Immunological Endophenotypes of Neuropsychiatric Disorders

The link between the immune system and appropriate neurological development and function is now becoming well established. However, the role the immune system plays in most neuropsychiatric disorders remains poorly understood. More work is needed to better describe the nature of immune dysfunctions in neuropsychiatric disorders and whether they play a pathophysiological role or have associations with endophenotypes within these disorders.;For many decades is has been recognized that the nervous and immune system communicate with each other, and imbalances in one system also affects the other. The production of immune messengers in the form of cytokines from immune cells can directly alter neurological functions though cellular receptors, or indirectly by alterations to metabolism or the physiological environment. Similarly, common messengers utilized by the nervous system such as glutamate or GABA can both directly alter immune cell function through cell surface receptors, or indirectly though changes in the endocrine system. The current work describes the presence of immune dysfunction at the cellular level in three neuropsychiatric disorders.;In chapter 1 dynamic immune function is examined in subjects with Fragile X Syndrome (FXS). Despite previous findings showing increased proinflammatory cytokines in subjects with FXS in plasma, dynamic cytokine production from peripheral blood mononuclear cells (PBMC) in children with FXS was found to be similar to aged matched controls. However, when these cells were immunologically challenged in the presence of a group I metabotropic glutamate receptor agonist (DHPG) they showed a dissimilar response compared with cells from controls, such that cells from children with FXS produced more proinflammatory cytokines. Our findings suggest that innate myeloid cells such as monocytes, respond inappropriately to group I mGluR signaling in subjects with FXS. This may have implications for other brain resident myeloid cells such as microglia whereby endogenous glutamate signaling would fail to regulate microglial responses altering the balance maintained between the nervous and immune system in children with FXS. Additional work in mouse models of FXS are warranted to confirm the importance of these findings.;Chapter 2 examines the cellular immune functions of carriers of an expansion of a CGG repeat in the noncoding region of the FMR1 gene. Previous work has shown that male carriers of these mutations presenting with Fragile X-associated tremor/ataxia syndrome (FXTAS) have elevated cellular proinflammatory cytokines responses, whereas female carriers have increased rates of autoimmunity. When immune cells from female permutation carriers were immunologically challenged they had decreased production of cytokines that were associated with increased CGG repeat length. Flow cytometric analysis of T cells from these subjects also showed decreased cell surface makers of activation. Similarly, mice carrying a CGG expansion also displayed similar impaired cytokine production. These results suggest that deficits in immune responses in premutation carriers may lead to increased immune susceptibility to infections or altered responses to stressors that may eventually lead to unregulated autoinflammatory conditions.;Finally, in chapter 3 immune profiling in autism spectrum disorder (ASD) is used to describe a potential immune endophenotype in a heterogeneous cohort of subjects. Children with ASD were clustered into subsets based on dynamic production of cytokines from PBMC that were immunologically challenged. In clusters of subjects that exhibited increased, or proinflammatory immune profiles, there were greater impairments in behavioral outcome than children with ASD that did not display inflamed activated profile in both innate immune cell responses and T cell responses. These findings may suggest that there is an immune sub-phenotype within the ASD population that correlates with more severe behavior.;Ongoing research seeks to further elucidate the role the immune system plays in neuropsychiatric disorders. Animal and cellular models will aide future work in the field, and may help to better understand the mechanistic aspects aberrant immune responses play in these disorders. Collectively this thesis describes immune endophenotypes in a set of neuropsychiatric disorders, and provides a novel method for examining complex disorders such as ASD which may benefit future research both in ASD and in other complex neuropsychiatric disorders.