Multiple Complement Pathway-related Proteins Might Regulate Immunopathogenesis of Major Depressive Disorder.

Objective: Exacerbated inflammatory pathway has emerged as a predominant etiological construct of major depressive disorder (MDD). Innate immune molecules like complement proteins induce inflammatory responses and also regulate key neurobiological processes. However, there is a dearth of literature on the impact of critical complement proteins in MDD. Herein, plasma profiling of seven complement proteins was carried out to obtain a better insight into the role of the complement pathway in MDD. Methods: Plasma levels of C1q, C3, C3b/iC3b, C4, Factor B, Factor H, and properdin were assayed in 22 patients with MDD and 27 healthy controls by multiplex suspension assay. The patients with MDD were diagnosed as per DSM IV-TR. Hamilton Depression Rating Scale (HAM-D), Montgomery Depression Rating Scale and Clinical Global Improvement were used for clinical assessments of the patients. The plasma levels of these complement proteins were also correlated with various clinical scores and phenotypes of MDD. Results: The patients with MDD and healthy controls did not differ in terms of age and gender (p > 0.1). The patients with MDD had a mean duration of illness of around 3 years, with average number of depressive episodes being 6 and the mean HAM-D score was 19. Of the seven complement components, the plasma levels of C1q, Factor B, and Factor H (p ≤ 0.05) were significantly elevated in MDD patients compared to healthy controls. However, the plasma levels of these complement proteins were not found to correlate with the clinical profile of MDD patients. Conclusion: Both Factor B and Factor H are crucial in the induction and regulation of the alternative pathway of complement activation. The alternative pathway also plays a critical role in inflammation. These findings suggest an important role of the alternative complement pathway in immuno-inflammation in MDD.

Long-term Add-on Yoga Therapy Modulates Oxidative Stress Pathway and Offers Clinical Benefits in Major Depressive Disorder: A Randomized Controlled Trial.

Background: Yoga therapy (YT) as an adjunct treatment has reportedly been demonstrated to offer clinical benefits in major depressive disorder (MDD). Although a few biological pathways are suggested to mediate the effects of yoga, the precise mechanistic basis remains unknown. Oxidative stress pathway activation has consistently been linked to the pathobiology of MDD. Whether YT has a modulatory effect on the oxidative stress pathway in MDD is not adequately understood. Aim and Objectives: In this study, we examined the impact of a course (3 months) of yoga as an add on therapy on the markers of the oxidative stress pathway in MDD patients. Methods: Thirty-three MDD patients were randomized to the YT (n = 16) and waitlist control (WC) (n = 17) groups. Colorimetric estimation of the plasma malondialdehyde (MDA) and total antioxidant (AO) levels was performed in all the study participants using commercially available kits at the baseline and after 3 months. Results: A significant reduction of plasma MDA levels was observed in MDD patients of YT group (P = 0.05) after 3 months of YT. Notably, the plasma MDA levels also decreased in MDD patients of WC group (P = 0.015) after the trial period. In addition, levels of total AO showed a trend toward significance only in MDD patients after 3 months of YT (P = 0.07). Conclusion: The current study suggests that the benefits of YT might be mediated through its modulatory role on the oxidative stress pathway in MDD.

A proof-of-concept study of maternal immune activation mediated induction of Toll-like receptor (TLR) and inflammasome pathways leading to neuroprogressive changes and schizophrenia-like behaviours in offspring.

Infection, particularly prenatal infection, leads to an enhanced risk of schizophrenia in the offspring. Interestingly, few data exist on the pathway(s) such as TLR and inflammasome, primarily involved in sensing the microorganisms and inducing downstream inflammatory responses, apoptosis and neuroprogressive changes that drive prenatal infection-induced risk of schizophrenia. Herein, we aimed to discern whether prenatal infection-induced maternal immune activation (MIA) causes schizophrenia-like behaviours through activation of TLR and inflammasome pathways in the brain of offspring. Sprague Dawley rats (n=15/group) were injected either with poly (I:C) or LPS or saline at gestational day (GD)-12. Significantly elevated plasma levels of IL-6, TNF-α and IL-17A assessed after 24 hours were observed in both the poly (I:C) and LPS-treated rats, while IL-1ß was only elevated in LPS-treated rats, indicating MIA. The offspring of poly (I:C)-and LPS-treated dams displayed increased anxiety-like behaviours, deficits in social behaviours and prepulse inhibition. The hippocampus of offspring rats showed increased expression of Tlr3, Tlr4, Nlrp3, Il1b, and Il18 of poly (I:C) and Tlr4, Nlrp3, Cas1, Il1b, and Il18 of LPS-treated dams. Furthermore, Tlr and inflammasome genes were associated with social deficits and impaired prepulse inhibition in offspring rats. The results suggest that MIA due to prenatal infection can trigger TLR and inflammasome pathways and enhances the risk of schizophrenia-like behaviours in the later stages of life of the offspring.

Maternal Immune Activation Causes Schizophrenia-like Behaviors in the Offspring through Activation of Immune-Inflammatory, Oxidative and Apoptotic Pathways, and Lowered Antioxidant Defenses and Neuroprotection.

Schizophrenia is a complex neuropsychiatric disorder, influenced by a combined action of genes and environmental factors. The neurodevelopmental origin is one of the most widely recognized etiological models of this heterogeneous disorder. Environmental factors, especially infections during gestation, appear to be a major risk determinant of neurodevelopmental basis of schizophrenia. Prenatal infection may cause maternal immune activation (MIA) and enhance risk of schizophrenia in the offspring. However, the precise mechanistic basis through which MIA causes long-lasting schizophrenia-like behavioral deficits in offspring remains inadequately understood. Herein, we aimed to delineate whether prenatal infection-induced MIA causes schizophrenia-like behaviors through its long-lasting effects on immune-inflammatory and apoptotic pathways, oxidative stress toxicity, and antioxidant defenses in the brain of offspring. Sprague-Dawley rats were divided into three groups (n = 15/group) and were injected with poly (I:C), LPS, and saline at gestational day (GD)-12. Except IL-1ß, plasma levels of IL-6, TNF-α, and IL-17A assessed after 24 h were significantly elevated in both the poly (I:C)- and LPS-treated pregnant rats, indicating MIA. The rats born to dams treated with poly (I:C) and LPS displayed increased anxiety-like behaviors and significant deficits in social behaviors. Furthermore, the hippocampus of the offspring rats of both the poly (I:C)- and LPS-treated groups showed increased signs of lipid peroxidation, diminished total antioxidant content, and differentially upregulated expression of inflammatory (TNFα, IL6, and IL1ß), and apoptotic (Bax, Cas3, and Cas9) genes but decreased expression of neuroprotective (BDNF and Bcl2) genes. The results suggest long-standing effects of prenatal infections on schizophrenia-like behavioral deficits, which are mediated by immune-inflammatory and apoptotic pathways, increased oxidative stress toxicity, and lowered antioxidant and neuroprotective defenses. The findings suggest that prenatal infections may underpin neurodevelopmental aberrations and neuroprogression and subsequently schizophrenia-like symptoms.

Evidence of altered Th17 pathway signatures in the cerebrospinal fluid of patients with Guillain Barré Syndrome.

Data indexing the contribution of various immuno-inflammatory components in the cerebrospinal fluid (CSF) towards the pathophysiology of Guillain Barré Syndrome (GBS) are limited. Th17 pathway plays crucial role in many immune mediated disorders of the nervous system. This study was aimed at exploring the role of Th17 pathway related cytokines in the CSF of patients with GBS. Levels of multiple key cytokines of Th17 pathway in CSF of patients with GBS (N = 37) and controls (N = 37) were examined in this prospective study using Bio-plex Pro Human Th17 cytokine assays in a Multiplex Suspension Array platform. The findings were correlated with clinical features and electrophysiological subtypes. Three key cytokines of Th17 pathway (IL-6, IL-17A and IL-22) were significantly elevated in CSF of patients with GBS as compared to controls. There was a positive correlation between the levels of IL-6 and IL-17A as well as between the levels of IL-17A and IL-22 in the CSF of patients with GBS. The CSF levels of IL-6 and IL-22 were negatively correlated with the duration of symptoms of GBS. None of the studied cytokines correlated with functional disability scores at admission to hospital or with the electrophysiological subtypes. Identification of Th17 pathway signatures in CSF sheds more insights into the pathogenic role of Th17 cells in GBS. These findings complement the contemporary knowledge and tender further support towards the involvement of Th17 pathway in GBS.

Inflammatory Role of Cancer-Associated Fibroblasts in Invasive Breast Tumors Revealed Using a Fibrous Polymer Scaffold.

Inflammation in cancer fuels metastasis and worsens prognosis. Cancer-associated fibroblasts (CAFs) present in the tumor stroma play a vital role in mediating the cascade of cancer inflammation that drives metastasis by enhancing angiogenesis, tissue remodeling, and invasion. In vitro models that faithfully recapitulate CAF-mediated inflammation independent of coculturing with cancer cells are nonexistent. We have engineered fibrous matrices of poly(ε-caprolactone) (PCL) that can maintain the manifold tumor-promoting properties of patient-derived CAFs, which would otherwise require repetitive isolation and complex coculturing with cancer cells. On these fibrous matrices, CAFs proliferated and remodeled the extracellular matrix (ECM) in a parallel-patterned manner mimicking the ECM of high-grade breast tumors and induced stemness in breast cancer cells. The response of the fibroblasts was observed to be sensitive to the scaffold architecture and not the polymer composition. The CAFs cultured on fibrous matrices exhibited increased activation of the NF-κB pathway and downstream proinflammatory gene expression compared to CAFs cultured on conventional two-dimensional (2D) dishes and secreted higher levels of proinflammatory cytokines such as IL-6, GM-CSF, and MIP-3α. Consistent with this, we observed increased infiltration of inflammatory cells to the tumor site and enhanced invasiveness of the tumor in vivo when tumor cells were injected admixed with CAFs grown on fibrous matrices. These data suggest that CAFs better retain their tumor-promoting proinflammatory properties on fibrous polymeric matrices, which could serve as a unique model to investigate the mechanisms of stroma-induced inflammation in cancer progression.

Th17 pathway signatures in a large Indian cohort of Guillain Barré syndrome.

The etiopathogenesis of Guillain Barré Syndrome (GBS) is inadequately understood. The role of immuno-inflammatory Th17 pathway was examined in GBS patients by genetic, gene expression and biochemical studies. Genotyping of G197A single nucleotide polymorphism within IL17 gene was carried out by PCR-RFLP method in 220 GBS patients. Quantification of gene expression of STAT3 and RORC and estimation of plasma level of IL-17A were carried out in a subset of patients. Significantly increased STAT3 gene expression in lymphocytes and plasma IL-17A levels were observed in GBS patients. This study adds new dimension and reinforces important implications of Th17 pathway in GBS.

Role of IL-6/RORC/IL-22 axis in driving Th17 pathway mediated immunopathogenesis of schizophrenia.

The immuno-inflammatory origin of schizophrenia in a subset of patients is viewed as a key element of an overarching etiological construct. Despite substantial research, the immune components exerting major effect are yet to be fully clarified. Disrupted T cell networks have consistently been linked to the pathogenesis of schizophrenia. Amongst the Th cell subsets, the Th17 cells have emerged as a paradigmatic lineage with significant functional implications in a vast number of immune mediated diseases including brain disorders such as schizophrenia. The present study was aimed at examining the functional role of the Th17 pathway in schizophrenia. To address this, genotyping of IL17A (rs2275913; G197A) Single Nucleotide Polymorphism was carried out by the PCR-RFLP method in 221 schizophrenia patients and 223 healthy control subjects. Gene expression of two transcription factors STAT3 and RORC was quantified in a subset of drug naïve schizophrenia patients (n = 56) and healthy controls (n = 52) by TaqMan assay. The plasma levels of fifteen cytokines belonging to Th17 pathway were estimated in a subset of drug naïve schizophrenia patients (n = 61) and healthy controls (n = 50) by using Bio-Plex Pro Human Th17 cytokine assays. The AA genotype was associated with higher total score of bizarre behaviour and apathy in female schizophrenia patients. A high gene expression level of RORC was observed in drug naïve schizophrenia patients. In addition, significantly elevated plasma levels of IL-6 and IL-22, and reduced levels of IL-1ß and IL-17F were noted in schizophrenia patients. Taken together, these findings indicate a dysregulated Th17 pathway in schizophrenia patients.

Comprehensive cytokine profiling provides evidence for a multi-lineage Th responses in Guillain Barré Syndrome.

Guillain Barré Syndrome (GBS) is one of the commonest acquired immune-mediated neuropathies, often preceded by infections. Although cellular immune responses are shown to substantially account for the pathophysiology of GBS, the precise mechanistic basis of risk and disease course remains enigmatic till date. Cytokines are best known for their abilities to drive cellular immunity and inflammation through their co-ordinated actions. Data obtained from clinical and animal model studies suggest important implications of some of the cytokines in the progression and recovery of GBS. However, these studies were performed on few cytokines and small set of GBS patients, thereby lacking a complete understanding of the patterns of association of cytokines representing Th1, Th2, and Th17 responses with GBS. We studied 65 well-characterized GBS patients and 73 age- and sex-matched healthy controls. A panel of 15 cytokines representing Th1, Th2 and Th17 pathways was assayed using Multiplex Suspension Array platform. Plasma levels of five cytokines were found to be altered in GBS patients compared to healthy control subjects: (i) IL-1ß exhibited reduced levels, and (ii) IFN-γ, IL-4, IL-21 and IL-33 were elevated in GBS patients. The most important finding of this study was up-regulated expression of IL-21 and IL-33 in patients with GBS. Given the role of IL-33 as an alarmin, the elevated level of this cytokine provides important indication about a much broader role of cytokines in GBS. This study also provides evidence towards a multi-lineage Th cells (Th1, Th2 and Th17) associated cytokine responses in the pathophysiology of GBS.