More than 100 years ago, studies in patients with infections associated immune activation with psychiatric disorders. The term “psychoneuroimmunology” arose in the 1980s, representing the bidirectional communication between the brain and the immune system and, more recently, post 2010, the term immunopsychiatry was introduced. The two terms represent different hierarchical models: is the immune system governed by the brain or does the immune system govern the brain? Immunology is one of the more complex fields of medicine, as is neuropsychiatry. How could one attempt combining the two? There is surely sufficient clinical and experimental evidence showing an increased incidence of emotional disorders in patients suffering from immune diseases, and an increased susceptibility to immune diseases in patients suffering from mental disorders, to make this a worthwhile pursuit. This issue of Dialogues in Clinical Neuroscience illustrates how the advances in medical science are at least beginning to allow us to attempt to tease out the interplay between the immune system and behavior.
In this issue, we have tried to introduce new concepts in psychoneuroimmunology, and begin with the State of the art article by Fulvio D’Acquisto (p 9) in which he presents an entirely new field of research on “affective immunology” (where immunity and emotions converge). Recent compelling evidence has shown that the emotional and immunological systems share more than a similarity of functions. Prof d’Acquisto highlights the parallels between psychological and immunological personality, and the crosstalk between emotions and the immune system, and makes the case for a more holistic approach in clinical practice with regard to immune and emotional disorders.
For the past few decades, changes in immune system activity have been identified as a hallmark feature of many chronic diseases, including depression, obesity, type 2 diabetes mellitus, atherosclerosis, and cancer. Following on from this, inflammation has been used as a paradigm for describing the role of the immune system in such disease states. In the first Clinical research paper, Katya and David Rubinow (p 19) elegantly remind readers of the complexity of the immune system and the potential dangers of equating immune function with inflammation. Such reductionism conceals complexity and may lead to inappropriate therapeutic interventions with unintended, adverse effects. They put in an appeal for the use of alternative models, such as allostasis and systems biology, that may facilitate a more textured understanding of immune regulation in metabolic and mood disorders. Mood disorders continue to be a significant burden to those affected, as well as their carers and health care providers. The limitations of current models of mood disorders and lack of effective treatment development have led to the consideration of several other physiological processes, biomarkers, and neurochemicals potentially involved in their development and treatment. Cytokines produced by the innate immune response (eg, IL-6, TNF-α) have been strongly linked to mood disorders and related symptoms, such as fatigue, cognitive impairment, and sleep disturbance. In the second clinical research article, Roger McIntyre and coauthors (p 27) review evidence implicating inflammation in various effector systems in mood disorders, with a particular focus on the intercommunication with glutamatergic signaling and immune system signaling, as well as metabolic parameters.
Evolutionary biologists have often regarded major stress-responsive systems as essential adaptive, survival-promoting mechanisms, and animal models have proved particularly useful in the study of physiological responses to stress. In particular, research on rodents has served as a starting point for understanding the molecular and cellular responses to stress, allowing for a greater understanding of how inflammatory factors, such as cytokines, chemokines, and prostaglandins, can influence brain function. In the Translational research article, Terrence Deak and colleagues (p 37) review how the mechanisms of the neuroimmune response to stress contribute to stress-related psychopathologies, based on findings from multiple species.
Epidemiological studies have repeatedly highlighted infections and autoimmune disorders as risk factors for schizophrenia and major depression. In a Pharmacological aspects paper, Norbert Müller (p 55) provides an overview of immunological aspects in the treatment of depression and schizophrenia. The author describes a historical overview of the basis of immunotherapy for schizophrenia and major depression, and then goes on to present the available evidence for a proinflammatory immune state and increased immune reactivity in at least a subgroup of patients with schizophrenia and major depression. Such studies have highlighted the importance of timing with regard to the effect of anti-inflammatory treatment and stage of disease.
As is now so well-known with cases of Zika virus infection and microcephaly, exposure to infection during pregnancy is associated with an increased risk for developmental brain disorders, including autism spectrum disorder (ASD). Autoimmunity has also been proposed as a major etiological component of ASD. Whether specific autoantibodies directed against brain targets are involved in ASD remains an open question and underlies some of the hope of immunotherapy for neuropsychiatric disorders. In the Brief report, Marion Leboyer’s group (p 65) presents some of their own experimental data, using a single molecule-based imaging approach, to investigate whether NMDAR-Ab IgG from ASD patient serum would have an effect on membrane NMDAR complexes at the synapse.
Cytokines can manifest as generally pro- or anti-inflammatory, depending upon the presence of other signaling molecules and the context in which they are induced. Postmortem analyses of brain and cerebrospinal fluid from patients with Parkinson disease show the accumulation of proinflammatory cytokines, confirming an ongoing neuroinflammation in the affected brain regions. These inflammatory mediators may activate transcription factors which then regulate downstream signaling pathways, that in turn promote death of dopaminergic neurons through death domain–containing receptors. Dopaminergic neurons are vulnerable to oxidative stress and inflammatory attack. In their Free Paper, Tiwari and Pal (p 71) review the different transcription factors and signaling pathways currently known to be involved in the etiology of Parkinson disease.
We hope that this issue will convince the readers of Dialogues in Clinical Neuroscience that there is a need to investigate the crosstalk between the immune system, neuropsychiatric disease, and behavior, with a wide assortment of methods and from many different viewpoints. A multidisciplinary approach will be essential in order to identify new biomarkers and novel therapeutic strategies for patients.
Deborah Morris-Rosendahl, PhD; César Carvajal, MD