Altered Immune Homeostasis Research Articles

Interactions Between Intestinal Microbiota and Innate Immune System in Pediatric Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is the result of an altered immune homeostasis within the intestinal mucosa against the gut microbiota, leading to chronic inflammation in genetically predisposed individuals. Under normal conditions, the immune system defends against pathogens and prevents the passage of excessive intestinal bacteria; regulatory pathways must maintain a low-grade, controlled inflammation in a healthy gut, but also induce a protective response against pathogens. The innate immune system is the first-line defense from microbes; dendritic cells, macrophages, and epithelial cells produce an initial, immediate response. The immune system constantly controls commensal bacteria and utilizes constitutive antimicrobial mechanisms to sustain immune homeostasis. The discovery that several genes linked to IBD modulate microbial recognition and innate immune pathways, such as nucleotide oligomerization domain 2 (Nod2), and genes that mediate autophagy (ie, ATG16L1, IRGM), has highlighted the critical role of host-microbe interactions in controlling intestinal immune homeostasis. Commensal microorganisms actively interact with the intestinal mucosa and influence the activity of the immune system as well as the amplitude of the immune response. In contrast, host factors can influence microbes, which in turn modulate disease susceptibility. In this paper, we focus on the mechanisms that mediate host-microbe interactions and how the disruption of this balance leads to chronic intestinal inflammation in IBD.

Immune Biomarkers of BRONJ in High-Risk Cancer Patients

Bisphosphonate-related osteonecrosis of the jaws (BRONJ) is an adverse effect of bisphosphonate therapy, with highest incidence reported in the oncologic patients receiving intravenous bisphosphonates (BP). Our group previously established that Zolendronate, a potent intravenous BP, caused BRONJ-like disease in mice by suppressing the adaptive regulatory T cell (Tregs) and activating the inflammatory T helper producing interleukin 17 cells (Th17), thereby decreasing the ratio of Treg/Th17. C-telopeptide (CTX), an indicator of bone turnover, is currently used by some clinicians to predict treatment response in BRONJ patients. Here, we determined whether the altered immune homeostasis elicited by bisphosphonate therapy, specifically a suppressed Treg/Th17 renders cancer patients susceptible to BRONJ.

Quantitative Assessment of Regulatory Proteins in Blood as Markers of Radiation Effects in the Late Period After Occupational Exposure

The objective of this research was quantitative assessment of serum and membrane regulatory proteins in blood from nuclear workers as markers of radiation-induced alterations in immune homeostasis in the late period after protracted exposure of nuclear workers with different doses. The effector and regulatory lymphocytes were measured using a flow cytofluorometer in workers from the main facilities of the Mayak PA (aged ∼60 y up to 80 y) in the late period after combined exposure to external gamma-rays and internal alpha-radiation from incorporated 239Pu. The control group included non-occupationally exposed members of the Ozyorsk population matched by gender and age to the group of Mayak workers. Thirty serum proteins involved in regulation of immune homeostasis, such as growth factors, multifunctional interleukins, pro- and anti-inflammatory cytokines, and their receptors, were measured using ELISA in blood serum specimens from the Radiobiology Human Tissue Repository. The dosimetry estimates were obtained using Doses-2005. The correlation analysis revealed a statistically significant direct relationship of T-killers and plutonium body burden and a decreasing level of T-helpers with accumulated external dose in exposed individuals. There were differences in expression of membrane markers in young regulatory cells (double null T-lymphocytes, NKT-lymphocytes, regulatory T-cells, and an increase of activated forms of T-lymphocytes), which indicated an active role of regulatory cells in maintaining immune homeostasis in terms of protracted exposure. The assessment of regulatory proteins in blood indicated that growth factors (EGF, TGF-β1, PDGF), multifunctional interleukins (IL-17A, IL-18), and pro-inflammatory cytokines (IL-1β and INF-γ) could be potential markers of radiation-induced alterations in protein status. An imbalance of pro- and antiinflammatory proteins in blood and variations of protein profiles at the lower exposure levels (gamma-ray dose <1 Gy, plutonium body burden <0.74 kBq) in the late period after protracted exposure were less pronounced than at the higher exposure levels, which was probably explained by compensatory-adaptive responses in the late period among senile individuals with polypathology.

Patient knowledge in inflammatory bowel disease: CCKNOW, how much do they know?

investigation on a cohort of children diagnosed with IBD between 1989 and 2003 whom were registered in the IBD center at Texas Children's Hospital. Children demographics, including age, sex, and age at diagnosis, were obtained. The diagnosis of IBD was based on clinical, radiological, endoscopic, and histological examinations. Disease distribution was identified on the basis of a review of all endoscopic, colonoscopic, pathological, and radiological records. All of the patients underwent a detailed whole-body examination by a gastroenterologist and rheumatologist. Diagnosis of arthritis was made by the assigned rheumatologist. We identified the date of onset of diagnosis for each IBD and arthritis. Results: There were 420 children diagnosed with IBD between1989-2003, 230 (55%) had CD, 112 (26.5%) had UC and 78 (18.5%) had IC. The prevalence of IBD-related arthritis (IBDA) among the total IBD population was 13%; 17% in CD, 11% ulcerative colitis; 4% IC; p = 0.02). There was no gender effect on IBDA, 52% of the overall patients were girls. The mean age at first diagnosis of IBDA was identical for boys and girls (12.5+3.2). No difference was observed among the three studied ethnic groups, IBDA was found in 11% of African-American children diagnosed with IBD, 12% in Caucasians, and 15% in Hispanics (P=0.2). Arthritis was peripheral in 35 cases (64%), axial in 10 cases (18%), combined peripheral and axial in 8 cases (14.5%) and spondyliothesis in 2 cases (3.5%). In 17 cases (31%), arthritis was diagnosed at a mean 20 (+28.2) months prior to the diagnosis of IBD. The remaining 69% of the arthritis cases were diagnosed after a mean duration of IBD of 28 (+26.5) months. Conclusions: IBDA is a frequent extra-intestinal complication of IBD and usually diagnosed after the IBD onset. Crohn's disease patients have a higher risk to develop IBDA than UC or IC. IBD may share environmental triggers, genetic susceptibilities or alterations in immune homeostasis with arthritis

Effects of Chronic Ascariasis and Trichuriasis on Cytokine Production and Gene Expression in Human Blood: A Cross-Sectional Study

BackgroundChronic soil-transmitted helminth (STH) infections are associated with effects on systemic immune responses that could be caused by alterations in immune homeostasis. To investigate this, we measured the impact in children of STH infections on cytokine responses and gene expression in unstimulated blood.Methodology/Principal FindingsSixty children were classified as having chronic, light, or no STH infections. Peripheral blood mononuclear cells were cultured in medium for 5 days to measure cytokine accumulation. RNA was isolated from peripheral blood and gene expression analysed using microarrays. Different infection groups were compared for the purpose of analysis: STH infection (combined chronic and light vs. uninfected groups) and chronic STH infection (chronic vs. combined light and uninfected groups). The chronic STH infection effect was associated with elevated production of GM-CSF (P = 0.007), IL-2 (P = 0.03), IL-5 (P = 0.01), and IL-10 (P = 0.01). Data reduction suggested that chronic infections were primarily associated with an immune phenotype characterized by elevated IL-5 and IL-10, typical of a modified Th2-like response. Chronic STH infections were associated with the up-regulation of genes associated with immune homeostasis (IDO, P = 0.03; CCL23, P = 0.008, HRK, P = 0.005), down-regulation of microRNA hsa-let-7d (P = 0.01) and differential regulation of several genes associated with granulocyte-mediated inflammation (IL-8, down-regulated, P = 0.0002; RNASE2, up-regulated, P = 0.009; RNASE3, up-regulated, p = 0.03).Conclusions/SignificanceChronic STH infections were associated with a cytokine response indicative of a modified Th2 response. There was evidence that STH infections were associated with a pattern of gene expression suggestive of the induction of homeostatic mechanisms, the differential expression of several inflammatory genes and the down-regulation of microRNA has-let-7d. Effects on immune homeostasis and the development of a modified Th2 immune response during chronic STH infections could explain the systemic immunologic effects that have been associated with these infections such as impaired immune responses to vaccines and the suppression of inflammatory diseases.

Immunomodulation by Intravenous Immunoglobulin: Role of Regulatory T Cells

An altered immune homeostasis as a result of deficiency or defective function of CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) is common in several autoimmune diseases. Hence, therapeutic strategies to render Tregs functionally competent are being investigated. Intravenous immunoglobulin (IVIG) is being increasingly used for the treatment of a wide range of autoimmune and inflammatory diseases. Recent studies have demonstrated that IVIG induces the expansion of Tregs and enhances their suppressive functions. These effects of IVIG on Tregs correlate with the beneficial effects of IVIG in patients with autoimmune diseases. Thus, modulation of Tregs by IVIG represents a novel mode of action that explains the therapeutic effects of IVIG in T cell-mediated autoimmune diseases. However, the molecular mechanisms involved in IVIG-mediated modulation of Tregs are unclear and need further investigation.

Echocardiography indices, heart rate variability and cytokine profile in pregnant women

Objective. To analyze heart rhythm variability, hemodinamics, pro- and anti-inflammatory plasma cytokines production in pregnant women. General clinical examination was carried out in both groups, echocardiography, Holter monitoring with subsequent calculation of generally accepted heart rate variability indices were performed. The circadian heart rate index (ratio day/night) was calculated. It was found that pregnancy-induced hypertension was accompanied by impaired cytokine balance. Altered immune homeostasis has been established to be a leading factor in the pattern of gestational complications.

Thymocytes, Pre‐B Cells, and Organ Changes in a Mouse Model of Chronic Ethanol Ingestion—Absence of Subset‐Specific Glucocorticoid‐Induced Immune Cell Loss

The well-known immune deficiency of the chronic alcoholic dictates the need for a long-term rodent ethanol administration model to evaluate the baseline immunologic effects of chronic ethanol abuse, and investigate the genetic determinants of those effects. Much published work with rodents has shown clearly that acute ethanol administration and short-term ethanol-containing liquid diets both cause elevated corticosterone and can cause significant thymocyte, pre-B cell and peripheral lymphocyte losses. Such losses may mask more subtle alterations in immune homeostasis, and in any case are generally short-lived compared with the span of chronic ethanol abuse. Thus, it is important to have a model in which long-term immune alterations can be studied free of corticosteroid-induced cell losses. We have utilized chronic 20% (w/v) ethanol in water administration to several mouse strains for prolonged periods of time and evaluated serum corticosterone, immunologic stress parameters, and other organ changes by standard methods. We now confirm earlier reports that chronic ethanol in water administration to mice does not produce net elevations of corticosterone, although diurnal variation is altered. Importantly, there is neither selective loss of immune cell populations known to be corticosteroid sensitive, CD4+CD8+ thymocytes and pre-B cells, nor are changes observed in the histologic appearance of the thymus. Nonetheless, there are significant chronic ethanol effects in other tissues, including reduced heart weight, mild hepatic steatosis, alterations of gut flora, increased serum peptidoglycan, and as published elsewhere, immune system abnormalities. This model of ethanol administration is convenient, sustainable for up to 1 year, demonstrably feasible in several mouse strains, permits good weight gains in most strains, and results in significant changes in a number of organs. The administration method also will permit modeling of long-term steady abuse punctuated by major binges, and is suitable for supplementation studies using water soluble additives. Overall, the method is useful for a wide range of studies requiring a chronic low-stress method of ethanol administration.

T-lymphocyte subpopulations in type I diabetes mellitus. A longitudinal study.

Monoclonal antibodies were used to characterize peripheral T-lymphocyte subpopulations in 23 patients with type I diabetes mellitus. Initial measurements were made at diagnosis and in 10 of the patients further studies were carried out at 1, 3 and 6 months. T-cell subsets were also measured in 16 patients with type II diabetes, in 16 patients with various autoimmune diseases and in 17 healthy control subjects. At diagnosis, the type I diabetic patients showed a significant decrease in the percentage of cytotoxic/suppressor cells. Both total T-cells and helper/inducer cells were normal. However, when the helper/inducer population was analyzed in the context of islet cell antibodies (ICAs), it was found that those patients possessing ICAs had significantly higher proportions of helper/inducer cells than those lacking them. A significant inverse correlation was seen between the proportions of total T-cells and NK/K cells. At 1 month, the proportions of cytotoxic/suppressor cells returned to normal, whilst the helper/inducer cells showed a transient depression. By 6 months, the only change seen was a significant increase in the percentage total t-cells. No relationship was found between T-cell subset perturbation and metabolic control, as assessed by measurement of hemoglobin A1 (HbA1). The type II diabetic patients showed a significant increase in the percentage of total T cells. The autoimmune patients also showed a significant increase in the proportions of total T-cells; this appeared to reflect an increase in the helper/inducer subset. In the autoimmune patients these findings occurred in conjunction with significant decreases in the absolute numbers of each T-cell subset. It is surmised that, in some cases of type I diabetes, alterations in immune homeostasis may permit autoimmune processes, which lead to cell damage at the onset of diabetes.