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

Abstract

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 β-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 GM1 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 VH genes revealed that mAb 24.3.1 VH gene was encoded by the VH1 germline gene family which encodes other anti-ganglioside VH 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.

Immune Dysfunction in Tourette Syndrome

“…Other groups, however, did not confirm these findings, and their true pathogenic potential has not been demonstrated yet [43,44]. Other putative self-antigens, previously identified in Sydenham's chorea, such as lysoganglioside GM1 and tubulin [45], have not been adequately explored in typical TS, although one study did not identify anti-lysoganglioside GM1 antibodies in 24 youngsters with TS/OCD (80% of whom fulfilled PANDAS criteria) [33].…”

Antibody binding to neuronal surface in Sydenham chorea, but not in PANDAS or Tourette syndrome

“…In this study, we have not proposed which antigen is involved in IgG cell surface binding. Previously proposed antigens in SC include lysoganglioside, tubulin, and glycoytic enzymes, 6,8,19 although it is possible that the dominant pathogenic antibody is yet to be defined.…”

Behavioral, Pharmacological, and Immunological Abnormalities after Streptococcal Exposure: A Novel Rat Model of Sydenham Chorea and Related Neuropsychiatric Disorders

“…Second, we tested whether motor abnormalities and increased compulsivity in GAS rats would respond to the same drugs used to treat motor symptoms and compulsions in SC/PANDAS (D2 blockers and selective serotonin reuptake inhibitors (SSRIs), respectively, Demiroren et al, 2007;Shannon and Fenichel, 1990;Swedo et al, 1998;SE Swedo, unpublished observation). Third, we tested whether sera of GAS rats will have the same immune responses as sera from SC/PANDAS patients, including reaction against GAS antigens (Bronze and Dale, 1993;Husby et al, 1976;Kirvan et al, 2003Kirvan et al, , 2006b) and brain tissue and tubulin (Kirvan et al, 2007), and induction of CaMK II signaling in SK-N-SH neuronal cell line (Kirvan et al, 2003(Kirvan et al, , 2006a. Fourth, we examined rat brains for antibody deposition (expected), gross neural damage (not expected), and changes in the dopaminergic, serotonergic, glutamatergic, and GABAergic systems, which have been implicated in the pathophysiology of motor and tic disorders and OCD (Bhattacharyya and Chakraborty, 2007;Singer and Loiselle, 2003;Singer and Minzer, 2003;Stein, 2002).…”