Antibodies against neural, nuclear, cytoskeletal, and streptococcal epitopes in children and adults with Tourette’s syndrome, Sydenham’s chorea, and autoimmune disorders
Introduction
Tic disorders are common in childhood, affecting 1 to 4% of school aged children and adolescents Comings et al 1990, Costello et al 1996, Kadesjo and Gillberg 2000, Mason et al 1998. Tic disorders, including Tourette’s syndrome (TS) follow a waxing and waning course, and most patients will experience a complete or partial remission of symptoms by the end of the second decade (Leckman et al 1998). Medications, including the alpha 2 agonist clonidine and typical and atypical neuroleptics, can reduce the frequency and intensity of tics, but not eliminate them.
The causes of tic disorders are unknown but likely involve a combination of genetic and environmental factors (Leckman and Riddle, 2000; Lombroso and Leckman 1997). Poststreptococcal autoimmune mechanisms have been postulated to be an environmental trigger, and Sydenham’s chorea (SC), a late manifestation of rheumatic fever, has been proposed as a model for understanding the pathobiology of at least a subset of TS patients (Swedo 1994).
Molecular mimicry is thought to be one mechanism active in SC through a chain of events in which antibodies against group A β-hemolytic streptococci crossreact with cells in the basal ganglia to produce inflammation Castillo et al 1999, Husby et al 1976, Kotby et al 1998, Ryan and Antony 1999. This results in a range of neurologic and psychiatric symptoms, including chorea, muscle weakness, motor and vocal tics, obsessions, compulsions, attentional difficulties, and emotional lability Mercadante et al 1997, Mercadante et al 2000, Swedo et al 1993. Several studies have noted the presence of potentially crossreactive antistreptococcal/antineuronal antibodies in the sera of patients with tic disorders Kiessling et al 1993, Kiessling et al 1994, Müller et al 2000, Singer et al 1998, Singer et al 1999, Swedo et al 1997, Tucker et al 1996. Swedo et al (1998) proposed that this subgroup of tic disorder patients, identified by the acronym PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections), follows a unique clinical course. Although this hypothesis is strengthened by volumetric magnetic resonance imaging (MRI) studies (Giedd et al 2000) and by the finding that plasma exchange and intravenous immunoglobulin treatment are effective in reducing tic symptoms in PANDAS cases (Perlmutter et al 1999), this conceptualization remains controversial Kurlan 1998, Murphy et al 2000, Shulman 1999, Singer et al 2000.
Antibodies to nuclear and cytoplasmic epitopes are frequently observed in autoimmune disorders including systemic lupus erythematosus (SLE), Sjögerns syndrome, polymyositis, rheumatoid arthritis, autoimmune liver diseases, and systemic sclerosis Rose 1996, Senecal et al 1985. The picture is less clear regarding the presence of antinuclear antibodies (ANAs) in the sera of TS and SC patients because both positive and negative findings have been reported Abraham et al 1997, Husby et al 1976, Singer et al 1997.
To evaluate the immune hypothesis of TS further, we sought to determine if we could detect the presence of serum autoantibodies against neural, nuclear, and cytoskeletal epitopes. We specifically hypothesized that 1) patients with TS, SC, and autoimmune disorders would have elevated titers of total and IgG class antineural antibodies compared with normal control subjects and that the staining patterns for TS and SC would be distinct from one another; 2) TS or SC patients, as well as patients with autoimmune disorders, would have elevated total and IgG class ANAs and anticytoskeletal antibodies (ACSKAs) compared with normal control subjects; 3) TS and SC patients would have elevated titers of antisteptococcal antibodies compared with normal control subjects and patients with autoimmune disorders; and 4) TS patients with elevated antineural antibodies would show a higher comorbidity of OCD and ADHD and that their level of tic severity would be associated with levels of antisteptococcal antibodies.
Section snippets
Subject recruitment and characterization
Subjects (n = 227) were 8 to 85 years old and included 103 female and 124 male children and adults. Written informed consent was obtained for all participants.
Normal control subjects (n = 67), aged 8 to 61 years old (mean age [SD], 23.3 [12.5] years; 27 female and 40 male subjects, 31 children and adolescents and 36 adults), were recruited from a list of 10,000 names purchased from a telemarketing company. They were identified by the company as having individuals in specified age ranges and as
Antineural antibodies
Total antineural antibodies were assayed in 218 individuals (Table 1). Consistent with first hypothesis, patients with TS, SC, and the autoimmune disorders were found to have elevated titers of total antineural antibodies compared with the control subjects (Figure 1A, Kruskal-Wallis H Test = 58.5, df = 3, p < .0001). As depicted in Figure 1A, the mean rank for the total antineural antibodies was highest for the patients with autoimmune disorders, followed by the SC, TS, and control groups,
Discussion
This study identified a significant elevation in the level of antineural antibodies in the sera of TS and SC patients, as well as in patients with autoimmune disorders, compared with healthy control subjects. Although these results support our first hypothesis, the data concerning TS are not entirely compelling. First, in the case of TS, the increase in total antineural antibodies nearly disappeared when the subjects studied were stratified by age (children and adolescents: p = .051; adults p =
Acknowledgements
This work was supported by NIH Grant Nos. MH18768, MH49351, RR06022, and MH01237 (BSP); K02 MH01527 (PJL); AA12044 and DA12468 (HZ); and Brazilian government Grant Nos. FAPESP (96/11991–0, 96/7425–0, 97/5815–8, 99/08560–6, 99/12205–7) and CNPq (521369/96–7). The authors thank Drs. Debra Bessen, Donald J. Cohen, Charles A. Janeway, Yukiko Kano, Louise S. Kiessling, Roger Kurlan, David L. Pauls, Susan E. Swedo, Jane Taylor, Marcos Sera, and Daniel Tucker for their comments on an earlier version
References (66)
A rapid and sensitive method for the quantification of microgram quantities of protein utilizing the principle of protein-dye binding
Anal Biochem
(1976)- et al.
Patterns of nuclear immunofluorescence and reactivities to recombinant nuclear antigens in autoimmune hepatitis
Gastroenterology
(1994) - et al.
Thyroidal stimulation of tubulin and actin in rat brain cytoskeleton
Int J Dev Neurosci
(1994) - et al.
Anti-telencephalic antibodies in Tourette syndrome cause neuronal dysfunction
J Neuroimmunol
(2000) - et al.
Tourette’s disorderEpidemiology and comorbidity in primary school children
J Am Acad Child Adolesc Psychiatry
(2000) - et al.
The schedule for affective disorders and schizophrenia for school-age children—present and lifetime version (K-SADS-PL)Initial reliability and validity data
J Am Acad Child Adolesc Psychiatry
(1997) - et al.
The pathogenesis of Tourette’s syndromeRole of epigenetic factors active in early CNS development
Biol Psychiatry
(1993) - et al.
Tourette’s syndromeWhen habit forming units form habits of their own?
Neuron
(2000) - et al.
The Yale Global Tic Severity ScaleInitial testing of a clinician-rated scale of tic severity
J Am Acad Child Adolesc Psychiatry
(1989) - et al.
Hidden autoantibodies