Wu, X., Hao, J., Jiang, K. et al. Neuroinflammation and pathways that contribute to tourette syndrome. Ital J Pediatr 51, 63 (2025). https://doi.org/10.1186/s13052-025-01874-3
A 2025 narrative review published in Italian Journal of Pediatrics examines growing evidence that immune and inflammatory mechanisms contribute to Tourette syndrome (TS), particularly in a subset of patients whose symptoms are triggered or worsened by infections or allergic reactions. While TS has traditionally been framed as a neurodevelopmental disorder driven by neurotransmitter imbalance, this review integrates two decades of research showing that neuroinflammation, immune activation, and neural–immune crosstalk play an important role in tic onset and exacerbation.
Tourette syndrome is characterized by motor and vocal tics lasting more than one year, typically beginning in childhood, and frequently co-occurs with ADHD, OCD, and other neuropsychiatric symptoms. The authors focus on how immune responses can disrupt dopamine- and glutamate-based signaling within the cortex–striatum–thalamus–cortex (CSTC) circuit, a core pathway implicated in TS.
Infections and Allergies as Triggers
The review highlights that a subset of individuals with TS experience symptom onset or worsening following immune challenges, including infections and allergic reactions.
Reported triggers include:
- Bacterial infections
- Group A Streptococcus (GAS) is the most consistently implicated
- Streptococcus-associated tics form the basis of the PANDAS hypothesis
- Other bacteria (e.g., Staphylococcus aureus, Pseudomonas aeruginosa) have been linked to tic exacerbation
- Viral infections
- Enterovirus, HSV, VZV, CMV, coxsackievirus B
- SARS-CoV-2 and COVID-19–associated tic-like behaviors
- Other pathogens
- Mycoplasma pneumoniae, Chlamydia species, Borrelia burgdorferi
- Allergic reactions
- Higher rates of allergic rhinitis, asthma, eczema, food allergy
- Elevated IgE levels and sensitization to inhalant allergens
These findings suggest that immune activation, not just infection itself, may be key to symptom expression.
How Immune Activation May Lead to Tics
The authors outline multiple, overlapping mechanisms by which immune responses may disrupt brain function in TS.
Peripheral immune system activation
- Reduced regulatory T cells (Tregs) and increased CD8+ T cells
- Elevated pro-inflammatory cytokines including IL-6, TNF-α, IL-17, IFN-γ
- Hyperreactive immune state following infection or allergy
Blood–brain barrier disruption
- Inflammatory cytokines increase BBB permeability
- Peripheral immune signals gain access to the central nervous system
Microglial activation
- Microglia shift toward a pro-inflammatory (M1) phenotype
- Associated with:
- Increased chemokine CCL5
- Upregulation of immune-related genes
- Histamine deficiency and altered histidine decarboxylase activity
- Resulting neurotoxicity affects striatal dopaminergic neurons
Neurotransmitter imbalance
- Dopamine and glutamate dysregulation within the basal ganglia
- Loss of inhibitory control over motor circuits
- Increased neuronal excitability contributing to tics
Anti-Neuronal Antibodies and Molecular Mimicry
The review also summarizes evidence for autoantibody involvement, particularly following streptococcal infections.
- Streptococcal antigens share structural similarities with neuronal targets
- Antibodies may cross-react with:
- Dopamine D1 and D2 receptors
- Lysoganglioside GM1
- Tubulin and other neuronal surface antigens
- Binding occurs in basal ganglia, hippocampus, cerebellum, and dentate gyrus
- These antibodies may:
- Activate microglia
- Alter dopamine signaling
- Contribute to tic generation and other neuropsychiatric symptoms
Importantly, the authors note that specific pathogenic autoantibodies in TS remain incompletely defined, and further identification is a priority.
Inflammatory Signaling Pathways Implicated in TS
Several immune-related signaling pathways are highlighted as converging points between inflammation and neurotransmitter dysfunction:
- CaMKII pathway
- Activated by anti-neuronal antibodies and NMDA receptor signaling
- Influences dopamine release and tyrosine hydroxylase activity
- JAK2–STAT3 pathway
- Drives expression of inflammatory genes
- Activated by IL-6, IL-1β, and TNF-α
- NF-κB pathway
- Central regulator of microglial activation and neuroinflammation
- Interacts with multiple upstream immune pathways
Additional pathways discussed include NMDA–MAPK, PI3K–AKT–mTOR, and gut–brain axis signaling.
Broader Implications
The authors emphasize that Tourette syndrome should not be viewed as a single, uniform condition. Instead, TS likely includes biologically distinct subgroups, including individuals whose symptoms are strongly influenced by immune and inflammatory processes.
Key takeaways:
- Neuroinflammation can act as a trigger or amplifier of tics
- Infection- or allergy-associated tics are commonly observed clinically
- Immune mechanisms help explain symptom fluctuation and exacerbations
- Understanding these pathways may open doors to new therapeutic approaches
Why This Matters
This review reinforces a growing shift in neuropsychiatry: immune signaling and brain function are deeply interconnected. For Tourette syndrome, it provides a biologically plausible framework linking infections, inflammation, neurotransmitter imbalance, and tic expression — particularly relevant to patients with abrupt onset, relapsing courses, or comorbid immune features.
As with PANS and PANDAS, the findings support the need for:
- Careful attention to timing and triggers
- Recognition of immune-related subtypes
- Continued research into targeted, mechanism-based treatments
Gabriella True
