology, hypotheses, and animal models. Ment Retard Dev Disabil Res Rev 2001; 7: 200–210.

    Article  CAS  PubMed  Google Scholar 

  6. Maia DP, Teixeira Jr AL, Quintao Cunningham MC, Cardoso F . Obsessive compulsive behavior, hyperactivity, and attention deficit disorder in Sydenham chorea. Neurology 2005; 64: 1799–1801.

    Article  PubMed  Google Scholar 

  7. Goldenberg J, Ferraz MB, Fonseca AS, Hilario MO, Bastos W, Sachetti S . Sydenham chorea: clinical and laboratory findings. Analysis of 187 cases. Rev Paul Med 1992; 110: 152–157.

    CAS  PubMed  Google Scholar 

  8. Swedo SE, Leonard HL, Mittleman BB, Allen AJ, Rapoport JL, Dow SP et al. Identification of children with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections by a marker associated with rheumatic fever. Am J Psychiatry 1997; 154: 110–112.

    Article  CAS  PubMed  Google Scholar 

  9. Swedo SE, Leonard HL, Garvey M, Mittleman B, Allen AJ, Perlmutter S et al. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases. Am J Psychiatry 1998; 155: 264–271.

    CAS  PubMed  Google Scholar 

  10. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th edn. Text Revision (DSM-IV-TR) American Psychiatric Press: Washington, DC, 1994.

  11. Hirschtritt ME, Hammond CJ, Luckenbaugh D, Buhle J, Thurm AE, Casey BJ et al. Executive and attention functioning among children in the PANDAS subgroup. Child Neuropsychol 2008; 1: 1–16.

    Google Scholar 

  12. Kerbeshian J, Burd L, Tait A . Chain reaction or time bomb: a neuropsychiatric-developmental/neurodevelopmental formulation of tourettisms, pervasive developmental disorder, and schizophreniform symptomatology associated with PANDAS. World J Biol Psychiatry 2007; 8: 201–207.

    Article  PubMed  Google Scholar 

  13. Calkin CV, Carandang CG . Certain eating disorders may be a neuropsychiatric manifestation of PANDAS: case report. J Can Acad Child Adolesc Psychiatry 2007; 16: 132–135.

    PubMed Central  PubMed  Google Scholar 

  14. Peterson BS, Leckman JF, Tucker D, Scahill L, Staib L, Zhang H et al. Preliminary findings of antistreptococcal antibody titers and basal ganglia volumes in tic, obsessive-compulsive, and attention deficit/hyperactivity disorders. Arch Gen Psychiatry 2000; 57: 364–372.

    Article  CAS  PubMed  Google Scholar 

  15. Sokol MS . Infection-triggered anorexia nervosa in children: clinical description of four cases. J Child Adolesc Psychopharmacol 2000; 10: 133–145.

    Article  CAS  PubMed  Google Scholar 

  16. Sokol MS, Ward PE, Tamiya H, Kondo DG, Houston D, Zabriskie JB . D8/17 expression on B lymphocytes in anorexia nervosa. Am J Psychiatry 2002; 159: 1430–1432.

    Article  PubMed  Google Scholar 

  17. Leslie DL, Kozma L, Martin A, Landeros A, Katsovich L, King RA et al. Neuropsychiatric disorders associated with streptococcal infection: a case–control study among privately insured children. J Am Acad Child Adolesc Psychiatry 2008; 47: 1166–1172.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Hollander E, DelGiudice-Asch G, Simon L, Schmeidler J, Cartwright C, DeCaria CM et al. B lymphocyte antigen D8/17 and repetitive behaviors in autism. Am J Psychiatry 1999; 156: 317–320.

    CAS  PubMed  Google Scholar 

  19. Margutti P, Delunardo F, Ortona E . Autoantibodies associated with psychiatric disorders. Curr Neurovasc Res 2006; 3: 149–157.

    Article  CAS  PubMed  Google Scholar 

  20. Singer HS, Loiselle CR, Lee O, Minzer K, Swedo S, Grus FH . Anti-basal ganglia antibodies in PANDAS. Mov Disord 2004; 19: 406–415.

    Article  PubMed  Google Scholar 

  21. Pavone P, Bianchini R, Parano E, Incorpora G, Rizzo R, Mazzone L et al. Anti-brain antibodies in PANDAS versus uncomplicated streptococcal infection. Pediatr Neurol 2004; 30: 107–110.

    Article  PubMed  Google Scholar 

  22. Martino D, Church A, Giovannoni G . Are antibasal ganglia antibodies important, and clinically useful? Pract Neurol 2007; 7: 32–41.

    PubMed  Google Scholar 

  23. Dale RC . Post-streptococcal autoimmune disorders of the central nervous system. Dev Med Child Neurol 2005; 47: 785–791.

    Article  PubMed  Google Scholar 

  24. Bronze MS, Dale JB . Epitopes of streptococcal M proteins that evoke antibodies that cross-react with human brain. J Immunol 1993; 151: 2820–2828.

    CAS  PubMed  Google Scholar 

  25. Kirvan CA, Swedo SE, Heuser JS, Cunningham MW . Mimicry and autoantibody-mediated neuronal cell signaling in Sydenham chorea. Nat Med 2003; 9: 914–920.

    Article  CAS  PubMed  Google Scholar 

  26. Swedo SE, Garvey M, Snider L, Hamilton C, Leonard HL . The PANDAS subgroup: recognition and treatment. CNS Spectr 2001; 6: 419–422, 425–416.

    Article  CAS  PubMed  Google Scholar 

  27. Snider LA, Lougee L, Slattery M, Grant P, Swedo SE . Antibiotic prophylaxis with azithromycin or penicillin for childhood-onset neuropsychiatric disorders. Biol Psychiatry 2005; 57: 788–792.

    Article  CAS  PubMed  Google Scholar 

  28. Hoffman KL, Hornig M, Yaddanapudi K, Jabado O, Lipkin WI . A murine model for neuropsychiatric disorders associated with group A beta-hemolytic streptococcal infection. J Neurosci 2004; 24: 1780–1791.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kowal C, Degiorgio LA, Lee JY, Edgar MA, Huerta PT, Volpe BT et al. Human lupus autoantibodies against NMDA receptors mediate cognitive impairment. Proc Natl Acad Sci USA 2006; 103: 19854–19859.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kowal C, DeGiorgio LA, Nakaoka T, Hetherington H, Huerta PT, Diamond B et al. Cognition and immunity; antibody impairs memory. Immunity 2004; 21: 179–188.

    Article  CAS  PubMed  Google Scholar 

  31. Nonaka N, Hileman SM, Shioda S, Vo TQ, Banks WA . Effects of lipopolysaccharide on leptin transport across the blood–brain barrier. Brain Res 2004; 1016: 58–65.

    Article  CAS  PubMed  Google Scholar 

  32. Banks WA, Kastin AJ, Brennan JM, Vallance KL . Adsorptive endocytosis of HIV-1gp120 by blood–brain barrier is enhanced by lipopolysaccharide. Exp Neurol 1999; 156: 165–171.

    Article  CAS  PubMed  Google Scholar 

  33. Xaio H, Banks WA, Niehoff ML, Morley JE . Effect of LPS on the permeability of the blood–brain barrier to insulin. Brain Res 2001; 896: 36–42.

    Article  CAS  PubMed  Google Scholar 

  34. Wispelwey B, Lesse AJ, Hansen EJ, Scheld WM . Haemophilus influenzae lipopolysaccharide-induced blood brain barrier permeability during experimental meningitis in the rat. J Clin Invest 1988; 82: 1339–1346.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Vekovischeva OY, Aitta-Aho T, Echenko O, Kankaanpaa A, Seppala T, Honkanen A et al. Reduced aggression in AMPA-type glutamate receptor GluR-A subunit-deficient mice. Genes Brain Behav 2004; 3: 253–265.

    Article  CAS  PubMed  Google Scholar 

  36. Nicot A, Otto T, Brabet P, Dicicco-Bloom EM . Altered social behavior in pituitary adenylate cyclase-activating polypeptide type I receptor-deficient mice. J Neurosci 2004; 24: 8786–8795.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Gheusi G, Cremer H, McLean H, Chazal G, Vincent JD, Lledo PM . Importance of newly generated neurons in the adult olfactory bulb for odor discrimination. Proc Natl Acad Sci USA 2000; 97: 1823–1828.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Douma BR, Korte SM, Buwalda B, la Fleur SE, Bohus B, Luiten PG . Repeated blockade of mineralocorticoid receptors, but not of glucocorticoid receptors impairs food rewarded spatial learning. Psychoneuroendocrinology 1998; 23: 33–44.

    Article  CAS  PubMed  Google Scholar 

  39. Packard MG, McGaugh JL . Inactivation of hippocampus or caudate nucleus with lidocaine differentially affects expression of place and response learning. Neurobiol Learn Mem 1996; 65: 65–72.

    Article  CAS  PubMed  Google Scholar 

  40. Mandolesi L, Leggio MG, Graziano A, Neri P, Petrosini L . Cerebellar contribution to spatial event processing: involvement in procedural and working memory components. Eur J Neurosci 2001; 14: 2011–2022.

    Article  CAS  PubMed  Google Scholar 

  41. Kesner RP . Behavioral analysis of the contribution of the hippocampus and parietal cortex to the processing of information: interactions and dissociations. Hippocampus 2000; 10: 483–490.

    Article  CAS  PubMed  Google Scholar 

  42. Downen M, Amaral TD, Hua LL, Zhao ML, Lee SC . Neuronal death in cytokine-activated primary human brain cell culture: role of tumor necrosis factor-alpha. Glia 1999; 28: 114–127.

    Article  CAS  PubMed  Google Scholar 

  43. Church AJ, Dale RC, Cardoso F, Candler PM, Chapman MD, Allen ML et al. CSF and serum immune parameters in Sydenham's chorea: evidence of an autoimmune syndrome? J Neuroimmunol 2003; 136: 149–153.

    Article  CAS  PubMed  Google Scholar 

  44. Husby G, Forre O, Williams Jr RC . IgG subclass, variable H-chain subgroup, and light chain-type composition of antineuronal antibody in Huntington's disease and Sydenham's chorea. Clin Immunol Immunopathol 1979; 14: 361–367.

    Article  CAS  PubMed  Google Scholar 

  45. Huerta PT, Kowal C, DeGiorgio LA, Volpe BT, Diamond B . Immunity and behavior: antibodies alter emotion. Proc Natl Acad Sci USA 2006; 103: 678–683.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. DeGiorgio LA, Konstantinov KN, Lee SC, Hardin JA, Volpe BT, Diamond B . A subset of lupus anti-DNA antibodies cross-reacts with the NR2 glutamate receptor in systemic lupus erythematosus. Nat Med 2001; 7: 1189–1193.

    Article  CAS  PubMed  Google Scholar 

  47. Husby G, van de Rijn I, Zabriskie JB, Ardin ZH, Williams Jr RC . Anti-neuronal antibody in Sydenham's chorea. Lancet 1977; 1: 1208.

    Article  CAS  PubMed  Google Scholar 

  48. Kirvan CA, Swedo SE, Snider LA, Cunningham MW . Antibody-mediated neuronal cell signaling in behavior and movement disorders. J Neuroimmunol 2006; 179: 173–179.

    Article  CAS  PubMed  Google Scholar 

  49. Dale RC . Autoimmunity and the basal ganglia: new insights into old diseases. QJM 2003; 96: 183–191.

    Article  CAS  PubMed  Google Scholar 

  50. Heath RG, McCarron KL, O’Neil CE . Antiseptal brain antibody in IgG of schizophrenic patients. Biol Psychiatry 1989; 25: 725–733.

    Article  CAS  PubMed  Google Scholar 

  51. Henneberg AE, Horter S, Ruffert S . Increased prevalence of antibrain antibodies in the sera from schizophrenic patients. Schizophr Res 1994; 14: 15–22.

    Article  CAS  PubMed  Google Scholar 

  52. Silva SC, Correia C, Fesel C, Barreto M, Coutinho AM, Marques C et al. Autoantibody repertoires to brain tissue in autism nuclear families. J Neuroimmunol 2004; 152: 176–182.

    Article  CAS  PubMed  Google Scholar 

  53. 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.

    Article  CAS  PubMed  Google Scholar 

  54. van Praag H, Schinder AF, Christie BR, Toni N, Palmer TD, Gage FH . Functional neurogenesis in the adult hippocampus. Nature 2002; 415: 1030–1034.

    Article  CAS  PubMed  Google Scholar 

  55. Gabbay V, Coffey BJ, Babb JS, Meyer L, Wachtel C, Anam S et al. Pediatric autoimmune neuropsychiatric disorders associated with streptococcus: comparison of diagnosis and treatment in the community and at a specialty clinic. Pediatrics 2008; 122: 273–278.

    Article  PubMed  Google Scholar 

  56. Comings DE, Comings BG . Clinical and genetic relationships between autism-pervasive developmental disorder and Tourette syndrome: a study of 19 cases. Am J Med Genet 1991; 39: 180–191.

    Article  CAS  PubMed  Google Scholar 

  57. Buxbaum JD, Silverman J, Keddache M, Smith CJ, Hollander E, Ramoz N et al. Linkage analysis for autism in a subset families with obsessive-compulsive behaviors: evidence for an autism susceptibility gene on chromosome 1 and further support for susceptibility genes on chromosome 6 and 19. Mol Psychiatry 2004; 9: 144–150.

    Article  CAS  PubMed  Google Scholar 

  58. Lougee L, Perlmutter SJ, Nicolson R, Garvey MA, Swedo SE . Psychiatric disorders in first-degree relatives of children with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). J Am Acad Child Adolesc Psychiatry 2000; 39: 1120–1126.

    Article  CAS  PubMed  Google Scholar 

  59. Martino D, Giovannoni G . Autoaggressive immune-mediated movement disorders. Adv Neurol 2005; 96: 320–335.

    PubMed  Google Scholar 

  60. Wills A, Dale R, Giovannoni G . Gluten ataxia and post-streptococcal central nervous system syndromes: emerging immune-mediated disorders of the central nervous system? Curr Treat Options Neurol 2005; 7: 183–189.

    Article  PubMed  Google Scholar 

  61. Guillot PV, Roubertoux PL, Crusio WE . Hippocampal mossy fiber distributions and intermale aggression in seven inbred mouse strains. Brain Res 1994; 660: 167–169.

    Article  CAS  PubMed  Google Scholar 

  62. Crawley JN . Mouse behavioral assays relevant to the symptoms of autism. Brain Pathol 2007; 17: 448–459.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Esposito P, Chandler N, Kandere K, Basu S, Jacobson S, Connolly R et al. Corticotropin-releasing hormone and brain mast cells regulate blood-brain-barrier permeability induced by acute stress. J Pharmacol Exp Ther 2002; 303: 1061–1066.

    Article  CAS  PubMed  Google Scholar 

  64. Carvey PM, Zhao CH, Hendey B, Lum H, Trachtenberg J, Desai BS et al. 6-Hydroxydopamine-induced alterations in blood–brain barrier permeability. Eur J Neurosci 2005; 22: 1158–1168.

    Article  CAS  PubMed  Google Scholar 

  65. Kuang F, Wang BR, Zhang P, Fei LL, Jia Y, Duan XL et al. Extravasation of blood-borne immunoglobulin G through blood–brain barrier during adrenaline-induced transient hypertension in the rat. Int J Neurosci 2004; 114: 575–591.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Vishal Kapoor and Kelly Betz for technical assistance. This work was supported by a Young Investigator Award to KY from the National Alliance for Research on Schizophrenia and Depression (NARSAD; mentor, WIL) and a donation to MH from Joan and George Hornig.

Author information

Author notes

  1. K Yaddanapudi and M Hornig: These authors contributed equally to this work.

Authors and Affiliations

  1. Center for Infection and Immunity and Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA

    K Yaddanapudi, M Hornig, R Serge, J De Miranda, A Baghban, G Villar & W I Lipkin

Authors
  1. K Yaddanapudi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Hornig
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R Serge
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J De Miranda
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A Baghban
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. G Villar
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. W I Lipkin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M Hornig.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Molecular Psychiatry website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yaddanapudi, K., Hornig, M., Serge, R. et al. Passive transfer of streptococcus-induced antibodies reproduces behavioral disturbances in a mouse model of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection. Mol Psychiatry 15, 712–726 (2010). https://doi.org/10.1038/mp.2009.77

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2009.77

Keywords

This article is cited by

Search

Advanced search

Quick links