Immune System Abnormalities Research Articles

Dysregulation of Th1, Th2, Th17, and T regulatory cell-related transcription factor signaling in children with autism

Autism is a neurodevelopmental disorder characterized by stereotypic repetitive behaviors, impaired social interactions, and communication deficits. Numerous immune system abnormalities have been described in individuals with autism including abnormalities in the ratio of Th1/Th2/Th17 cells; however, the expression of the transcription factors responsible for the regulation and differentiation of Th1/Th2/Th17/Treg cells has not previously been evaluated. Peripheral blood mononuclear cells (PBMCs) from children with autism (AU) or typically developing (TD) control children were stimulated with phorbol-12-myristate 13-acetate (PMA) and ionomycin in the presence of brefeldin A. The expressions of Foxp3, RORγt, STAT-3, T-bet, and GATA-3 mRNAs and proteins were then assessed. Our study shows that children with AU displayed altered immune profiles and function, characterized by a systemic deficit of Foxp3+ T regulatory (Treg) cells and increased RORγt+, T-bet+, GATA-3+, and production by CD4+ T cells as compared to TD. This was confirmed by real-time PCR (RT-PCR) and western blot analyses. Our results suggest that autism impacts transcription factor signaling, which results in an immunological imbalance. Therefore, the restoration of transcription factor signaling may have a great therapeutic potential in the treatment of autistic disorders.

Childhood histoplasmosis in Colombia: Clinical and laboratory observations of 45 patients.

Histoplasmosis is an important mycosis in the Americas; and in children with no immune system abnormalities, histoplasmosis is typically a self-limited process. In contrast, in children with immune problems, disease manifestations are frequently more severe and include dissemination. From 1984 to 2010, a retrospective study of paediatric patients who had been diagnosed with histoplasmosis was performed. A total of 45 pediatric cases of histoplasmosis were identified. The most important risk factor was malnutrition (37%), followed by environmental exposure (33%). The patients exhibited pulmonary infiltrates (83%), fever (76%), cough, constitutional symptoms (38%), headache (35%), and lymph node hypertrophy (33%). Concerning the clinical forms, 64% of the patients presented with the progressive disseminated form that frequently affected the central nervous system (48%). Diagnostic laboratory tests indicated that the cultures were positive for 80% of the patients, the agar gel immunodiffusion was reactive in 95%, the M band of the precipitate was more commonly observed (81%), and the complement fixation tests were reactive in 88% of the patients. The timely diagnosis of histoplasmosis is important, and for this reason, it is hoped that the results of this study will lead pediatricians toward a better understanding of this mycosis in children.

Changes in Soluble CD18 in Murine Autoimmune Arthritis and Rheumatoid Arthritis Reflect Disease Establishment and Treatment Response.

IntroductionIn rheumatoid arthritis (RA) immune activation and presence of autoantibodies may precede clinical onset of disease, and joint destruction can progress despite remission. However, the underlying temporal changes of such immune system abnormalities in the inflammatory response during treat-to-target strategies remain poorly understood. We have previously reported low levels of the soluble form of CD18 (sCD18) in plasma from patients with chronic RA and spondyloarthritis. Here, we study the changes of sCD18 before and during treatment of early RA and following arthritis induction in murine models of rheumatoid arthritis.MethodsThe level of sCD18 was analyzed with a time-resolved immunoflourometric assay in 1) plasma from early treatment naïve RA patients during a treat-to-target strategy (the OPERA cohort), 2) plasma from chronic RA patients, 3) serum from SKG and CIA mice following arthritis induction, and 4) supernatants from synovial fluid mononuclear cells (SFMCs) and peripheral blood mononuclear cells (PBMCs) from 6 RA patients cultured with TNFα or adalimumab.ResultsPlasma levels of sCD18 were decreased in chronic RA patients compared with early RA patients and in early RA patients compared with healthy controls. After 12 months of treatment the levels in early RA patients were similar to healthy controls. This normalization of plasma sCD18 levels was more pronounced in patients with very early disease who achieved an early ACR response. Plasma sCD18 levels were associated with radiographic progression. Correspondingly, the serum level of sCD18 was decreased in SKG mice 6 weeks after arthritis induction compared with healthy littermates. The sCD18 levels in both SKG and CIA mice exhibited a biphasic course after arthritis induction with an initial increase above baseline followed by a decline. Shedding of CD18 from RA SFMC and RA PBMC cultures was increased by TNFα and decreased by adalimumab.ConclusionsThe plasma sCD18 levels were altered in patients with RA, in mice with autoimmune arthritis and in cell cultures treated with TNFα and adalimumab. Decreased levels of plasma sCD18 could reflect autoimmunity in transition from early to chronic disease and normalization in response to treatment could reflect autoimmunity in remission.

Levels of IL-8 and TNF-α decrease in Parkinson’s disease

Background: Peripheral immune system abnormalities are associated with Parkinson’s disease, but role of inflammatory factors in Parkinson’s disease has not been consistently proven yet. Thus, population-based studies are needed in the addition of peripheral dysfunction knowledge associated with Parkinson’s disease. IL-8 and TNF-α are inflammatory factors that might be involved in PD. The aim of the present study was to evaluate the levels of IL-8 and TNF-α in Parkinson’s disease patients from India.Methods: Serum samples were collected from Parkinson’s disease patients (n = 81) and their respective controls (n = 83). The levels of IL-8 and TNF-α were determined using Enzyme-linked immunosorbent assay.Results: The levels of IL-8 (patients = 222.70 ± 200.91 pg/ml, controls = 1584.44 ± 504.44 pg/ml; p < 0.001) and TNF-α (patients = 45.67 ± 24.69 pg/ml, controls = 638.25 ± 511.02 pg/ml; p < 0.001) were lower in the serum of Parkinson’s disease patients than controls and the differences were statistically significant. Their levels were also significantly lower in both male and female patients as compared with their respective controls (p < 0.001). IL-8 was significantly lower in the female controls when compared with the male controls (p < 0.001). Their levels were not influenced by disease severity. Significant weak correlation was found between disease duration and the level of IL-8, but not with age at onset among patients. However, the level of TNF-α did not show correlation with disease duration and age at onset among patients.Conclusion: The levels of IL-8 and TNF-α were significantly lower in serum of Parkinson’s disease patients, which suggested that inflammatory factors might exert their effect and more specifically, inflammation might play crucial role in Parkinson’s disease.

Lymphocytic interstitial pneumonia in a patient with Sjögren's syndrome

Lymphocytic interstitial pneumonia (LIP) is a rare benign lymphoproliferative disorder characterized by diffuse infiltration of the pulmonary parenchymal interstitium by polyclonal lymphocytes and plasma cells. LIP has been associated with a variety of clinical conditions; such as connective tissue disorders and other immune system abnormalities. Treatment usually involves administration of corticosteroids and other immunosuppressants. We report on a 38-year-old female patient who complained of shortness of breath, dry mouth, and dry eyes for more than 1 month, and was positive for Raynaud`s phenomenon. Based on surgical biopsy, she was diagnosed as having LIP accompanied by Sjogren`s syndrome. The patient was treated with highdose steroids followed by maintenance therapy for approximately 2 years, and her condition improved.

Oxidative stress, innate immunity, and age-related macular degeneration.

Age-related macular degeneration (AMD) is a leading cause of vision loss affecting tens of millions of elderly worldwide. Early AMD is characterized by the appearance of soft drusen, as well as pigmentary changes in the retinal pigment epithelium (RPE). These soft, confluent drusen can progress into two forms of advanced AMD: geographic atrophy (GA, or dry AMD) or choroidal neovascularization (CNV, or wet AMD). Both forms of AMD result in a similar clinical progression in terms of loss of central vision. The exact mechanism for developing early AMD, as well as triggers responsible for progressing to advanced stage of disease, is still largely unknown. However, significant evidence exists demonstrating a complex interplay of genetic and environmental factors as causes of AMD progression. Multiple genes and/or single nucleotide polymorphisms (SNPs) have been found associated with AMD, including various genes involved in the complement pathway, lipid metabolism and extracellular matrix (ECM) remodeling. Of the known genetic contributors to disease risk, the CFH Y402H and HTRA1/ARMS polymorphisms contribute to more than 50% of the genetic risk for AMD. Environmentally, oxidative stress plays a critical role in many aging diseases including cardiovascular disease, cancer, Alzheimer’s disease and AMD. Due to the exposure to sunlight and high oxygen concentration, the oxidative stress burden is higher in the eye than other tissues, which can be further complicated by additional oxidative stressors such as smoking. Increasingly, evidence is accumulating suggesting that functional abnormalities of the innate immune system incurred via high risk genotypes may be contributing to the pathogenesis of AMD by altering the inflammatory homeostasis in the eye, specifically in the handling of oxidation products. As the eye in non-pathological instances maintains a low level of inflammation despite the presence of a relative abundance of potentially inflammatory molecules, we have previously hypothesized that the tight homeostatic control of inflammation via the innate immune system is likely critical for avoidance of disease progression. However, the presence of a multitude of potential triggers of inflammation results in a sensitive balance in which perturbations thereof would subsequently alter the inflammatory state of the retina, leading to a state of chronic inflammation and pathologic progression. In this review, we will highlight the background literature surrounding the known genetic and environmental contributors to AMD risk, as well as a discussion of the potential mechanistic interplay of these factors that lead to disease pathogenesis with particular emphasis on the delicate control of inflammatory homeostasis and the centrality of the innate immune system in this process.

A homozygous STIM1 mutation impairs store-operated calcium entry and natural killer cell effector function without clinical immunodeficiency

A homozygous STIM1 mutation impairs store-operated calcium entry and natural killer cell effector function without clinical immunodeficiency

Modulation of Cytokine Network in the Comorbidity of Schizophrenia and Tuberculosis.

Schizophrenia is a severe complex disabling disease that has impaired about 1% of the total population. It is widely recognized that schizophrenia is caused by the abnormal immune system. However, the current genome-wide association study (GWAS) of schizophrenia did not identify any cytokine molecules except genes in the major histocompatibility complex (MHC) region, suggesting that new strategies are needed to find out the effects of cytokines during the development of Schizophrenia. Recently, increasing evidences have found the comorbidity of schizophrenia with tuberculosis. To narrow down the scope of cytokines and reveal the core culprit, we first systematically review the common cytokines between these two diseases, followed by summarizing the core cytokines' interaction and modulation. The findings thus obtained may provide useful insights into the pathogeneses of both schizophrenia and tuberculosis from the angle of cytokines.

Autoimmune rheumatic disease and sleep: a review.

Sleep has an important role to play in the human immune system and it is critical in the restoration and maintenance of homeostasis. Sleep deprivation and disorders may have a profound impact on health, well being and the ability to resist infection. Autoimmune rheumatic diseases are multisystem disorders that involve complicated hormonal and immunological pathophysiology. Previous studies have suggested that sleep deprivation may lead to immunological disturbance in experimental mouse models. Sleep disorders may trigger immune system abnormalities inducing autoantibody production, possibly leading to the development of autoimmune disease such as systemic lupus erythematosus, scleroderma or rheumatoid arthritis. Indeed, in experimental models, it has been suggested that sleep deprivation may induce the onset of autoimmune disease. Chronic deprivation of sleep is common in modern society and has been seen in various autoimmune inflammatory rheumatic diseases. We have reviewed various aspects of sleep deprivation and sleep apnoea syndrome, and their effects on the immune system and their relevance to autoimmune diseases. We hope that these data will encourage greater awareness of the role that improved sleep hygiene may play in the management of these rheumatic diseases.

Loss of arylformamidase with reduced thymidine kinase expression leads to impaired glucose tolerance.

ABSTRACTTryptophan metabolites have been linked in observational studies with type 2 diabetes, cognitive disorders, inflammation and immune system regulation. A rate-limiting enzyme in tryptophan conversion is arylformamidase (Afmid), and a double knockout of this gene and thymidine kinase (Tk) has been reported to cause renal failure and abnormal immune system regulation. In order to further investigate possible links between abnormal tryptophan catabolism and diabetes and to examine the effect of single Afmid knockout, we have carried out metabolic phenotyping of an exon 2 Afmid gene knockout. These mice exhibit impaired glucose tolerance, although their insulin sensitivity is unchanged in comparison to wild-type animals. This phenotype results from a defect in glucose stimulated insulin secretion and these mice show reduced islet mass with age. No evidence of a renal phenotype was found, suggesting that this published phenotype resulted from loss of Tk expression in the double knockout. However, despite specifically removing only exon 2 of Afmid in our experiments we also observed some reduction of Tk expression, possibly due to a regulatory element in this region. In summary, our findings support a link between abnormal tryptophan metabolism and diabetes and highlight beta cell function for further mechanistic analysis.

Evidence for abnormal cytokine expression in Gulf War Illness: A preliminary analysis of daily immune monitoring data

BackgroundGulf War Illness (GWI) is a clinically heterogeneous chronic condition that affects many veterans of the 1990–1991 Persian Gulf War. One of the most prevalent and debilitating symptoms of GWI is abnormal fatigue. The mechanisms underlying GWI generally, and fatigue symptoms specifically, have yet to be conclusively identified, although immune system abnormalities are suspected to be involved. The first goal of this immune monitoring study was to determine if GWI is associated with higher absolute levels and daily variability of pro-inflammatory immune factors. The second goal was to explore the relationship between day-to-day immune marker fluctuations and daily self-reported fatigue severity. MethodsWe recruited veterans with GWI and healthy veteran control (HV) participants to provide self-reported fatigue severity data and blood samples, over 25 consecutive days. We profiled inflammatory processes by using a longitudinal, daily immune-monitoring approach. For each day, serum cytokine and chemokine concentrations were determined using multiplex assays.ResultsSeven veterans with GWI and eight healthy veteran control (HV) participants completed the study protocol. We found that GWI was associated with higher variability in the expression of eotaxin-1 (p < 0.001). For GWI participants, higher fatigue severity days were associated with greater IL-1β (p = 0.008) and IL-15 (p < 0.001).ConclusionsOur findings provide preliminary evidence that the immune system is involved in the pathophysiology of GWI. Longitudinal immune profiling approaches may be helpful in discovering targets for novel therapies in conditions such as GWI.

Silicosis and renal disease: insights from a case of IgA nephropathy

A 68-yr-old male, smoker, is admitted for proteinuria (2,800 mg/24 h) and reduced renal function (serum creatinine 2 mg/dl, GFR 35 ml/min). Renter, he started working 20-yr-old as a sandstone cave miner. Despite the high levels of silica dusts, he reported no mandatory use of airways protection devices during the first 25 yr of activity. No clinical or radiological signs of silicosis or pneumoconiosis where reported until the year of retirement (1997). Erythrocyte sedimentation rate (91 mm/h) and C reactive protein (35 mg/l) suggested a pro-inflammatory status. High serum IgA was found (465 mg/dl). A renal biopsy identified glomerular sclerosis with IgA deposition, signs of diffuse vasculitis and tubular atrophia suggesting a diagnosis of IgA nephropathy. Chest X-Rays showed emphysema and diffuse nodularity suggesting diagnosis of silicosis. Chest tomography was also positive for mild signs of silicosis with silicotic nodules and without honeycombing. IgA nephropathy is the most common type of glomerulonephritis worldwide. Several clues suggest a genetic or acquired abnormality of immune system as a trigger of the increased production of IgA. In our case report, simultaneous kidney and pulmonary disease could suggest same triggers (e.g. exposure to virus, bacteria or environmental agents) inducing IgA synthesis and pulmonary immune system activation.

Interleukin (IL)- 6 inhibition - Follow-up data of the German AID-registry1

Systemic juvenile idiopathic arthritis (SJIA) is regarded as an autoinflammatory disease (AID) of unknown etiology related to abnormalities of the innate immune system. A major role in the pathogenesis has been ascribed to proinflammatory cytokines as interleukin (IL)-6 and IL-1.

Relationship between vitamin D, VDBP, VDR and asthma in children

More and more studies have indicated that the relationship between vitamin D pathway and asthma, and the mechanisms include multiple abnormal aspects of vitamin D pathway leading to abnormal embryonic development and immune system disorders and so on.This review summarizes the relationship between vitamin D, vitamin D binding protein, vitamin D receptors, related gene polymorphisms and the immune system to describe the pathogenesis of asthma. Key words: Vitamin D; Vitamin D binding protein; Vitamin D receptor; Asthma

Cytokine and immune system abnormalities in fibromyalgia and other central sensitivity syndromes.

The nervous system as well as the immune system use common signaling molecules for intra- and inter-system communications. Specifically, both entities produce a similar array of peptide and non-peptide transmitters that act on a common set of receptors present in the two systems. One important set of such signaling molecules are cytokines. The wide distribution of cytokine receptors throughout the body, including the immune and the nervous system allows direct communication between these two entities. In addition to cytokines the nervous system and immune system also communicate with each other using shared ligands such as neurotransmitters and neuroendocrine hormones, and their respective receptors. Some of the most important clinical interactions between these two systems are associated with the "sickness response" as well as pain and analgesia. This "sickness response" which has been frequently attributed to inflammatory cytokines, strongly resembles the core symptoms of fibromyalgia and other Central Sensitivity Syndromes (CSS). Therefore a large number of research studies have focused on the relationship between peripheral cytokines and CSS. However, a lack of consistent associations was observed between CSS symptoms and peripheral cytokines which seem to suggest that maybe cytokines abnormalities of the central nervous system contribute to the pathogenesis of these illnesses. Better knowledge of cytokine -nervous system interactions may ultimately benefit the development of interventions that improve CSS manifestations including the "sickness response" and chronic pain.

Pathogenesis of Systemic Sclerosis.

Systemic scleroderma (SSc) is one of the most complex systemic autoimmune diseases. It targets the vasculature, connective tissue-producing cells (namely fibroblasts/myofibroblasts), and components of the innate and adaptive immune systems. Clinical and pathologic manifestations of SSc are the result of: (1) innate/adaptive immune system abnormalities leading to production of autoantibodies and cell-mediated autoimmunity, (2) microvascular endothelial cell/small vessel fibroproliferative vasculopathy, and (3) fibroblast dysfunction generating excessive accumulation of collagen and other matrix components in skin and internal organs. All three of these processes interact and affect each other. The disease is heterogeneous in its clinical presentation that likely reflects different genetic or triggering factor (i.e., infection or environmental toxin) influences on the immune system, vasculature, and connective tissue cells. The roles played by other ubiquitous molecular entities (such as lysophospholipids, endocannabinoids, and their diverse receptors and vitamin D) in influencing the immune system, vasculature, and connective tissue cells are just beginning to be realized and studied and may provide insights into new therapeutic approaches to treat SSc.

BERTAHAN DENGAN LUPUS: GAMBARAN RESILIENSI PADA ODAPUS

Lupus is a chronic, autoimmune disease in which an abnormal immune system can cause inflammation on several organ or body systems. The risk of mortality rate caused by Lupus is high and late diagnosis is also prevalent which impact the psychological aspect of individual affected with Lupus (so-called Odapus). Therefore, resiliency is needed; that is individual ability to survive and keep optimistic attitude towards recovery. This study aims to describe the resiliency of the affected individuals with Lupus. This is a qualitative study. Eight persons affected with Lupus who were still coping with Lupus participated in this study. The results indicated that subjects developed a negatives constructs to adapt with Lupus. Therefore, psychological intervention is needed to improve their resiliency.

Toxicology of Organochlorines: Implications of Presence in Breast Milk

Background: Organochlorine pesticides (OCPs) are compounds that have been widely used in agriculture to control pests and also in the field of public health to control of paludism dissemination and other vectors. Currently, they are banned in most countries because they constitute a great threat to human health and ecosystems. The high affinity for adipose tissue and its slow metabolism place OCPs in the group of bioacumulative substances. Hence, OCPs passage into breast milk is high and involves a severe risk for infants. Objective: Analyze the toxicity including toxicodynamic and toxicokinetic of organochlorine (OC) and evaluate perinatal and infant toxicity after its exposure through breast milk. Methods: A desk top systematic literature research was carried out to explore the toxicity of OCPs. We conducted an extensive literature review using databases such as Web of Knowledge, Google search engine, Science Direct, Medline, Scopus, Lilacs databases and involved observational Mini-review Article Ezequiel et al.; JALSI, 2(2): xxx-xxx, 2015; Article no.JALSI.2015.006 50 studies on low-dose exposure in humans. Results: 1) OCPs constitute a real threat to ecosystems and public health. 2) They are concentrated in breast milk and breastfeeding contributes to worsen this exposure during the lactation period. 3) They have severe effects on CNS and the immune system, inducing mutagenesis, carcinogenesis, teratogenesis, metabolic and reproductive abnormalities 3) The human fetus and infant exposure to OCPs cause learning disabilities, low intelligence quotient, attention deficit and hyperactivity. Conclusions: For children, the best way to determine the risk of OC exposure is the analysis of breast milk samples and milk producing animals.

Zinc in gut-brain interaction in autism and neurological disorders.

A growing amount of research indicates that abnormalities in the gastrointestinal (GI) system during development might be a common factor in multiple neurological disorders and might be responsible for some of the shared comorbidities seen among these diseases. For example, many patients with Autism Spectrum Disorder (ASD) have symptoms associated with GI disorders. Maternal zinc status may be an important factor given the multifaceted effect of zinc on gut development and morphology in the offspring. Zinc status influences and is influenced by multiple factors and an interdependence of prenatal and early life stress, immune system abnormalities, impaired GI functions, and zinc deficiency can be hypothesized. In line with this, systemic inflammatory events and prenatal stress have been reported to increase the risk for ASD. Thus, here, we will review the current literature on the role of zinc in gut formation, a possible link between gut and brain development in ASD and other neurological disorders with shared comorbidities, and tie in possible effects on the immune system. Based on these data, we present a novel model outlining how alterations in the maternal zinc status might pathologically impact the offspring leading to impairments in brain functions later in life.

Immunomodulatory Effects of Probiotic Supplementation in Schizophrenia Patients: A Randomized, Placebo-Controlled Trial.

Although peripheral immune system abnormalities have been linked to schizophrenia pathophysiology, standard antipsychotic drugs show limited immunological effects. Thus, more effective treatment approaches are required. Probiotics are microorganisms that modulate the immune response of the host and, therefore, may be beneficial to schizophrenia patients. The aim of this study was to examine the possible immunomodulatory effects of probiotic supplementation in chronic schizophrenia patients. The concentrations of 47 immune-related serum proteins were measured using multiplexed immunoassays in samples collected from patients before and after 14 weeks of adjuvant treatment with probiotics (Lactobacillus rhamnosus strain GG and Bifidobacterium animalis subsp. lactis strain Bb12; n = 31) or placebo (n = 27). Probiotic add-on treatment significantly reduced levels of von Willebrand factor (vWF) and increased levels of monocyte chemotactic protein-1 (MCP-1), brain-derived neurotrophic factor (BDNF), RANTES, and macrophage inflammatory protein-1 beta (MIP-1) beta with borderline significance (P ≤ 0.08). In silico pathway analysis revealed that probiotic-induced alterations are related to regulation of immune and intestinal epithelial cells through the IL-17 family of cytokines. We hypothesize that supplementation of probiotics to schizophrenia patients may improve control of gastrointestinal leakage.