g(m1)-ganglioside and Chorea

Topics: Anion Exchange Protein 1, Erythrocyte; Autoantibodies; Chorea; Diagnosis, Differential; Erythrocytes; G(M1) Ganglioside; Humans; Prognosis

How autoantibodies target the brain and lead to disease in disorders such as Sydenham chorea (SC) is not known. SC is characterized by autoantibodies against the brain and is the main neurologic manifestation of streptococcal-induced rheumatic fever. Previously, our novel SC-derived mAb 24.3.1 was found to recognize streptococcal and brain Ags. To investigate in vivo targets of human mAb 24.3.1, VH/VL genes were expressed in B cells of transgenic (Tg) mice as functional chimeric human VH 24.3.1-mouse C-region IgG1(a) autoantibody. Chimeric human-mouse IgG1(a) autoantibody colocalized with tyrosine hydroxylase in the basal ganglia within dopaminergic neurons in vivo in VH 24.3.1 Tg mice. Both human mAb 24.3.1 and IgG1(a) in Tg sera were found to react with human dopamine D2 receptor (D2R). Reactivity of chorea-derived mAb 24.3.1 or SC IgG with D2R was confirmed by dose-dependent inhibitory signaling of D2R as a potential consequence of targeting dopaminergic neurons, reaction with surface-exposed FLAG epitope-tagged D2R, and blocking of Ab reactivity by an extracellular D2R peptide. IgG from SC and a related subset of streptococcal-associated behavioral disorders called "pediatric autoimmune neuropsychiatric disorder associated with streptococci" (PANDAS) with small choreiform movements reacted in ELISA with D2R. Reaction with FLAG-tagged D2R distinguished SC from PANDAS, whereas sera from both SC and PANDAS induced inhibitory signaling of D2R on transfected cells comparably to dopamine. In this study, we define a mechanism by which the brain may be altered by Ab in movement and behavioral disorders.

Topics: Animals; Antigens, Bacterial; Autoantibodies; Basal Ganglia; Child; Chorea; Cross Reactions; Dopamine; Dopaminergic Neurons; G(M1) Ganglioside; HEK293 Cells; Humans; Immunoglobulin G; Mice; Mice, Inbred C57BL; Mice, Transgenic; Receptors, Dopamine D2; Recombinant Fusion Proteins; Rheumatic Fever; Signal Transduction; Streptococcal Infections; Transgenes

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-beta-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.

Topics: Acetylglucosamine; Adolescent; Antibodies, Monoclonal; Autoantibodies; Brain; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Calcium-Calmodulin-Dependent Protein Kinases; Chorea; Enzyme Activation; Female; G(M1) Ganglioside; Humans; Immune Sera; Molecular Mimicry; Neurons; Signal Transduction; Streptococcus

A patient with chorea-acanthocytosis presenting with axonal neuropathy showed an elevation in IgM polyclonal antibodies to the GM1 ganglioside, which were estimated by enzyme-linked immunosorbent assay and complement-mediated liposome immune lysis assay (LILA). This is the first demonstration of such antibodies in chorea-acanthocytosis. Anti-GM1 antibodies might have directly caused the axonal neuropathy by binding to GM1 or cross-reactive antigens in the nerves.

Topics: Acanthocytes; Adult; Antibodies; Axons; Chorea; Enzyme-Linked Immunosorbent Assay; G(M1) Ganglioside; Humans; Male; Neuromuscular Diseases