Immune Signaling in neural development, synaptic plasticity and disease

Harvard University, Cambridge, Massachusetts, United States
Nature reviews Neuroscience (Impact Factor: 31.43). 08/2004; 5(7):521-31. DOI: 10.1038/nrn1428
Source: PubMed


Research has long supported the view that the brain is immunologically privileged, in part because normal, uninfected neurons were not thought to express major histocompatibility complex (MHC) class I molecules. Recently, however, it has been shown that neurons normally express MHC class I molecules in vivo. Furthermore, accumulating evidence indicates that neuronal MHC class I does not simply function in an immune capacity, but is also crucial for normal brain development, neuronal differentiation, synaptic plasticity and even behaviour. These findings point to new directions for research, and imply that immune proteins could be involved in the origin and expression of neurological disorders.

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Available from: Lisa M Boulanger
    • "Furthermore, given that MHC class proteins are expressed on neurons, as well as microglia (Boulanger & Shatz, 2004), immune system markers capable of identifying neurons could determine potentially shared mechanisms between central nervous and immune system pathways, which may have implications for the proposed inflammatory hypothesis of schizophrenia. In particular, schizophrenia may not be primarily a disorder of inflammation but arise from disturbances of overlapping downstream molecular pathways, common to both immune and central nervous systems. "
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    ABSTRACT: Schizophrenia is a debilitating disorder that typically begins in adolescence, and is characterized by perceptual abnormalities, delusions, cognitive and behavioural disturbances and functional impairments. While current treatments can be effective, they are often insufficient to alleviate the full range of symptoms. Schizophrenia is associated with brain structural abnormalities including grey and white matter volume loss and impaired connectivity. Recent findings suggest these abnormalities follow a neuroprogressive course in the earliest stages of the illness, which may be associated with episodes of acute relapse. Neuroinflammation has been proposed as a potential mechanism underlying these brain changes, with evidence of increased density and activation of microglia, the brain's resident immune cells, at various stages of illness. We review evidence for microglial dysfunction in schizophrenia from both neuroimaging and neuropathological data, with a specific focus on studies examining microglial activation in relation to grey and white matter pathology. The available studies indicate the link between microglial dysfunction and brain change in schizophrenia remains an intriguing hypothesis worthy of further examination. Future studies in schizophrenia should: (i) use multimodal imaging to clarify this association by mapping brain changes longitudinally across illness stages in relation to microglial activation, (ii) clarify the nature of microglial dysfunction with markers specific to activation states and phenotypes, (iii) examine the role of microglia and neurons with reference to their overlapping roles in neuroinflammatory pathways and (iv) examine the impact of novel immunomodulatory treatments on brain structure in schizophrenia.
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    • "Cytokines are proteins involved in the activation, coordination and suppression of immune responses. Their neuromodulatory actions appear to be critical for the regulation of neuroplasticity, cell resilience and apoptosis (Boulanger and Shatz, 2004; Golan et al., 2004; Bauer et al., 2007). Macrophages are activated during innate immune response in two functional distinct states (M1 and M2), producing different cytokines. "
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    ABSTRACT: Schizophrenia is accompanied by alterations in immuno-inflammatory pathways, including abnormalities in cytokine profile. The immune assessment of patients in a first episode of psychosis (FEP) and particularly in drug naïve patients is very important to further elucidate this association. The objectives of this study are to delineate the cytokine profile (IL-2, IL-10, IL-4, IL-6, IFNγ, TNFα and IL-17) in FEP patients (n=55) versus healthy controls (n=57) and to examine whether the presence of depressive symptoms in FEP is accompanied by a specific cytokine profile. We found increased levels of IL-6, IL-10 and TNFα in FEP patients when compared to healthy controls. FEP patients with depression showed higher IL-4 and TNFα levels versus those without depression. Cytokine levels were not correlated to the total PANSS and the positive or negative subscale scores. Our results suggest that FEP is accompanied by a cytokine profile indicative of monocytic and T regulatory cell (Treg) activation. Depression in FEP is accompanied by monocytic and Th-2 activation, whereas FEP without depression is characterized by Treg activation only. In conclusion, depression emerged as a key component explaining the cytokines imbalance in FEP that is responsible for a large part of the immune-inflammatory abnormalities described. Copyright © 2015 Elsevier B.V. All rights reserved.
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    • "This is significant as mitochondrial dysfunction in ASD has been repeatedly reported in immune cells [125] [134] [145] with such mitochondrial dysfunction linked to abnormalities in immune cell function [125]. In addition, abnormalities in microglia have been linked to abnormal brain development in Rett syndrome [175], and studies suggest that the immune system may be essential for synaptic pruning during development [176]. Thus, abnormalities in immune cell function as a result of mitochondrial dysfunction may also result in seizures in children with ASD. "
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