Immunoneuropsychiatry — novel perspectives on brain disorders

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Abstract

Immune processes have a vital role in CNS homeostasis, resilience and brain reserve. Our cognitive and social abilities rely on a highly sensitive and fine-tuned equilibrium of immune responses that involve both innate and adaptive immunity. Autoimmunity, chronic inflammation, infection and psychosocial stress can tip the scales towards disruption of higher-order networks. However, not only classical neuroinflammatory diseases, such as multiple sclerosis and autoimmune encephalitis, are caused by immune dysregulation that affects CNS function. Recent insight indicates that similar processes are involved in psychiatric diseases such as schizophrenia, autism spectrum disorder, bipolar disorder and depression. Pathways that are common to these disorders include microglial activation, pro-inflammatory cytokines, molecular mimicry, anti-neuronal autoantibodies, self-reactive T cells and disturbance of the blood-brain barrier. These discoveries challenge our traditional classification of neurological and psychiatric diseases. New clinical paths are required to identify subgroups of neuropsychiatric disorders that are phenotypically distinct but pathogenically related and to pave the way for mechanism-based immune treatments. Combined expertise from neurologists and psychiatrists will foster translation of these paths into clinical practice. The aim of this Review is to highlight outstanding findings that have transformed our understanding of neuropsychiatric diseases and to suggest new diagnostic and therapeutic criteria for the emerging field of immunoneuropsychiatry.

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Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis.

Ethan Hughes, Xiaoyu Peng, Amy Gleichman … (2010)

We recently described a severe, potentially lethal, but treatment-responsive encephalitis that associates with autoantibodies to the NMDA receptor (NMDAR) and results in behavioral symptoms similar to those obtained with models of genetic or pharmacologic attenuation of NMDAR function. Here, we demonstrate that patients' NMDAR antibodies cause a selective and reversible decrease in NMDAR surface density and synaptic localization that correlates with patients' antibody titers. The mechanism of this decrease is selective antibody-mediated capping and internalization of surface NMDARs, as Fab fragments prepared from patients' antibodies did not decrease surface receptor density, but subsequent cross-linking with anti-Fab antibodies recapitulated the decrease caused by intact patient NMDAR antibodies. Moreover, whole-cell patch-clamp recordings of miniature EPSCs in cultured rat hippocampal neurons showed that patients' antibodies specifically decreased synaptic NMDAR-mediated currents, without affecting AMPA receptor-mediated currents. In contrast to these profound effects on NMDARs, patients' antibodies did not alter the localization or expression of other glutamate receptors or synaptic proteins, number of synapses, dendritic spines, dendritic complexity, or cell survival. In addition, NMDAR density was dramatically reduced in the hippocampus of female Lewis rats infused with patients' antibodies, similar to the decrease observed in the hippocampus of autopsied patients. These studies establish the cellular mechanisms through which antibodies of patients with anti-NMDAR encephalitis cause a specific, titer-dependent, and reversible loss of NMDARs. The loss of this subtype of glutamate receptors eliminates NMDAR-mediated synaptic function, resulting in the learning, memory, and other behavioral deficits observed in patients with anti-NMDAR encephalitis.

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Eric Beattie, David Stellwagen, Wade Morishita … (2002)

Activity-dependent modulation of synaptic efficacy in the brain contributes to neural circuit development and experience-dependent plasticity. Although glia are affected by activity and ensheathe synapses, their influence on synaptic strength has largely been ignored. Here, we show that a protein produced by glia, tumor necrosis factor alpha (TNFalpha), enhances synaptic efficacy by increasing surface expression of AMPA receptors. Preventing the actions of endogenous TNFalpha has the opposite effects. Thus, the continual presence of TNFalpha is required for preservation of synaptic strength at excitatory synapses. Through its effects on AMPA receptor trafficking, TNFalpha may play roles in synaptic plasticity and modulating responses to neural injury.

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Effect of anti-inflammatory treatment on depression, depressive symptoms, and adverse effects: a systematic review and meta-analysis of randomized clinical trials.

Ole Köhler, Michael Benros, Merete Nordentoft … (2014)

Several studies have reported antidepressant effects of anti-inflammatory treatment; however, the results have been conflicting and detrimental adverse effects may contraindicate the use of anti-inflammatory agents. To systematically review the antidepressant and possible adverse effects of anti-inflammatory interventions. Trials published prior to December, 31, 2013, were identified searching Cochrane Central Register of Controlled Trials, PubMed, EMBASE, PsychINFO, Clinicaltrials.gov, and relevant review articles. Randomized placebo-controlled trials assessing the efficacy and adverse effects of pharmacologic anti-inflammatory treatment in adults with depressive symptoms, including those who fulfilled the criteria for depression. Data were extracted by 2 independent reviewers. Pooled standard mean difference (SMD) and odds ratios (ORs) were calculated. Depression scores after treatment and adverse effects. Ten publications reporting on 14 trials (6262 participants) were included: 10 trials evaluated the use of nonsteroidal anti-inflammatory drugs (NSAIDs) (n=4,258) and 4 investigated cytokine inhibitors (n=2,004). The pooled effect estimate suggested that anti-inflammatory treatment reduced depressive symptoms (SMD, -0.34; 95% CI, -0.57 to -0.11; I2=90%) compared with placebo. This effect was observed in studies including patients with depression (SMD, -0.54; 95% CI, -1.08 to -0.01; I2=68%) and depressive symptoms (SMD, -0.27; 95% CI, -0.53 to -0.01; I2=68%). The heterogeneity of the studies was not explained by differences in inclusion of clinical depression vs depressive symptoms or use of NSAIDs vs cytokine inhibitors. Subanalyses emphasized the antidepressant properties of the selective cyclooxygenase 2 inhibitor celecoxib (SMD, -0.29; 95% CI, -0.49 to -0.08; I2=73%) on remission (OR, 7.89; 95% CI, 2.94 to 21.17; I2=0%) and response (OR, 6.59; 95% CI, 2.24 to 19.42; I2=0%). Among the 6 studies reporting on adverse effects, we found no evidence of an increased number of gastrointestinal or cardiovascular events after 6 weeks or infections after 12 weeks of anti-inflammatory treatment compared with placebo. All trials were associated with a high risk of bias owing to potentially compromised internal validity. Our analysis suggests that anti-inflammatory treatment, in particular celecoxib, decreases depressive symptoms without increased risks of adverse effects. However, a high risk of bias and high heterogeneity made the mean estimate uncertain. This study supports a proof-of-concept concerning the use of anti-inflammatory treatment in depression. Identification of subgroups that could benefit from such treatment might be warranted.