Joseph J. Hallett

Antibodies against human putamen in children with Tourette syndrome

Background Similar to the model for Sydenhams chorea, antineuronal antibodies, which develop in response to a preceding streptococcal infection, have been speculated to have a role in the development of Tourette syndrome (TS). Methods Serum antibodies against human caudate, putamen, and globus pallidus (interna and externa) were assayed by enzyme-linked immunosorbent assay (ELISA) and Western blot techniques and results were correlated with clinical characteristics and markers of streptococcal infection. Subjects A total of 41 children with TS (mean age, 11.3 years) and 39 controls (mean age, 12.1 years) were included. Results Compared with controls, TS subjects had a significant increase in the mean (p = 0.006) and median (p = 0.002) ELISA optical density (OD) levels of serum antibodies against putamen, but not caudate or globus pallidus. Western blots on 20 control and 20 TS serum samples showed that specific antibodies to caudatelputamen occurred more frequently in TS subjects at 83, 67, and 60 kDa; antigens were present in a synaptosomal fraction. TS subjects with a positive family history of tics had higher OD values (p ≤ 0.04), but no association was shown with age of tic onset, tic severity, sudden onset of tics, or presence of attention-deficit hyperactivity disorder or obsessive-compulsive disorder. Risk ratio calculations in TS and control groups and in study subjects dichotomized for high and low putamen OD values were similar for titers of antistreptolysin O ≥166 or antideoxyribonuclease B ≥ 170. A subgroup analysis limited to subjects with elevated streptococcal titers, however, showed a significantly (p ≥ 0.004) larger number of TS subjects with elevated OD levels. Conclusion Children and adolescents with TS had significantly higher serum levels of antineuronal antibodies against putamen than did controls, but their relation to clinical characteristics and markers for streptococcal infection remains equivocal.

Anti-striatal antibodies in Tourette syndrome cause neuronal dysfunction

Serologic studies of children with Tourette syndrome (TS) have detected anti-neuronal antibodies but their role in TS has not been explored. Stereotypies and episodic utterances, analogous to involuntary movements seen in TS, were induced in rats by intrastriatal microinfusion of TS sera or gamma immunoglobulins (IgG) under noninflammatory conditions, as found in TS. Immunohistochemical analysis confirmed the presence of IgG selectively bound to striatal neurons. These data support the hypothesis that binding of an anti-neuronal antibody from some children with TS induced striatal dysfunction and suggest a possible cause for the basal ganglia alterations observed in children with TS.

Hierarchy of immune responses to antigen in the normal brain.

For approximately 100 years the brain has been classified as an “immunologically privileged organ” based on the observations that tissue transplants into cerebral cortex survive longer than tissue transplants into conventional peripheral sites (Shirai 1921; Murphy and Sturm 1923; Medawar 1948; Scheinberg et al. 1966). Various conclusions and presumptions were attributed to these studies, including two predominant beliefs that: (1) there is no lymphatic drainage to alert the immune system to the presence of antigen in the brain (afferent arm of immunity), and (2) the tight endothelial junctions of the cerebral vasculature (blood-brain barrier; BBB) prevent blood lymphocytes from facilitating antigen elimination in the brain (efferent arm of immunity; for reviews see Barker and Billingham 1977; Brent 1990; Waksman 1998).

Neuroimmunology of tics and other childhood hyperkinesias.

The etiology of tics and other childhood hyperkinesias is unclear despite attempts to link these movement disorders to neurotransmitter abnormalities and genes. This article will review the studies that suggest that some movement disorders are the result of immunologic factors.

Genetics of Childhood Disorders: XXXV. Autoimmune Disorders, Part 8: Animal Models for Noninflammatory Autoimmune Disorders of the Brain

Useful animal models for the investigation of autoimmune disorders that involve the brain are essential, especially in children in whom access to the CNS is limited. The paucity of such models can hinder an understanding of causation, pathogenic mechanisms, and treatments. This is particularly true when one is investigating postulated antibody-mediated disorders in which evidence supporting pathogenesis is derived from in vitro studies. The interpretation of such studies is confounded by the frequent nonpathogenic antineuronal antibody binding associated with chronic disorders, such as autism, type 1 diabetes mellitus, as well as normal aging. Differentiating pathogenic from nonpathogenic antibodies cannot be done without a biological assay such as an animal model. This need is seen in the ongoing discussion of the pathogenesis of autoantibodies in childhood Tourette syndrome (TS), obsessivecompulsive disorder (OCD), pediatric autoimmune neuropsychiatric disorders associated with streptococcus (PANDAS), and Sydenham chorea (SC). An animal model should reflect the type of immune response occurring or postulated to occur in the brain, utilize brain regions involved in the disorder, and maintain the brain’s unique immune environment. When studying putative immune brain disorders, it is useful to initially group disorders by the presence or absence of acute inflammation. This distinction is important because

Evidence of Striatal Autoimmunity in Cerebrospinal Fluid in a Child with a Movement Disorder

Evidence of Striatal Autoimmunity in Cerebrospinal Fluid in a Child with a Movement Disorder

TS-PANDAS: Absorption with Streptococcal M-Proteins Alters Serological Antineuronal Membrane Antibody Band Patterns 59

TS-PANDAS: Absorption with Streptococcal M-Proteins Alters Serological Antineuronal Membrane Antibody Band Patterns 59

ANTINEURONAL ANTIBODIES, ANTISTREPTOCOCCAL ANTIBODIES AND TOURETTE SYNDROME: A PROSPECTIVE STUDY † 1762

ANTINEURONAL ANTIBODIES, ANTISTREPTOCOCCAL ANTIBODIES AND TOURETTE SYNDROME: A PROSPECTIVE STUDY † 1762