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Tubulin Is a Neuronal Target of Autoantibodies in Sydenham’s Chorea¹

Christine A. Kirvan^*, Carol J. Cox, Susan E. Swedo and Madeleine W. Cunningham^2,

^* Department of Biological Sciences, California State University, Sacramento, CA 95819; Department of Microbiology and Immunology, University of Oklahoma, Oklahoma, City, OK 73104; and Pediatrics and Developmental Neuropsychiatry Branch, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892

Sydenham’s chorea is a CNS disorder and sequela of group A streptococcal infection where deposition of Abs in brain may result in movement and neuropsychiatric abnormalities. We studied human mAbs 24.3.1, 31.1.1, and 37.2.1 derived from chorea and selected for cross-reactivity with group A streptococci and brain Ags. Our novel findings reveal that Sydenham’s chorea mAbs target a 55-kDa brain protein with an N-terminal amino acid sequence of MREIVHLQ corresponding to -tubulin. Chorea mAb specificity for purified brain tubulin was confirmed in ELISA and Western immunoblot, and significant levels of anti-tubulin IgG were found in acute chorea sera and cerebrospinal fluid. Lysoganglioside G_M1 inhibited binding of chorea mAbs to tubulin and mAb reactivity with human caudate and putamen brain sections was blocked by anti-tubulin mAb. The chorea mAbs labeled both intra- and extracellular Ags of a neuronal cell line providing evidence suggesting mimicry between intracellular brain protein tubulin and extracellular lysoganglioside. In addition, chorea mAb 24.3.1 and acute chorea sera induced calcium/calmodulin-dependent protein kinase II activity in human neuronal cells. Nucleotide sequence analysis of the chorea mAb V_H genes revealed that mAb 24.3.1 V_H gene was encoded by the V_H1 germline gene family which encodes other anti-ganglioside V_H genes associated with motor neuropathies. mAb recognition of tubulin and the neuronal cell surface with initiation of cell signaling and dopamine release supports an emerging theme in autoimmunity whereby cross-reactive or polyreactive autoantibodies against intracellular Ags recognize cell surface epitopes potentially leading to disease.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ M.W.C. holds grants from the National Heart, Lung, and Blood Institute (HL35280 and HL56267) and is the recipient of an National Heart, Lung, and Blood Institute Merit Award. Our work reported herein was supported by the Oklahoma Center for the Advancement of Science and Technology.

² Address correspondence and reprint requests to Dr. Madeleine W. Cunningham, Department of Microbiology and Immunology, Biomedical Research Center Room 217, 975 N.E. 10th Street, Oklahoma City, OK 73104. E-mail address: madeleine-cunningham{at}ouhsc.edu

³ Abbreviations used in this paper: ARF, acute rheumatic fever; SC, Sydenham’s chorea; GlcNAc, N-acetyl--D-glucosamine; CaM kinase II, calcium-calmodulin-dependent protein kinase II; PVDF, polyvinyl difluoride; O-DG3, 9-O-acetyl-disialoganglioside G_D3.