Antineuronal antibodies in a heterogeneous group of youth and young adults with tics and obsessive-compulsive disorder.

BACKGROUND AND OBJECTIVE: Antineuronal antibodies have been implicated in tic and obsessive compulsive disorders (OCD) associated with group A streptococcal infections. We investigated antineuronal autoantibody levels as well as antibody-mediated neuronal cell signaling activity, as previously reported for Sydenham chorea and pediatric autoimmune neuropsychiatric disorder associated with streptococci (PANDAS), to determine immunological profiles for a large cohort of children with tics and/or OCD. METHODS: Study participants (n=311; ages 4-27 years, 66% male) were selected from a larger group of individuals with self-reported neuropsychiatric symptoms (n=742) and included only those with accurate knowledge of group A streptococcal infection status, except for four individuals in whom streptococcal infection status was unknown. Healthy control samples (n=16; ages 5-14 years, 81% male), came from the National Institute of Mental Health and Yale University. In addition to serum donations, participants and/or legal guardians provided neuropsychiatric and related medical histories of symptoms that had lasted >1 year. Antineuronal immunoglobulin G (IgG) titers were measured by standard enzyme-linked immunosorbent assay (ELISA) and compared with mean titers of normal age-matched sera against lysoganglioside, tubulin, and dopamine receptors (D1R and D2R). Antibody-mediated signaling of calcium calmodulin dependent protein kinase II (CaMKII) activity in a human neuronal cell line (SK-N-SH) was tested in serum. RESULTS: Of 311 individuals, 222 (71%) had evidence of group A streptococcal infection, which was associated with tics and/or OCD status (p=0.0087). Sera from individuals with tics and/or OCD (n=261) had evidence of elevated serum IgG antibodies against human D1R (p<0.0001) and lysoganglioside (p=0.0001), and higher serum activation of CaMKII activity (p<0.0001) in a human neuronal cell line compared with healthy controls (n=16). Furthermore, patients with tics and OCD had significantly increased activation of CaMKII activity compared with patients with only tics or only OCD (p<0.033 for each). CONCLUSION: Our study suggested a significant correlation of streptococcal-associated tics and OCD with elevated anti-D1R and antilysoganglioside antineuronal antibodies in serum concomitant with higher activation of CaMKII in human neuronal cells. Youth and young adults with chronic tics and OCD may have underlying infectious/immunologic etiology.

Effects of Chinese herbal medicine Ningdong granule on regulating dopamine (DA)/serotonin (5-TH) and gamma-amino butyric acid (GABA) in patients with Tourette syndrome.

Many studies have indicated that a variety of neurotransmitters are implicated in the pathophysiology of Tourette syndrome (TS), including dopamine (DA), serotonin (5-TH), homovanillic acid (HVA), and gamma-amino butyric acid (GABA). Our previous studies found that Ningdong granule (NDG) is effective on a rat model with TS. NDG can regulate the metabolic disturbance of DA, 5-TH and HVA in the rat brain. However, the mechanisms of NDG in patients with TS are still not clear. To further evaluate the efficiency, safety, and possible mechanisms of NDG, a randomized and double-blind study was carried out. One hundred and twenty patients with TS were enrolled in this study, that were randomly divided into 4 groups (NDG group, Haloperidol (Hal) group, NDG + Hal group and Control group). First, the efficiency of NDG was assessed using the Yale Global Tic Severity Score (YGTSS). Second, the concentration of DA, HVA, 5-TH, 5-hydroxyindoleacetic acid (5-HIAA) and GABA in sera were tested by ELISA. In addition, the influence of NDG on liver and renal function was recorded. We found that NDG could ameliorate tics significantly according the YGTSS score. The concentration of HVA and GABA were increased after treatment with NDG. Furthermore, we found that there was no liver or renal damage in children treated with NDG. We also found that the NDG + Hal group was more effective and safe compared with other groups. In conclusion, the current study indicates that NDG might be effective on patients with TS by regulating dopamine (DA)/serotonin (5-TH) and gamma-amino butyric acid (GABA).

Blood gene expression correlated with tic severity in medicated and unmedicated patients with Tourette Syndrome.

BACKGROUND: Tourette Syndrome (TS) has been linked to both genetic and environmental factors. Gene-expression studies provide valuable insight into the causes of TS; however, many studies of gene expression in TS do not account for the effects of medication. MATERIALS & METHODS: To investigate the effects of medication on gene expression in TS patients, RNA was isolated from the peripheral blood of 20 medicated TS subjects (MED) and 23 unmedicated TS subjects (UNMED), and quantified using whole-genome Affymetrix microarrays. RESULTS: D2 dopamine receptor expression correlated positively with tic severity in MED but not UNMED. GABA(A) receptor ε subunit expression negatively correlated with tic severity in UNMED but not MED. Phenylethanolamine N-methyltransferase expression positively correlated with tic severity in UNMED but not MED. CONCLUSION: Modulation of tics by TS medication is associated with changes in dopamine, norepinephrine and GABA pathways.

Protein array profiling of tic patient sera reveals a broad range and enhanced immune response against Group A Streptococcus antigens.

The human pathogen Group A Streptococcus (Streptococcus pyogenes, GAS) is widely recognized as a major cause of common pharyngitis as well as of severe invasive diseases and non-suppurative sequelae associated with the existence of GAS antigens eliciting host autoantibodies. It has been proposed that a subset of paediatric disorders characterized by tics and obsessive-compulsive symptoms would exacerbate in association with relapses of GAS-associated pharyngitis. This hypothesis is however still controversial. In the attempt to shed light on the contribution of GAS infections to the onset of neuropsychiatric or behavioral disorders affecting as many as 3% of children and adolescents, we tested the antibody response of tic patient sera to a representative panel of GAS antigens. In particular, 102 recombinant proteins were spotted on nitrocellulose-coated glass slides and probed against 61 sera collected from young patients with typical tic neuropsychiatric symptoms but with no overt GAS infection. Sera from 35 children with neither tic disorder nor overt GAS infection were also analyzed. The protein recognition patterns of these two sera groups were compared with those obtained using 239 sera from children with GAS-associated pharyngitis. This comparative analysis identified 25 antigens recognized by sera of the three patient groups and 21 antigens recognized by tic and pharyngitis sera, but poorly or not recognized by sera from children without tic. Interestingly, these antigens appeared to be, in quantitative terms, more immunogenic in tic than in pharyngitis patients. Additionally, a third group of antigens appeared to be preferentially and specifically recognized by tic sera. These findings provide the first evidence that tic patient sera exhibit immunological profiles typical of individuals who elicited a broad, specific and strong immune response against GAS. This may be relevant in the context of one of the hypothesis proposing that GAS antigen-dependent induction of autoantibodies in susceptible individuals may be involved the occurrence of tic disorders.