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Cellular and molecular mechanisms involving immune-competent cells can modulate normal brain development, influencing the genesis, refinement, and maintenance of neural circuits. There is increasing evidence in support of the contribution of an early immune priming to the abnormal trajectories of maturation of cortico-subcortical circuits associated with the generation of tics. During postnatal life, the hyperreactivity of systemic immune pathways and neuroinflammation may contribute to natural fluctuations of the behavioral features manifesting in Tourette syndrome and related disorders. Moreover, abnormalities in the parallel development of neural and immune systems, as well as in stress responses, are reflected in the higher risk of autoimmune and allergic illnesses in people with these neurodevelopmental disorders. There is still limited knowledge regarding the efficacy of direct and indirect immune-modulatory interventions in the treatment of these disorders. There are also limitations in knowledge of the key molecular pathways associated with gut dysbiosis that can influence neuroimmune interactions in these disorders. This chapter provides an up-to-date summary of the existing knowledge around these themes, highlighting existing gaps that need to be addressed by future research in order to develop breakthrough, disease-modifying, immunological, hormonal, and microbiota-based therapeutic interventions.

Several associations between patients with infections, particularly group A streptococcal (GAS) infections, and subsequent tics and obsessive–compulsive symptoms have been established in population-based studies, suggesting at least a nonspecific role of infections in a subgroup of patients with tics. Expanding the clinical entity of pediatric autoimmune neuropsychiatric disorders associated with streptococcus, a broader spectrum named pediatric acute-onset neuropsychiatric syndromes (PANS) has been proposed, which encompasses phenotypes dominated by obsessive–compulsive symptoms or eating behavior abnormalities and includes tics as accompanying features. PANS are defined by the temporal course but are not limited to post-infectious etiologies. In chronic tic disorders, GAS infections do not seem to be a major determinant of tic exacerbations, although a potential interactive effect with psychosocial stress cannot be excluded. The role of other pathogens in influencing course and onset of tic disorders remains uncertain. The complex interaction of patient-specific attributes (neurochemical and immune vulnerability genes leading to maladaptive neuropsychiatric or immune function) with environmental attributes (psychosocial stress, injuries, substance exposures, and pathogen-specific properties) creates an interesting and ongoing research challenge.