Immunotherapy with interferons may induce neuropsychiatric symptoms and disorders. Interferon-α-based immunotherapy is used to treat patients with chronic hepatitis C and metastatic renal cell carcinoma. Immunotherapy with interferon-α induces symptoms such as slowness, severe fatigue, hypersomnia, lethargy, depressed mood, mnemonic troubles, irritability, short temper, emotional lability, social withdrawal, lack of concentration and full blown major depression in a considerable number of patients treated. The exact mechanism whereby interferon-α induces depression has remained elusive. However, there is now some evidence that interferon-α-based immunotherapy induces the cytokine network, decreases the serotonergic turnover in the brain, and induces the catabolism of tryptophan. There is evidence that interferon-α immunotherapy-induced depression is related to an increased catabolism of tryptophan into kynurenine.
Depression is associated with inflammation, Th1 and Th17 responses, oxidative and nitrosative stress (O&NS), autoimmune responses against neoantigenic determinants, and neuroprogression (i.e., neurodegeneration, impaired plasticity and reduced neurogenesis). These pathways involve increased monocytic activation and interleukin-1 (IL-1) levels.This review will highlight the putative role of IL-1 in depression and the potential use of IL-1 signaling blockade as a treatment of depression. Electronic databases, i.e., Scopus, PUBMED and Google Scholar were employed using keywords: depression, depressive-like, interleukin-1, and interleukin-1 receptor antagonist (IL-1RA).Ample studies show that depression is accompanied by increased levels of IL-1 and IL-1RA, which attenuates the pro-inflammatory activities of IL-1. In some, but not all studies, antidepressant treatment decreased IL-1β levels. In translational models, IL-1β administration elicits depressive-like behaviors, neuroinflammation and neuroprogression, whereas treatment with IL-1RA yields antidepressant-like effects and attenuates neuroprogression. Anakinra, an IL-1RA, targets not only IL-1 signaling, but also Th1, Th17, O&NS and neuroprogressive pathways and therefore may be advanced to clinical Phase-II trials in depression due to medical conditions associated with an elevated IL-1/IL-1RA ratio.
There is now evidence that the pathophysiology of chronic fatigue syndrome (CFS) is related to inflammation and oxidative & nitrosative stress (ION and b) dam- age to membrane lipids, functional proteins and DNA by ON Pseudomonas Aeruginosa, Morganella Morganii, Pseudomonas Putida, Citrobacter Koseri, and Klebsielle Pneumoniae are significantly increased in patients with CFS. This suggests that in CFS there is an increased LPS translocation through a weakened tight junction barrier with subsequent gut-derived inflammation. This condition indicates an increased gut permeability or leaky gut. Treatment for 10-14 months with specific anti- inflammatory and -oxidative substances (NAIOSs), such as glutamine, N-acetyl cysteine and zinc, with or without immunoglobins intravenously (IVIg), significantly attenuates the initially increased IgA and IgM responses to LPS, showing that the gut-derived inflamma- tion is attenuated and thus that the weakened tight junction barrier is partly restored. The attenuation of gut-derived inflammation predicts the clinical improvement 10-14 months after intake of NAIOSs. The above findings show that an increased translocation of gram negative bacteria with subsequent inflammation is a new pathway that contributes to the systemic IO&NS responses in CFS.
Background Early life trauma (ELT) may drive mood disorder phenomenology, nitro-oxidative pathways and impairments in semantic memory. There are no data regarding the impact of ELT on affective phenomenology and whether these pathways are mediated by staging or lowered lipid-associated antioxidant defences. Methods This study examined healthy controls (n=54) and patients with affective disorders including major depression, bipolar disorder and anxiety disorders (n=118). ELT was assessed using the Child Trauma Questionnaire. In addition, we measured affective phenomenology and assayed advanced oxidation protein products; malondialdehyde, paraoxonase 1 (CMPAase) activity, high-sensitivity C-reactive protein (hsCRP), and high-density lipoprotein (HDL) cholesterol. Results ELT was associated into with increased risk for mood and comorbid anxiety disorders and a more severe phenomenology, including staging characteristics, depression and anxiety severity, suicidal behaviours, type of treatments, disabilities, body mass index, smoking behaviour and hsCRP, as well as lowered health-related quality of life, antioxidant defences and semantic memory. The number of mood episodes and CMPAase/HDL-cholesterol levels could be reliably combined into a new vulnerability staging-biomarker index, which mediates in part the effects of ELT on affective phenomenology and oxidative stress. Moreover, the effects of female sex on mood disorders and affective phenomenology are mediated by ELT. Discussion The cumulative effects of different ELT drive many aspects of affective phenomenology either directly or indirectly through effects of staging and/or lipid-associated antioxidant defences. The results show that children, especially girls, with ELT are at great risk to develop mood disorders and more severe phenotypes of affective disorders.
Both corticotropin releasing hormone (CRH) and serotonin (5-HT) participate in the stress response and are known to modulate cytokine release by human immune cells. Extracellular 5-HT concentrations at or above the serum values have negative immunoregulatory effects by inhibiting the production of interferon-γ (IFNγ), a pro-inflammatory cytokine produced by Th-1-like lymphocytes, whereas 5-HT has no significant effects on the production of interleukin-10 (IL10), an anti-inflammatory cytokine. In one study, CRH significantly decreases IFNγ production by cultured human peripheral blood immunocytes, whereas in other studies CRH increases the production of cytokines, such as IL-1, IL-2 and IL-6. The aims of the present study were to examine i) the effects of CRH, 10–9 M, 10–8 M and 10–7 M, on the stimulated production of IFNγ, IL-10 and tumor necrosis factor-α (TNFα) by human whole blood; and ii) whether CRH, 10–9 M, 10–8 M and 10–7 M, may antagonize some of the negative immunoregulatory effects of 5-HT, 1.5 µg/mL or 15 µg/mL. We found that CRH, 10–9 M, 10–8 M and 10–7 M, had no significant effects either on the stimulated production of IFNγ, IL-10 or TNFα or on the IFNγ/IL-10 production ratio, which reflects the pro-inflammatory capacity of the culture. 5-HT, 1,5 µg/dL and 15 µg/dL, significantly suppressed the production of IFN γ and TNFα and the IFNγ/IL-10 production ratio. CRH, 10–7 M, significantly reversed the 5-HT (1.5 µg/mL and 15 µg/mL)-induced suppression of IFNγ production. CRH at all concentrations significantly blocked the 5-HT (1.5 µg/mL and 15 µg/ mL)-induced suppression of TNFα production. The results suggest that CRH has no significant direct effects on the production of IFN γ, IL-10 and TNFα, but antagonizes the negative immunoregulatory effects of 5-HT on the production of IFNγ and TNFα and on the IFNγ/IL-10 production ratio.
Fibromyalgia (FM) is a prevalent disorder defined by the presence of chronic widespread pain in association with fatigue, sleep disturbances and cognitive dysfunction. Recent studies indicate that bipolar spectrum disorders frequently co-occur in individuals with FM. Furthermore, shared pathophysiological mechanisms anticipate remarkable phenomenological similarities between FM and BD. A comprehensive search of the English literature was carried out in the Pubmed/MEDLINE database through May 10th, 2015 to identify unique references pertaining to the epidemiology and shared pathophysiology between FM and bipolar disorder (BD). Overlapping neural circuits may underpin parallel clinical manifestations of both disorders. Fibromyalgia and BD are both characterized by functional abnormalities in the hypothalamic-pituitary-adrenal axis, higher levels of inflammatory mediators, oxidative and nitrosative stress as well as mitochondrial dysfunction. An over-activation of the kynurenine pathway in both illnesses drives tryptophan away from the production of serotonin and melatonin, leading to affective symptoms, circadian rhythm disturbances and abnormalities in pain processing. In addition, both disorders are associated with impaired neuroplasticity (e.g., altered brain-derived neurotrophic factor signaling). The recognition of the symptomatic and pathophysiological overlapping between FM and bipolar spectrum disorders has relevant etiological, clinical and therapeutic implications that deserve future research consideration.
There is now evidence that chronic fatigue syndrome (CFS) is accompanied by an increased translocation of endotoxins from gram-negative enterobacteria through the gut wall, as demonstrated by increased prevalences and median values for serum IgM and IgA against the endotoxins of gram-negative enterobacteria. This condition can also be described as increased gut permeability or leaky gut and indicates intestinal mucosal dysfunction (IMD). Here we report a case of a 13 year old girl with CFS who showed very high values for serum IgM against the LPS of some enterobacteria and signs of oxidative and nitrosative stress, activation of the inflammatory response system, and IgG3 subclass deficiency. Upon treatment with specific antioxidants and a "leaky gut diet", which both aim to treat increased gut permeability, and immunoglobins intravenously, the increased translocation of the LPS of gram negative enterobacteria normalized and this normalization was accompanied by a complete remission of the CFS symptoms.
