Immune-mediated animal models of Tourette syndrome

Abstract

An autoimmune diathesis has been proposed in Tourette syndrome (TS) and related neuropsychiatric disorders such as obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism and anorexia nervosa. Environmental triggers including infection and xenobiotics are hypothesized to lead to the production of brain-directed autoantibodies in a subset of genetically susceptible individuals. Although much work has focused on Group A Streptococcus (GAS), the role of this common childhood infection remains controversial. Animal model studies based on immune and autoantibody findings in TS have demonstrated immunoglobulin (Ig) deposits and stereotypic movements and related behavioral disturbances reminiscent of TS following exposure to GAS and other activators of host anti-microbial responses, soluble immune mediators and anti-GAS or anti-neuronal antibodies. Demonstration of the ability to recreate these abnormalities through passive transfer of serum IgG from GAS-immunized mice into naïve mice and abrogation of this activity through depletion of IgG has provided compelling evidence in support of the autoimmune hypothesis. Immunologically-based animal models of TS are a potent tool for dissecting the pathogenesis of this serious neuropsychiatric syndrome.

The Role of “Mixed” Orexigenic and Anorexigenic Signals and Autoantibodies Reacting with Appetite-Regulating Neuropeptides and Peptides of the Adipose Tissue-Gut-Brain Axis: Relevance to Food Intake and Nutritional Status in Patients with Anorexia Nervosa and Bulimia Nervosa

“…The ghrelin autoantibodies could alter the feeding regulatory neurocircuitry and eating behavior by changing of the signalling of the hormone ranging from transport to neutralization resulting in the phenomenon of ghrelin resistance in AN patients [48] (Table 1, Figure 2). Very recently, Acres et al [243] and Hornig and Lipkin [104] hypothesize that AN is an autoimmune disease and may also be associated with major histocompatibility complex (MHC) gene polymorphisms. Indeed, the development of type 1 diabetes in adolescence seems to place girls at risk for the subsequent development of AN and BN [244, 245].…”

“…At present, leptin, ghrelin, GOAT, NPY, tumour necrosis factor-alpha (TNF- α ) downregulating agents such as dexamethasone and potentially Aci, or their synthetic analogs [6, 7, 13, 56, 256–258] as well as selective serotonin reuptake inhibitors (SSRI) and serotonin NE reuptake inhibitors (SNRI) may be useful agents for the modulation of food intake, especially serotonin-dopamine antagonists (e.g., Olanzapine) which have been found to be effective for treating AN [256, 259]. In the treatment of eating disorders, modified blood-brain barrier in AN and BN is a therapeutic target for delivery of any therapeutics to the central nervous system [103, 104, 260] (Figure 2). The circulating autoantibodies against appetite-regulating neuropeptides and neurotransmitters can be purified and used as monoclonal antibodies in AN and BN.…”

“…In contrast to the decreased gut-barrier permeability during starvation in AN, increased levels of plasma FFA and the more ketone bodies produced increase the permeability of the blood-brain barrier during starvation and weight loss in patients with AN [103]. Moreover, starvation, stress, catecholamines, microbial antigens, poststreptococcal autoimmune process (PANDAS), and proinflammatory cytokines decrease blood-brain barrier integrity in parallel with decreased levels of the tight junction protein, occludin [104] (Figure 2). Hence, it is possible that access of high affinity autoantibodies against appetite-regulating neuropeptides and peptides in the brain centers normally protected by the blood-brain barrier may trigger the development of AN and BN (Figure 2).…”

Histamine regulation of microglia: Gene-environment interaction in the regulation of central nervous system inflammation

“…14, 15). Dysregulated neuroinflammation has been proposed to contribute to TS and a variety of other neuropsychiatric conditions (16-18), although these connections remain unproven in most cases. The possible role of HA as a regulator of neuroinflammatory processes in the brain has received scant attention.…”

Microglial Dysregulation in OCD, Tourette Syndrome, and PANDAS

“…Considerable evidence suggests that immune dysregulation may contribute to the pathophysiology Tourette syndrome [37, 38]. Evidence of microglial abnormalities, specifically, is much more limited.…”