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Mimicry and autoantibody-mediated neuronal cell signaling in Sydenham chorea

Abstract

Streptococcus pyogenes–induced acute rheumatic fever (ARF) is one of the best examples of postinfectious autoimmunity due to molecular mimicry between host and pathogen. Sydenham chorea is the major neurological manifestation of ARF but its pathogenesis has remained elusive, with no candidate autoantigen or mechanism of pathogenesis described. Chorea monoclonal antibodies showed specificity for mammalian lysoganglioside and N-acetyl-β-D-glucosamine (GlcNAc), the dominant epitope of the group A streptococcal (GAS) carbohydrate. Chorea antibodies targeted the surface of human neuronal cells, with specific induction of calcium/calmodulin-dependent protein (CaM) kinase II activity by monoclonal antibody 24.3.1 and sera from active chorea. Convalescent sera and sera from other streptococcal diseases in the absence of chorea did not activate the kinase. The new evidence implicates antibody-mediated neuronal cell signaling in the immunopathogenesis of Sydenham chorea and will lead to a better understanding of other antibody-mediated neurological disorders.

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Figure 1: Reactivity of chorea monoclonal antibodies with streptococcal and mammalian autoantigens.
Figure 2: Lysoganglioside GM1–specific reactivity of chorea monoclonal antibodies, sera and CSF.
Figure 3: Chorea antibodies recognize neuroblastoma cell surface and caudate putamen.
Figure 4: Induction of CaM kinase II by Sydenham chorea monoclonal antibodies and sera.

References

  1. Stollerman, G.H. Rheumatic fever in the 21st century. Clin. Infect. Dis. 33, 806–814 (2001).

    Article  CAS  PubMed  Google Scholar 

  2. Veasy, L., Tani, L.Y. & Hill, H.R. Persistence of acute rheumatic fever in the intermountain area of the United States. J. Pediatr. 124, 9–16 (1994).

    Article  CAS  PubMed  Google Scholar 

  3. Roberts, S. et al. Pathogenic mechanisms in rheumatic carditis: focus on the valvular endothelium. J. Infect. Dis. 183, 507–511 (2001).

    Article  CAS  PubMed  Google Scholar 

  4. Quinn, A., Kosanke, S., Fischetti, V.A., Factor, S.M. & Cunningham, M.W. Induction of autoimmune valvular heart disease by recombinant streptococcal M protein. Infect. Immun. 69, 4072–4078 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Galvin, J.E., Hemric, M.E., Ward, K. & Cunningham, M.W. Cytotoxic monoclonal antibody from rheumatic carditis recognizes heart valves and laminin. J. Clin. Invest. 106, 217–224 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Galvin, J.E. et al. Induction of myocarditis and valvulitis in Lewis rats by different epitopes of cardiac myosin and its implications in rheumatic carditis. Am. J. Pathol. 160, 297–306 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Antone, S.M., Adderson, E.E., Mertens, N.M. & Cunningham, M.W. Molecular analysis of V gene sequences encoding cytotoxic anti-streptococcal/anti-myosin monoclonal antibody 36.2.2 that recognizs the heart cell surface protein laminin. J. Immunol. 159, 5422–5430 (1997).

    CAS  PubMed  Google Scholar 

  8. Cunningham, M.W. Pathogenesis of group A streptococcal infections. Clin. Microbiol. Rev. 13, 472–511 (2000).

    Article  Google Scholar 

  9. Marques-Dias, M.J., Mercadante, M.T., Tucker, D. & Lombroso, P. Sydenham's chorea. Psychiatr. Clin. North Am. 20, 809–820 (1997).

    Article  CAS  PubMed  Google Scholar 

  10. Taranta, A. & Stollerman, G.H. The relationship of Sydenham's chorea to infection with group A streptococci. Am. J. Med. 20, 170–175 (1956).

    Article  CAS  PubMed  Google Scholar 

  11. Taranta, A. Relation of isolated recurrences of Sydenham's chorea to preceding streptococcal infections. N. Engl. J. Med. 260, 1204–1210 (1959).

    Article  CAS  PubMed  Google Scholar 

  12. Swedo, S.E. Sydenham's chorea: a model of childhood autoimmune neuropsychiatric disorders. JAMA 272, 1788–1791 (1994).

    Article  CAS  PubMed  Google Scholar 

  13. Cunningham, M.W. Streptococcal sequelae and molecular mimicry. in Effects of Microbes on the Immune System (eds. Fujinami, R.S. and Cunningham, M.W.) (Lippincott Williams and Wilkins, Philadelphia, 2000).

    Google Scholar 

  14. Swedo, S.E. et al. Sydenham's chorea: physical and psychological symptoms of St Vitus dance. Pediatrics 91, 706–713 (1993).

    CAS  PubMed  Google Scholar 

  15. Giedd, J.N. et al. Sydenham's chorea: magnetic resonance imaging of the basal ganglia. Neurology 45, 2199–2202 (1995).

    Article  CAS  PubMed  Google Scholar 

  16. Husby, G., van de Rijn, I., Zabriskie, J.B., Abdin, A.H. & Williams, R.C. Antibodies reacting with cytoplasm of subthalamic and caudate nuclei neurons in chorea and acute rheumatic fever. J. Exp. Med. 144, 1094–1110 (1976).

    Article  CAS  PubMed  Google Scholar 

  17. Bronze, M.S. & Dale, J.B. Epitopes of streptococcal M protein that evoke antibodies that cross-react with human brain. J. Immunol. 151, 2820–2828 (1993).

    CAS  PubMed  Google Scholar 

  18. Shikhman, A.R. & Cunningham, M.W. Immunological mimicry between N-acetyl-beta-D-glucosamine and cytokeratin peptides. Evidence for a microbially driven anti-keratin antibody response. J. Immunol. 152, 4375–4387 (1994).

    CAS  PubMed  Google Scholar 

  19. Svennerholm, L. Designation and schematic structure of gangliosides and allied glycosphingolipids. Prog. Brain Res. 101, XI–XIV (1994).

    Article  CAS  PubMed  Google Scholar 

  20. Kotani, M. & Tai, T. An immunohistochemical technique with a series of monoclonal antibodies to gangliosides: their differential distribution in the rat cerebellum. Brain Res. Brain Res. Protoc. 1, 152–156 (1997).

    Article  CAS  PubMed  Google Scholar 

  21. Shikhman, A.S., Greenspan, N.S. & Cunningham, M.W. A subset of mouse monoclonal antibodies cross-reactive with cytoskeletal proteins and group A streptococcal M protein recognizes N-acetyl-β-D-glucosamine. J. Immunol. 151, 3902–3913 (1993).

    CAS  PubMed  Google Scholar 

  22. Shikhman, A.R., Greenspan, N.S. & Cunningham, M.W. Cytokeratin peptide SFGSGFGGGY mimics N-acetyl-beta-D-glucosamine in reaction with antibodies and lectins, and induces in vivo anti-carbohydrate antibody response. J. Immunol. 153, 5593–5606 (1994).

    CAS  PubMed  Google Scholar 

  23. Hakomori, S. Glycosphingolipids in cellular interaction, differentiation, and oncogenesis. Annu. Rev. Biochem. 50, 733–764 (1981).

    Article  CAS  PubMed  Google Scholar 

  24. Hannun, Y.A. & Bell, R.M. Lysosphingolipids inhibit protein kinase C: implications for the sphingolipidoses. Science 235, 670–674 (1987).

    Article  CAS  PubMed  Google Scholar 

  25. Chen, C., Rainnie, D.G., Greene, R.W. & Tonegawa, S. Abnormal fear response and aggressive behavior in mutant mice deficient for alpha-calcium-calmodulin kinase II. Science 266, 291–294 (1994).

    Article  CAS  PubMed  Google Scholar 

  26. Silva, A.J., Stevens, C.F., Tonegawa, S. & Wang, Y. Deficient hippocampal long-term potentiation in alpha-calcium-calmodulin kinase II mutant mice. Science 257, 201–206 (1992).

    Article  CAS  PubMed  Google Scholar 

  27. Zhao, W., Lawen, A. & Ng, K.T. Changes in phosphorylation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in processing of short-term and long-term memories after passive avoidance learning. J. Neurosci. Res. 55, 557–568 (1999).

    Article  CAS  PubMed  Google Scholar 

  28. Schulman, H., Heist, K. & Srinivasan, M. Decoding Ca2+ signals to the nucleus by multifunctional CaM kinase. Prog. Brain Res. 105, 95–104 (1995).

    Article  CAS  PubMed  Google Scholar 

  29. Ishida, A. & Fujisawa, H. Stabilization of calmodulin-dependent protein kinase II through the autoinhibitory domain. J. Biol. Chem. 270, 2163–2170 (1995).

    Article  CAS  PubMed  Google Scholar 

  30. Quattrini, A. et al. Human IgM anti-GM1 autoantibodies modulate intracellular calcium homeostasis in neuroblastoma cells. J. Neuroimmunol. 114, 213–219 (2001).

    Article  CAS  PubMed  Google Scholar 

  31. Kasahara, K. et al. Involvement of gangliosides in glycosylphosphatidylinositol-anchored neuronal cell adhesion molecule TAG-1 signaling in lipid rafts. J. Biol. Chem. 275, 34701–34709 (2000).

    Article  CAS  PubMed  Google Scholar 

  32. Ang, C.W. et al. Guillain-Barré syndrome- and Miller Fisher syndrome-associated Campylobacter jejuni lipopolysaccharides induce anti-GM1 and anti-GQ1b antibodies in rabbits. Infect. Immun. 69, 2462–2469 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Yuki, N. Molecular mimicry between gangliosides and lipopolysaccharides of Campylobacter jejuni isolated from patients with Guillain-Barré syndrome and Miller Fisher syndrome. J. Infect. Dis. 176 (suppl. 2), S150–S153 (1997).

    Article  CAS  PubMed  Google Scholar 

  34. Weng, N.P., Yu-Lee, L.Y., Sanz, I., Patten, B.M. & Marcus, D.M. Structure and specificities of anti-ganglioside autoantibodies associated with motor neuropathies. J. Immunol. 149, 2518–2529 (1992).

    CAS  PubMed  Google Scholar 

  35. Weber, F., Rudel, R., Aulkemeyer, P. & Brinkmeier, H. Anti-GM1 antibodies can block neuronal voltage-gated sodium channels. Muscle Nerve 23, 1414–1420 (2000).

    Article  CAS  PubMed  Google Scholar 

  36. Takigawa, T. et al. The sera from GM1 ganglioside antibody positive patients with Guillain-Barre syndrome or chronic inflammatory demyelinating polyneuropathy blocks Na+ currents in rat single myelinated nerve fibers. Intern. Med. 39, 123–127 (2000).

    Article  CAS  PubMed  Google Scholar 

  37. Paparounas, K., O'Hanlon, G.M., O'Leary, C.P., Rowan, E.G. & Willison, H.J. Anti-ganglioside antibodies can bind peripheral nerve nodes of Ranvier and activate the complement cascade without inducing acute conduction block in vitro. Brain 122, 807–816 (1999).

    Article  PubMed  Google Scholar 

  38. O'Hanlon, G.M. et al. Anti-GQ1b ganglioside antibodies mediate complement-dependent destruction of the motor nerve terminal. Brain 124, 893–906 (2001).

    Article  CAS  PubMed  Google Scholar 

  39. Kantor, L., Hewlett, G.H. & Gnegy, M.E. Enhanced amphetamine- and K+-mediated dopamine release in rat striatum after repeated amphetamine: differential requirements for Ca2+- and calmodulin-dependent phosphorylation and synaptic vesicles. J. Neurosci. 19, 3801–3808 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Nausieda, P.A. et al. Chronic dopaminergic sensitivity after Sydenham's chorea. Neurology 33, 750–754 (1983).

    Article  CAS  PubMed  Google Scholar 

  41. Swedo, S.E. et al. High prevalence of obsessive-compulsive symptoms in patients with Sydenham's chorea. Am. J. Psychiatry 146, 246–249 (1989).

    Article  CAS  PubMed  Google Scholar 

  42. Peterson, B.S. et al. Preliminary findings of antistreptococcal antibody titers and basal ganglia volumes in tic, obsessive-compulsive, and attention deficit/hyperactivity disorders. Arch. Gen. Psychiatry 57, 364–372 (2000).

    Article  CAS  PubMed  Google Scholar 

  43. Ishida, A., Kameshita, I., Okuno, S., Kitani, A. & Fujisawa, H. A novel highly specific and potent inhibitor of calmodulin-dependent protein kinase II. Biochem. Biophys. Res. Commun. 212, 806–812 (1995).

    Article  CAS  PubMed  Google Scholar 

  44. Sueyoshi, N., Maehara, T. & Ito, M. Apoptosis of Neuro2a cells induced by lysosphingolipids with naturally occurring stereochemical configurations. J. Lipid Res. 42, 1197–1202 (2001).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank M. Hemric and L. Snider for helpful discussions and encouragement, A. Adesina for human brain tissue; S. Kosanke for photomicrograph preparation; and V. Fischetti for recombinant streptococcal M6 protein. This work was supported by grant HL35280 from the National Heart, Lung and Blood Institute (to M.W.C.). C.A.K. was supported by training grant 1T32-AI07633-01A1 from the National Institutes of Allergy and Infectious Diseases. M.W.C. is the recipient of a Merit Award from the National Heart, Blood and Lung Institute.

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Correspondence to Madeleine W Cunningham.

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Kirvan, C., Swedo, S., Heuser, J. et al. Mimicry and autoantibody-mediated neuronal cell signaling in Sydenham chorea. Nat Med 9, 914–920 (2003). https://doi.org/10.1038/nm892

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