Changes In Immune System Function Research Articles

New therapeutic approaches with biological drugs for eosinophilic granulomatosis with polyangiitis

Eosinophilic granulomatosis with polyangiitis (EGPA) is a multiorganic syndrome that affects the cardiovascular, neurologic, renal, and gastrointestinal systems with an incidence ranging from 0 case to 67 cases per one million person-years, and its pathophysiology remains unknown. It is believed that genetic factors, the environment, and changes in immune system function contribute to the development of EGPA, overlapping the immune mechanisms of vasculitides and the pathologic mechanisms in eosinophilic syndromes. This disease is commonly divided into two phenotypes depending on the presence of antineutrophil cytoplasmic antibodies (ANCA). ANCA-positive patients usually have more vasculitic manifestations like peripheral neuropathy, purpura, renal involvement, and biopsy-proven vasculitis. The keystone of EGPA therapy is systemic corticosteroids (CS) as monotherapy or in combination with other immunosuppressive treatments, and recently the efficacy of eosinophil-targeted biotherapy, anti-interleukin-5 (IL-5), has been shown to be efficacious in EGPA. Although this phenotype/phase distinction has not yet had an impact on the current treatment strategies, emerging targeted biotherapies under evaluation could lead to a phenotype-based approach and personalised treatment regimens for EGPA patients. The present review describes the new therapeutical approaches with biological drugs for EGPA.

ARTIKEL REVIEW : SISTEM IMUNITAS DALAM KEHAMILAN

Pregnancy is the process of continuing the existence of an organism, and preventing its extinction. During pregnancy, there is a fundamental human adaptation process that increases the body's resistance to the risk of external attack. Regardless of the role of the immune system in early pregnancy, an increase in the human immune system, which is the most important system for dealing with infections to protect the mother and the fetus, is one of the important adaptation responses to protect the mother as well as the fetus. Various physiological changes are interrelated, especially to ensure the growth of the baby in the uterus can take place properly. Anatomical, physiological and biochemical adaptations in pregnancy are profound. Many significant changes occur immediately after fertilization and continue throughout pregnancy and most occur in response to physiological stimulation by the baby and placenta. This article discusses the changes in immune system function involved in pregnancy.
 Keywords: immune system, pregnancy adaptation, pro-inflammatory and anti-inflammatory responses

Innate immune cGAS/STING in HFD‐induced obesity, prediabetes, and cognitive impairment

AbstractBackgroundIncreasing in parallel with the worldwide aging population are rates of cognitive impairment and dementia, including Alzheimer’s Disease and Alzheimer’s Disease Related‐Dementia. Understanding underlying mechanisms that promote cognitive impairment with aging is therefore critical. One factor that significantly increases the risk of cognitive impairment and is reaching pandemic levels is obesity and prediabetes/diabetes. Common mechanisms that could underly the relationship between obesity and prediabetes/diabetes with cognitive impairment are changes in immune system function, particularly microglial dependent changes. Specifically, the innate immune cGAS/STING pathway is implicated in both cognitive impairment and obesity and prediabetes/diabetes.Method1 yr old BL6 male mice were fed 60% HFD (high fat diet) or 10% SD (standard diet) for 13 weeks. Body weight and glucose tolerance were used to determine metabolic phenotype. Cognition was measured using social recognition and fear conditioning. Hippocampal inflammatory gene expression was determined using Nanostring nCounter and cGAS/STING specific protein expression using western blotting. Additionally, we induced a prediabetic phenotype in a human microglial cell line by treating microglia for 24 hr with either palmitate alone or a combination of insulin and palmitate. Cells were then assessed for cGAS/STING protein expression using western blotting.ResultHFD feeding resulted in increased weights and impaired glucose tolerance along with cognitive deficits. Hippocampal gene expression profiles showed changes in several genes, such as cGAS, STAT2, and IL‐6 and there were changes in hippocampal cGAS/STING proteins in HFD mice. In microglia, prediabetic conditions increased expression of multiple cGAS/STING proteins, along with the immunosenescence marker p21.ConclusionChanges in inflammatory profiles indicate that HFD dysregulates hippocampal inflammatory gene expression and cGAS/STING protein expression in obese prediabetic mice with cognitive impairment. Microglial cGAS/STING changes indicate that this cell type is particularly sensitive to prediabetic conditions and may promote premature immunosenescence. While more data are needed to fully understand cGAS/STING mediated microglial mechanisms of cognitive decline in obesity and prediabetes, these data support the hypothesis that inflammatory mechanisms are an important contributor and that the cGAS/STING pathway represents a potential target for future research.

P0913HYPERPHOSPHATEMIA INCREASE INFLAMMATION PROMOTING SENESCENCE AND MUSCLE DYSFUNCTION

Abstract Background and Aims Hyperphosphatemia has been associated with aging and chronic kidney disease (CKD). Sarcopenia, which is a related condition of these pathologies, is defined by loss of force and muscular mass. During aging, chronic systemic inflammation appears, termed inflammaging, due to changes in immune system function. Inflammaging has been associated with many age-related diseases including Sarcopenia and CKD. The work aimed to evaluate the effect of hyperphosphatemia on proinflammatory profile of cultured myoblast cells and to analyze, in old mice, the effect of a dietary restriction in the phosphate intake on the aging-related sarcopenia. Methods Culture murine myoblast C2C12 cells were used for in vitro experiments. Cells were treated with 10 mM beta-glycerophosphate (BGP) as phosphate donor for 24, 48 or 72h. Inflammation was assessed through IL6, TNFα and MCP-1 expression by RT-qPCR. Twenty-four months old, C57BL6 mice were used for in vivo studies. Mice were fed with a normal diet containing 0.6% of phosphate until 21 months, after that, one group of mice continued with a normal diet and the other group was fed with a hypophosphatemic diet, containing a 0.2% of phosphate, for the following 3 months. Old mice were compared with 5 months old mice. Muscle force was measured by a grip strength test. Serum phosphate concentration was evaluated with a commercial kit and inflammation was assessed through IL-1β expression levels by RT-qPCR. Results Results showed that BGP treatment augmented pro-inflammatory cytokines levels, in myoblast, at 72h. On the other hand, old mice had a 40% increase in serum phosphate concentration regarding young mice, and, in parallel, they showed a reduction in forelimb strength. Old animals feeding with a hypophosphatemic diet showed a decreased level of phosphate serum linked to a better muscle function. Pro-inflammatory cytokines expression was higher in old mice compared to young mice; those values were reduced in 24-month-mice fed with a low phosphate diet. Furthermore, there was a positive correlation between IL-1β expression levels and serum phosphate levels, suggesting that high levels of serum phosphate were increasing inflammation in vivo and a negative correlation between IL-1β and grip strength test, which shows that high levels of inflammation decrease muscular function Conclusion In this work, we propose that high levels of phosphate are related to inflammation in vitro and in vivo. This increase of proinflammatory cytokines decreases muscle function whereas dietary restriction of phosphate decreases inflammation and improves muscle function. These results could point to a direct link between elevated serum phosphate levels and inflammaging presented in sarcopenic people such as CKD patients and aged people.

Characteristics of the Immune System and the Risk of Developing Endogenous Psychosis at Juvenile Age

Study aim. To investigate immunological parameters at the early stages of development of juvenile schizophrenia. Materials and methods. Immunological profiles were determined in patients aged 16–25 years receiving in-patient treatment. Patients were divided into two groups. Group 1 consisted of 39 patients with psychopathological symptomatology at the non-psychotic level (prodrome group) and group 2 consisted of 38 patients with first onset of endogenous psychosis (psychosis group). Immunological parameters included phagocytic activity, lymphocyte natural killer cytotoxic activity, production of interleukins IL-1, IL-4, IL-10, and interferon γ, and circulating immune complex (CIC) levels. These investigations were performed before and after treatment. Results. The experiments reported here showed that changes in immune system function were seen in patients at the earliest stages of disease development, with activation of proinflammatory and anti-inflammatory interleukins, decreases in phagocytic index and natural killer lymphocyte cytotoxic activity, and phagocytic number. Development of psychosis was associated with persistence of the high level of IL-10 production, the decreased level of natural killer cytotoxic activity, and the decreased phagocytic index, with accumulation of CIC. Conclusions. The authors recommend the use of not only psychotropic, but also immunomodulatory agents at the early stage of the development of endogenous psychosis.

Gene Expression Analysis Of Peripheral Blood Following Resistance Exercise

PURPOSE: Phenotypic studies suggest a strong correlation between exhaustive resistance exercise and affects on the immune system. The goal of this study was to characterize the gene expression changes using Affymetrix microarrays during these exercise regiments and determine whether these expression changes correlate to standard differential blood counts or other immunophenotyping data. METHODS: Ten resistance-trained male collegiate athletes between 20-24 yr of age (22.30 ± 1.25 yr) with at least 2 yr resistance training experience (5.00 ± 2.31 yr) performed an acute bout of RE for 30.59 min (± 0.59). The RE included the back parallel squat and the leg press each at 45% & 55% of 1-RM for first 2 sets, and 65% of 1-RM for the remaining 4 sets. All exercises were performed with a 2:2 cadence followed by 2 min rest periods. Following a 12 hr fast, blood samples were collected at baseline, immediately following exercise, and at 2 hr postexercise. RNA was prepared by combining 3.75 ml of TriReagent BD to 1 ml of whole blood containing EDTA immediately after sampling and frozen at -80°C. RNA was extracted using the standard blood method outlined by the manufacturer, analyzed for quality, and prepared for hybridization to an Affymetrix U133a 2.0 GeneChip using the NuGEN Ovation WB system. RESULTS: Initial results of our microarray data indicate that, with high statistical significance, gene expression features are highly correlated with blood counts. Differentially expressed genes were statistically significantly associated with immune system function. CONCLUSION: These data suggest that an acute bout of RE induced substantial changes in immune system function that was reflected in differential gene expression. Support made possible by the Vermont Genetics Network through Grant Number P20 RR16462 from the INBRE Program of the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of NCRR or NIH.

The lymphocytic cholinergic system and its contribution to the regulation of immune activity

Lymphocytes express most of the cholinergic components found in the nervous system, including acetylcholine (ACh), choline acetyltransferase (ChAT), high affinity choline transporter, muscarinic and nicotinic ACh receptors (mAChRs and nAChRs, respectively), and acetylcholinesterase. Stimulation of T and B cells with ACh or another mAChR agonist elicits intracellular Ca 2+ signaling, up-regulation of c-fos expression, increased nitric oxide synthesis and IL-2-induced signal transduction, probably via M 3 and M 5 mAChR-mediated pathways. Acute stimulation of nAChRs with ACh or nicotine causes rapid and transient Ca 2+ signaling in T and B cells, probably via α7 nAChR subunit-mediated pathways. Chronic nicotine stimulation, by contrast, down-regulates nAChR expression and suppresses T cell activity. Activation of T cells with phytohemagglutinin or antibodies against cell surface molecules enhances lymphocytic cholinergic transmission by activating expression of ChAT and M 5 mAChR, which is suggestive of local cholinergic regulation of immune system activity. This idea is supported by the facts that lymphocytic cholinergic activity reflects well the changes in immune system function seen in animal models of immune deficiency and immune acceleration. Collectively, these data provide a compelling picture in which lymphocytes constitute a cholinergic system that is independent of cholinergic nerves, and which is involved in the regulation of immune function.

The role of interleukin-1 in stress-induced changes in immune system function.

The cellular-molecular mechanisms of changes in immune system function were studied, including the production of lymphocyte activating factor (LAF) and interleukin-1 (IL-1). the effects of IL-1 on target cells, and subsequent cytokine signal transduction via the sphingomyelin pathway, in different types of stress. These experiments showed that stress of different durations and intensities induced the formation of lymphocyte activating factors by peritoneal macrophages and increased IL-la levels in mouse blood. but led to different changes in the responses of target thymocytes to the committing actions of IL-1beta. which correlated with changes in the level of the humoral immune response. These data coincided with differently-directed stress-induced changes in the activity of membrane-bound neutral sphingomyelinase. the key enzyme in the sphingomyelin cascade, in cerebral cortex membrane fraction P2 from mouse brains. The results obtained here suggest that IL-1 is involved in the physiological mechanisms of stress reactions, operating at the levels of IL-1 production and its biological actions on lymphoid target cells, as well as at the level of cytokine signal transduction via the sphingomyelin pathway in nerve tissue.

Environmental modulation of the immune system via the endocrine system

Numerous studies have demonstrated that a variety of hormones have receptors and exert biologic actions on tissues of the immune system. Conversely, cytokines exert biologic actions on the endocrine system. This bidirectional interaction is likely involved in maintenance of physiological and immunologic homeostasis. This paper summarizes a variety of actions of growth hormone (GH), prolactin (PRL), insulin-like growth factor-I (IGF-I), glucocorticoids and thyroid hormones (TH) on the immune system. It then proceeds to put these actions into a hypothetical context whereby these hormones may mediate some changes in immune system function in response to environmental stimuli such as physical and emotional stress, nutritional deprivation and environmental temperature. In the first example, it is proposed that PRL secretion in response to stress may serve an immunomodulatory role in two ways. The first is by stimulating the immune system directly and the second is by dampening or reducing the degree to which glucocorticoids are secreted in response to stress. The second example suggests that the increase in GH secretion and reduced IGF-I secretion in response to protein/energy restriction may have two potential immunomodulatory actions. One action is a direct effect of GH on several components of the immune system. The other is the partitioning of nutrient use away from skeletal muscle growth and toward tissues of higher priority such as the immune system. The third example proposes that the increased secretion of TH during cold environmental temperatures not only increases basic metabolic rate, but also directly stimulates both primary and secondary lymphoid tissues. It is suggested, therefore, that these three hormones are involved in maintaining immune system homeostasis in response to environmental change.

Long-term intracerebroventricular corticotropin-releasing hormone administration induces distinct changes in rat splenocyte activation and cytokine expression.

The effects of long-term corticotropin-releasing hormone (CRH) infusion in the lateral ventricle of the rat on hypothalamic-pituitary-adrenocortical (HPA) axis parameters and on the immune system function were studied. Compared with infusion of vehicle, the CRH treatment produced a sustained overactivity of the HPA axis, as evidenced by elevated plasma ACTH and corticosterone levels, increased anterior pituitary POMC messenger RNA (mRNA) expression, and adrenal enlargement. Long-term CRH treatment also inhibited body weight gain and reduced thymus and spleen weight. In the CRH-treated animals, both Concanavalin A (Con A)-induced T lymphocyte proliferation and lipopolysaccharide (LPS)-induced B lymphocyte mitogenesis was largely suppressed. Surprisingly, interleukin-2 (IL-2) levels were higher in supernatants of splenocyte cultures from CRH-treated rats than in those of control animals. However, IL-2 receptor alpha chain (IL-2R alpha) mRNA expression after Con A stimulation was highly suppressed in the CRH-treated animals. In addition, Northern blot analysis of RNA from splenocytes isolated from spleens of CRH-treated rats revealed a marked expression of IL-1 beta mRNA, in contrast to the barely detectable levels of this cytokine in control animals. Moreover, incubation of total splenocytes and spleen macrophages with LPS resulted in an enhanced induction of IL-1 beta mRNA in cells of CRH-treated rats compared with that of control animals. When adrenalectomized rats were treated with CRH or vehicle, the effects of the CRH treatment on T and B cell proliferation, IL-2 production, and IL-1 beta mRNA expression were abolished. Thus, a continuously increased HPA axis drive results in disparate changes in immune system function. Whether the observed changes in cytokine expression should be regarded as physiologically adaptive adjustments in support of immune function or as potentially pathological anomalies remains to be elucidated.

Long-term intracerebroventricular corticotropin-releasing hormone administration induces distinct changes in rat splenocyte activation and cytokine expression

The effects of long-term corticotropin-releasing hormone (CRH) infusion in the lateral ventricle of the rat on hypothalamic-pituitary-adrenocortical (HPA) axis parameters and on the immune system function were studied. Compared with infusion of vehicle, the CRH treatment produced a sustained overactivity of the HPA axis, as evidenced by elevated plasma ACTH and corticosterone levels, increased anterior pituitary POMC messenger RNA (mRNA) expression, and adrenal enlargement. Long-term CRH treatment also inhibited body weight gain and reduced thymus and spleen weight. In the CRH-treated animals, both Concanavalin A (Con A)-induced T lymphocyte proliferation and lipopolysaccharide (LPS)-induced B lymphocyte mitogenesis was largely suppressed. Surprisingly, interleukin-2 (IL-2) levels were higher in supernatants of splenocyte cultures from CRH-treated rats than in those of control animals. However, IL-2 receptor alpha chain (IL-2R alpha) mRNA expression after Con A stimulation was highly suppressed in the CRH-treated animals. In addition, Northern blot analysis of RNA from splenocytes isolated from spleens of CRH-treated rats revealed a marked expression of IL-1 beta mRNA, in contrast to the barely detectable levels of this cytokine in control animals. Moreover, incubation of total splenocytes and spleen macrophages with LPS resulted in an enhanced induction of IL-1 beta mRNA in cells of CRH-treated rats compared with that of control animals. When adrenalectomized rats were treated with CRH or vehicle, the effects of the CRH treatment on T and B cell proliferation, IL-2 production, and IL-1 beta mRNA expression were abolished. Thus, a continuously increased HPA axis drive results in disparate changes in immune system function. Whether the observed changes in cytokine expression should be regarded as physiologically adaptive adjustments in support of immune function or as potentially pathological anomalies remains to be elucidated.

ETHANOL AND DIET-INDUCED ALTERATIONS IN KUPFFER CELL FUNCTION

The effects of 6 weeks of alcohol feeding on phagocytic, metabolic and secretory functions as well as gene expression of hepatic Kupffer cells were evaluated in vitro using cultured Kupffer cells isolated from male Sprague-Dawley rats. The rats were fed either Teklad pelleted rat chow or the 1982 Lieber-DeCarli liquid diet containing 6% ethanol (36% calories) or the same liquid diet with maltose-dextrin isocalorically substituted for the alcohol. Weight gain was greatest in the chow-fed animals and least in those receiving ethanol. The alcohol-containing diet stimulated Kupffer cell phagocytosis, mitochondrial reduction of MTT, secretion of tumor necrosis factor (TNF) and expression of TNF mRNA. However, each of these cell functions was also enhanced by the control Lieber-DeCarli liquid diet alone and the stimulating effect of the control diet often exceeded that induced by ethanol. The results suggest that early in chronic alcohol consumption, the immune system may be stimulated by ethanol, and that during studies of ethanol-induced changes in immune system function, close attention must be given to potentially confounding effects of the diet.

The Effect of Various Contexts of Stress on the Mouse Spleen Lymphocytes and Macrophage Co-stimulatory Activity

Mice stressed daily by brief cold water immersions for 1, 8 or 14 days showed changes in immune system function which were dependent on the number of mice per cage, frequency of stress exposures and total number of stress exposures. Changed percentages of spleen B and CD4, but not of CD8 cells were determined when the mice were stressed either once or twice daily. With CD4 cells, increased percentages were seen after stress once daily but a decreased percentage was seen after stress twice daily. Furthermore, the Concanavalin A-stimulated spleen cell mitogenesis was decreased after 1 day of stress in mice stressed once daily as opposed to after 8 and 14 days of stress in mice stressed twice daily. After 14 days of stress, the lipopolysaccharide stimulated mitogenesis was increased if the mice were stressed once daily but decreased if the mice were stressed twice daily. With two mice per cage, we observed a decreased spleen cell mitogenesis after 14 days of stress. With four mice per cage, the spleen cell mitogenesis was decreased after 8 and 14 days of stress. If spleen cell populations from mice stressed twice daily for 8 days were depleted of macrophages and CD4 or CD8 cells, the effect of stress on the mitogenesis was removed from the CD8 cells. Spleen cells of mice stressed for 14 days showed a decreased mitogenesis when depleted of adherent cells and reconstituted with adherent cells from control mice. Furthermore, the adherent cells from these mice had decreased ability to support mitogenesis of adherent cell-depleted spleen cells from control mice as well as a decreased IL-1 production.

Fc receptor-mediated phagocytosis: Abnormalities associated with diabetes mellitus

The family of Fc receptors (FcR) for IgG play pivotal roles in affector, effector, and regulatory functions of cells of the immune system. Thus, changes in expression and activation of FcRs may contribute to a variety of disease manifestations that are the consequence of abnormalities in immune system function. Patients with diabetes mellitus are often plagued with recurrent bacterial and mycotic infections, as well as large and small vessel injury which may in part be immune mediated and which lead to organ dysfunction. Hormone-mediated changes in immune system function have been postulated to contribute to a variety of the complications experienced by patients with diabetes mellitus. It is the purpose of this review to summarize current knowledge regarding abnormalities in immune system function in diabetes mellitus with special emphasis on classical hormonal modulation of Fc receptor-mediated phagocytosis.