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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.

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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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