Anti-Brain Autoantibodies and Altered Excitatory Neurotransmitters in Obsessive–Compulsive Disorder

Abstract

Although serum autoantibodies directed against basal ganglia (BG) implicate autoimmunity in the pathogenesis of obsessive-compulsive disorder (OCD), it is unclear whether these antibodies can cross the blood-brain barrier to bind against BG or other components of the OCD circuit. It is also unclear how they might lead to hyperactivity in the OCD circuit. We examined this by investigating the presence of autoantibodies directed against the BG or thalamus in the serum as well as CSF of 23 OCD patients compared with 23 matched psychiatrically normal controls using western blot. We further investigated CSF amino acid (glutamate, GABA, taurine, and glycine) levels and also examined the extent to which these levels were related to the presence of autoantibodies. There was evidence of significantly more binding of CSF autoantibodies to homogenate of BG as well as to homogenate of thalamus among OCD patients compared with controls. There was no significant difference in binding between patient and control sera except for a trend toward more bands to BG and thalamic protein corresponding to 43 kD among OCD patients compared with controls. CSF glutamate and glycine levels were also significantly higher in OCD patients compared with controls, and further multivariate analysis of variance showed that CSF glycine levels were higher in those OCD patients who had autoantibodies compared with those without. The results of our study implicate autoimmune mechanisms in the pathogenesis of OCD and also provide preliminary evidence that autoantibodies against BG and thalamus may cause OCD by modulating excitatory neurotransmission.

Behavioral, Pharmacological, and Immunological Abnormalities after Streptococcal Exposure: A Novel Rat Model of Sydenham Chorea and Related Neuropsychiatric Disorders

“…Finally, antibodies (IgG) deposited in the striatum, thalamus, and frontal cortex of streptococcal-exposed rats, in line with evidence implicating the striatum in the pathogenesis of SC and PANDAS, and the striatum and frontal cortex in the pathophysiology of OCD. Thus, anti-striatal antibodies have been reported in serum and cerebrospinal fluid of SC (Bronze and Dale, 1993;Church et al, 2002;Husby et al, 1976), PANDAS (Gause et al, 2009;Pavone et al, 2004), and adult OCD patients (Bhattacharyya et al, 2009). In addition, functional imaging studies found hypermetabolism in the striatum of SC patients (Dilenge et al, 1999;Weindl et al, 1993) and in the striatum and frontal cortex of OCD patients (Huyser et al, 2009), which normalized after successful treatment (Dilenge et al, 1999;Huyser et al, 2009;Weindl et al, 1993), and imaging studies in PANDAS patients reported that the basal ganglia were enlarged (Giedd et al, 2000) and size correlated with anti-neural antibody titers (Giedd et al, 2000;Peterson et al, 2000).…”

N-Acetyl Cysteine (NAC) in the Treatment of Obsessive-Compulsive Disorder: A 16-Week, Double-Blind, Randomised, Placebo-Controlled Study

“…Glutamate is the primary neurotransmitter within the CSTC and, while not currently conclusive, evidence suggests that disruptions in glutamate neurotransmission are apparent in patients with OCD [8][9][10]. Significantly higher levels of glutamate have been found in the cerebral spinal fluid and various regions of the brain, including the right caudate and orbitofrontal cortex of OCD patients [11][12][13]. High levels of glutamate are known to elicit oxidative stress [14], and increased oxidative stress has been detected in serum samples from those diagnosed with OCD [15][16][17], appearing to correlate with symptom severity [18].…”

Searching for the Immune Basis of Obsessive-Compulsive Disorder

“…To further investigate the role of ABGA in OCD, Bhattacharyya et al [35] examined ABGA in the serum and cerebrospinal fluid (CSF), and measured CSF amino acids (GABA, glutamate, glycine and taurine) in 23 drug-naïve adult OCD patients compared with 23 healthy controls. There was no significant difference in serum autoantibodies binding to basal ganglia homogenates (as assessed by Western blot), but there was more binding of CSF autoantibodies in OCD patients in contrast with controls, possibly indicating intrathecal ABGA synthesis.…”