Anti-striatal antibodies in Tourette syndrome cause neuronal dysfunction
Introduction
Tourette syndrome (TS) is the most severe, often disabling, form of a spectrum of childhood-onset disorders in which chronic motor and phonic tics are central symptoms. Tics are stereotypic, involuntary, purposeless and repetitive movements. In TS, they persist for years during which they wax and wane in frequency and severity. Examples of stereotypic movements include head twitches, grimaces and sounds, if the respiratory muscles are involved. While the cause of TS is unknown, an immunohistochemical study has demonstrated that gamma immunoglobulins (IgG) from some children with TS or chronic tics bind to neurons in the caudate nucleus of human cadaver brains (Kiessling et al., 1993). The specificity of anti-neuronal antibody binding to the caudate nucleus is notable because the basal ganglia are thought to have a central role in the pathogenesis of TS. Neuroimaging studies of the basal ganglia have demonstrated changes in size and dopamine receptor density in TS subjects (Peterson et al., 1993, Wolf et al., 1996). Further evidence for the involvement of the dopamine receptor rich basal ganglia in TS comes from clinical studies in which dopaminergic medications were found to provide the most effective treatments for TS (Singer and Walkup, 1991).
Even though an association has been demonstrated between TS and the presence of serum IgG that is immunoreactive with neurons in vitro, the pathogenic potential of TS sera or its isolated IgG in humans has not been established. An initial step in demonstration of such a potential would be to show that TS sera or its isolated IgG can alter neuronal function in basal ganglia in animals. In the past, studies of this type were constrained by the lack of an animal model that allowed antibodies to be presented to basal ganglia without disrupting the blood–brain barrier (BBB) which restricts entry of serum antibodies into brain parenchyma.
Recently, a rodent model has been developed for studying humoral immunity in the normal brain (Harling-Berg et al., 1999). By modifying this model, the effect of antibodies on specific brain regions can be studied. This modified model combines the established immunologic protocol of adaptive transfer that has been used to identify pathogenic antibodies (Toyka et al., 1975) with stereotactic techniques that allow placement of cannula in regions of the neostriatum (analogous to the human basal ganglia) known to cause stereotypic movements when pharmacologically stimulated (Dickerson et al., 1994, Delfs and Kelley, 1990). A study was undertaken using this protocol to determine the potential for TS sera and its IgG to cause stereotypic movements in rats and to bind to neostriatal neurons.
Section snippets
Sera
All sera were taken from our serum bank. Table 1 gives clinical information on the children with TS whose sera were used in this study. Control sera were from healthy children. Collection of sera was performed under a protocol approved by the Institutional Review Board and after consent was obtained.
Microinfusion procedures
A stainless steel cannula was stereotactically placed under sterile conditions into each striatum of an anesthetized male Fischer 344 rat (180–200 g) at coordinates: anteroposterior plane, +0.2 mm
Results
All TS sera were from boys who were symptomatic and contained anti-neuronal IgG class antibodies determined by a neuroblastoma-membrane-ELISA (NM-ELISA) (Table 1). Control sera from healthy boys were negative on the NM-ELISA. Two separate studies were performed microinfusing either sera from TS children (study 1) or IgG isolated from these sera (study 2).
In study 1, marked differences were observed in stereotypic movements of TS rats compared to control rats during the microinfusion period and
Discussion
Results from the first study indicate that transferable factors in TS sera can induce persistent stereotypic motor activity when microinfused into rat striata. These results establish that TS sera with anti-neuronal antibodies contain a pathogenic factor that can induce stereotypies in rats that are analogous to tics in humans. Of particular interest are the EU. Presumably they represent sudden, involuntary contractions of the rat respiratory muscles resulting from the effect of serum factors
Acknowledgments
This study was supported by a grant from the Tourette Syndrome Association. The authors also wish to thank Scott Nolan, Victoria Ku-LaBlanc and Jaya Agrawal for their generous technical assistance.
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