The first findings that depression is characterized by cell-mediated immune activation and inflammation were published between 1990–1993 (Maes et al.). Recently, it was reported that – based on ...meta-analysis results – depression is an inflammatory disorder because the plasma levels of two cytokines are increased, i.e. interleukin-(IL)-6 and tumor necrosis factor-α (TNFα). The same meta-analysis found that plasma IL-2 and interferon-(IFN)γ levels are not altered in depression, suggesting that there is no T cell activation in that illness. The present paper reviews the body of evidence that depression is accompanied by cell-mediated immune activation. The findings include: increased serum levels of the soluble IL-2 receptor (sIL-2R) and the sCD8 molecule; increased numbers and percentages of T cells bearing T cell activation markers, such as CD2+CD25+, CD3+CD25+, and HLA-DR+; increased stimulated production of IFNγ; higher neopterin and sTNFR-1 or sTNFR-2 levels; induction of indoleamine 2,3-dioxygenase (IDO) with lowered levels of plasma tryptophan and increased levels of tryptophan catabolites along the IDO pathway (TRYCATs); and glucocorticoid resistance in immune cells. Interferon-α (IFNα)-based immunotherapy shows that baseline and IFNα-induced activation of T cells, IDO activity and TRYCAT formation are related to the development of IFNα-induced depressive symptoms. Animal models of depression show that a cell-mediated immune response is related to the development of depression-like behavior. Antidepressants and mood stabilizers suppress different aspects of cell-mediated immunity and rather specifically target IFNγ production. This review shows that inflammation and cell-mediated immune activation are key factors in depression.
Machine learning approaches, such as soft independent modeling of class analogy (SIMCA) and pathway analysis, were introduced in depression research in the 1990s (Maes et al.) to construct ...neuroimmune endophenotype classes. The goal of this paper is to examine the promise of precision psychiatry to use information about a depressed person's own pan-omics, environmental, and lifestyle data, or to tailor preventative measures and medical treatments to endophenotype subgroups of depressed patients in order to achieve the best clinical outcome for each individual. Three steps are emerging in precision medicine: (1) the optimization and refining of classical models and constructing digital twins; (2) the use of precision medicine to construct endophenotype classes and pathway phenotypes, and (3) constructing a digital self of each patient. The root cause of why precision psychiatry cannot develop into true sciences is that there is no correct (cross-validated and reliable) model of clinical depression as a serious medical disorder discriminating it from a normal emotional distress response including sadness, grief and demoralization. Here, we explain how we used (un)supervised machine learning such as partial least squares path analysis, SIMCA and factor analysis to construct (a) a new precision depression model; (b) a new endophenotype class, namely major dysmood disorder (MDMD), which is a nosological class defined by severe symptoms and neuro-oxidative toxicity; and a new pathway phenotype, namely the reoccurrence of illness (ROI) index, which is a latent vector extracted from staging characteristics (number of depression and manic episodes and suicide attempts), and (c) an ideocratic profile with personalized scores based on all MDMD features.
Activation of the Toll-like receptor 4 (TLR4) complex, a receptor of the innate immune system, may underpin the pathophysiology of many human diseases, including asthma, cardiovascular disorder, ...diabetes, obesity, metabolic syndrome, autoimmune disorders, neuroinflammatory disorders, schizophrenia, bipolar disorder, autism, clinical depression, chronic fatigue syndrome, alcohol abuse, and toluene inhalation. TLRs are pattern recognition receptors that recognize damage-associated molecular patterns and pathogen-associated molecular patterns, including lipopolysaccharide (LPS) from gram-negative bacteria. Here we focus on the environmental factors, which are known to trigger TLR4, e.g., ozone, atmosphere particulate matter, long-lived reactive oxygen intermediate, pentachlorophenol, ionizing radiation, and toluene. Activation of the TLR4 pathways may cause chronic inflammation and increased production of reactive oxygen and nitrogen species (ROS/RNS) and oxidative and nitrosative stress and therefore TLR-related diseases. This implies that drugs or substances that modify these pathways may prevent or improve the abovementioned diseases. Here we review some of the most promising drugs and agents that have the potential to attenuate TLR-mediated inflammation, e.g., anti-LPS strategies that aim to neutralize LPS (synthetic anti-LPS peptides and recombinant factor C) and TLR4/MyD88 antagonists, including eritoran, CyP, EM-163, epigallocatechin-3-gallate, 6-shogaol, cinnamon extract,
N
-acetylcysteine, melatonin, and molecular hydrogen. The authors posit that activation of the TLR radical (ROS/RNS) cycle is a common pathway underpinning many “civilization” disorders and that targeting the TLR radical cycle may be an effective method to treat many inflammatory disorders.
The gut and mitochondria have emerged as two important hubs at the cutting edge of research across a diverse array of medical conditions, including most psychiatric conditions. This article ...highlights the interaction of the gut and mitochondria over the course of development, with an emphasis on the consequences for transdiagnostic processes across psychiatry, but with relevance to wider medical conditions. As well as raised levels of circulating lipopolysaccharide (LPS) arising from increased gut permeability, the loss of the short-chain fatty acid, butyrate, is an important mediator of how gut dysbiosis modulates mitochondrial function. Reactive cells, central glia and systemic immune cells are also modulated by the gut, in part via impacts on mitochondrial function in these cells. Gut-driven alterations in the activity of reactive cells over the course of development are proposed to be an important determinant of the transdiagnostic influence of glia and the immune system. Stress, including prenatal stress, also acts via the gut. The suppression of butyrate, coupled to raised LPS, drives oxidative and nitrosative stress signalling that culminates in the activation of acidic sphingomyelinase-induced ceramide. Raised ceramide levels negatively regulate mitochondrial function, both directly and via its negative impact on daytime, arousal-promoting orexin and night-time sleep-promoting pineal gland-derived melatonin. Both orexin and melatonin positively regulate mitochondria oxidative phosphorylation. Consequently, gut-mediated increases in ceramide have impacts on the circadian rhythm and the circadian regulation of mitochondrial function. Butyrate, orexin and melatonin can positively regulate mitochondria via the disinhibition of the pyruvate dehydrogenase complex, leading to increased conversion of pyruvate to acetyl- CoA. Acetyl-CoA is a necessary co-substrate for the initiation of the melatonergic pathway in mitochondria and therefore the beneficial effects of mitochondria melatonin synthesis on mitochondrial function. This has a number of treatment implications across psychiatric and wider medical conditions, including the utilization of sodium butyrate and melatonin. Overall, gut dysbiosis and increased gut permeability have significant impacts on central and systemic homeostasis via the regulation of mitochondrial function, especially in central glia and systemic immune cells.
Here, we review a novel concept namely the compensatory immune-regulatory reflex system (CIRS) as applied to the pathophysiology of major depressive disorder (MDD) and bipolar disorder (BD). There is ...evidence that a substantial subset of individuals with MDD and BD exhibit an activation of the immune-inflammatory response system (IRS), as indicated by an increased production of macrophagic M1 and T helper (Th)-1 pro-inflammatory cytokines, interleukin (IL)-6 trans-signaling, positive acute phase proteins (APPs), and complement factors. These immune aberrations appear to be evident during the course of major affective episodes of either depressive or (hypo) manic polarity. Here, we review (a) the current state of the art of CIRS functions in both mood disorders and (b) the possible role of CIRS-related biomarkers for the understanding of affective disorders within the framework of precision psychiatry that could also provide novel drug targets for both MDD and BD. CIRS-related abnormalities in mood disorders include elevated Th-2 and T regulatory (Treg) activities with increased IL-4 and IL-10 production, classical IL-6 signaling, increased levels of sIL-1R antagonist (sIL-1RA), soluble IL-2 (sIL-2R) and tumor necrosis factor–α- receptors, and positive APPs, including haptoglobin, hemopexin, α1-acid glycoprotein, α1-antitrypsin, and ceruloplasmin. It is concluded that CIRS is involved in MDD and BD by regulating the primary immune-inflammatory response, thereby contributing to spontaneous and antidepressant-promoted recovery from the acute phase of illness. Signs of activated IRS and CIRS pathways are observed in the remitted phases of both disorders indicating that there is no return to the original homeostasis after an acute episode, while later episodes of mood disorders are characterized by sensitized IRS and CIRS responses. New z-unit weighted composite biomarker scores are proposed, which reflect different aspects of IRS versus CIRS activation and may be used to estimate different IRS/CIRS activity ratios in mood and other neuroimmune disorders.
There is robust evidence that major depression (MDD) is accompanied by a low-grade activation of the immune-inflammatory response system, which is involved in the pathophysiology of this disorder. It ...is also becoming apparent that glia cells are in reciprocal communication with neurons, orchestrate various neuromodulatory, homeostatic, metabolic, and immune mechanisms, and have a crucial role in neuroinflammatory mechanisms in MDD. Those cells mediate the central nervous system (CNS) response to systemic inflammation and psychological stress, but at the same time, they may be an origin of the inflammatory response in the CNS. The sources of activation of the inflammatory response in MDD are immense; however, in recent years, it is becoming increasingly evident that the gastrointestinal tract with gut-associated lymphoid tissue (GALT) and increased intestinal permeability to bacterial LPS and food-derived antigens contribute to activation of low-grade inflammatory response with subsequent psychiatric manifestations. Furthermore, an excessive permeability to gut-derived antigenic material may lead to subsequent autoimmunities which are also known to be comorbid with MDD. In this review, we discuss fascinating interactions between the gastrointestinal tract, increased intestinal permeability, intestinal microbiota, and glia-neuron cross talk, and their roles in the pathogenesis of the inflammatory hypothesis of MDD. To emphasize those crucial intercommunications for the brain functions, we propose the term of microbiota-gut-immune-glia (MGIG) axis.
This paper reviews recent work on the biological underpinnings of clinical depression emphasizing the crucial role of immunoinflammatory and oxidative and nitrosative stress (O&NS) pathways in ...driving changes in neuronal regulating tryptophan catabolites (TRYCATs). The essence of the association of O&NS pathways with autoimmune responses in depression is via damage to lipid membranes, anchorage molecules and functional proteins that lead to changes in their chemical structures creating new modified epitopes (neoepitopes), which are highly immunogenic. The abovementioned pathways together with decreased antioxidant levels, including zinc, coenzyme Q10, glutathione and vitamin E, and melatonin are intimately involved in different aspects of depression, including mitochondrial functions and the regulation of cAMP / circadian genes, allowing for impacts across different aspects of symptom patterning. Immuno- inflammatory and O&NS processes may additionally cause alterations in blood-brain barrier permeability and neuroprogression, that is tissue damage, including neurodegeneration and apoptosis, and decreased neurogenesis and neuroplasticity. Activation of those interconnected pathways is relevant to the pathophysiology of acute and chronic depression and the progressive course (staging) of clinical depression. This implies that compounds that target these pathways may be useful to treat acute episodes and prevent further progression of the disease. We herein review some promising compounds, such as melatonin, melatonin receptor agonists, allopregnanolone, PDE4 inhibitors, statins, aspirin, sodium benzoate, tryptophan-enriched diets, and antioxidants, including epigallocatechin gallate, curcumin, quercitin, alpha-lipoic acid and resveratrol.
'Encephalomyelitis disseminata' (multiple sclerosis) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are both classified as diseases of the central nervous system by the World Health ...Organization. This review aims to compare the phenomenological and neuroimmune characteristics of MS with those of ME/CFS.
There are remarkable phenomenological and neuroimmune overlaps between both disorders. Patients with ME/CFS and MS both experience severe levels of disabling fatigue and a worsening of symptoms following exercise and resort to energy conservation strategies in an attempt to meet the energy demands of day-to-day living. Debilitating autonomic symptoms, diminished cardiac responses to exercise, orthostatic intolerance and postural hypotension are experienced by patients with both illnesses. Both disorders show a relapsing-remitting or progressive course, while infections and psychosocial stress play a large part in worsening of fatigue symptoms. Activated immunoinflammatory, oxidative and nitrosative (O+NS) pathways and autoimmunity occur in both illnesses. The consequences of O+NS damage to self-epitopes is evidenced by the almost bewildering and almost identical array of autoantibodies formed against damaged epitopes seen in both illnesses. Mitochondrial dysfunctions, including lowered levels of ATP, decreased phosphocreatine synthesis and impaired oxidative phosphorylation, are heavily involved in the pathophysiology of both MS and ME/CFS. The findings produced by neuroimaging techniques are quite similar in both illnesses and show decreased cerebral blood flow, atrophy, gray matter reduction, white matter hyperintensities, increased cerebral lactate and choline signaling and lowered acetyl-aspartate levels.
This review shows that there are neuroimmune similarities between MS and ME/CFS. This further substantiates the view that ME/CFS is a neuroimmune illness and that patients with MS are immunologically primed to develop symptoms of ME/CFS.
It is of considerable translational importance whether depression is a form or a consequence of sickness behavior. Sickness behavior is a behavioral complex induced by infections and immune trauma ...and mediated by pro-inflammatory cytokines. It is an adaptive response that enhances recovery by conserving energy to combat acute inflammation. There are considerable phenomenological similarities between sickness behavior and depression, for example, behavioral inhibition, anorexia and weight loss, and melancholic (anhedonia), physio-somatic (fatigue, hyperalgesia, malaise), anxiety and neurocognitive symptoms. In clinical depression, however, a transition occurs to sensitization of immuno-inflammatory pathways, progressive damage by oxidative and nitrosative stress to lipids, proteins, and DNA, and autoimmune responses directed against self-epitopes. The latter mechanisms are the substrate of a neuroprogressive process, whereby multiple depressive episodes cause neural tissue damage and consequent functional and cognitive sequelae. Thus, shared immuno-inflammatory pathways underpin the physiology of sickness behavior and the pathophysiology of clinical depression explaining their partially overlapping phenomenology. Inflammation may provoke a Janus-faced response with a good, acute side, generating protective inflammation through sickness behavior and a bad, chronic side, for example, clinical depression, a lifelong disorder with positive feedback loops between (neuro)inflammation and (neuro)degenerative processes following less well defined triggers.
The genesis of severe fatigue and disability in people following acute pathogen invasion involves the activation of Toll-like receptors followed by the upregulation of proinflammatory cytokines and ...the activation of microglia and astrocytes. Many patients suffering from neuroinflammatory and autoimmune diseases, such as multiple sclerosis, Parkinson's disease and systemic lupus erythematosus, also commonly suffer from severe disabling fatigue. Such patients also present with chronic peripheral immune activation and systemic inflammation in the guise of elevated proinflammtory cytokines, oxidative stress and activated Toll-like receptors. This is also true of many patients presenting with severe, apparently idiopathic, fatigue accompanied by profound levels of physical and cognitive disability often afforded the non-specific diagnosis of chronic fatigue syndrome.
Multiple lines of evidence demonstrate a positive association between the degree of peripheral immune activation, inflammation and oxidative stress, gray matter atrophy, glucose hypometabolism and cerebral hypoperfusion in illness, such as multiple sclerosis, Parkinson's disease and chronic fatigue syndrome. Most, if not all, of these abnormalities can be explained by a reduction in the numbers and function of astrocytes secondary to peripheral immune activation and inflammation. This is also true of the widespread mitochondrial dysfunction seen in otherwise normal tissue in neuroinflammatory, neurodegenerative and autoimmune diseases and in many patients with disabling, apparently idiopathic, fatigue. Given the strong association between peripheral immune activation and neuroinflammation with the genesis of fatigue the latter group of patients should be examined using FLAIR magnetic resonance imaging (MRI) and tested for the presence of peripheral immune activation.
It is concluded that peripheral inflammation and immune activation, together with the subsequent activation of glial cells and mitochondrial damage, likely account for the severe levels of intractable fatigue and disability seen in many patients with neuroimmune and autoimmune diseases.This would also appear to be the case for many patients afforded a diagnosis of Chronic Fatigue Syndrome.
PDF
