Markers Of Systemic Immune Activation Research Articles

Abstract 19053: Peripheral Eosinophil Count is Associated With Left Ventricular Systolic Dysfunction During Spontaneous Coronary Artery Dissection

Background: Spontaneous coronary artery dissection (SCAD) is an underdiagnosed condition disproportionally affecting young women, particularly during the peripartum period and/or in the presence of systemic inflammatory and autoimmune diseases. Tissue-level studies have demonstrated inflammatory infiltrates with adventitial or peri-adventitial eosinophilia at the site of SCAD lesions. Less is known regarding how systemic markers of immune activation associate with cardiac dysfunction in SCAD. Hypotheses: Higher eosinophil count and Neutrophil-to-Lymphocyte Ratio (NLR) associate with LV systolic dysfunction in SCAD patients. Methods: In individuals diagnosed with SCAD who underwent CBC with differential and echocardiography within the same presenting hospital encounter, we performed age- and sex-adjusted logistic regressions with eosinophil count (% of differential) and NLR (% of differential) as primary exposures and LVEF<55% as the dichotomous endpoint. A p<0.05 was considered statistically significant. We explored associations of neutrophil, lymphocyte, monocyte, and basophil counts with LVEF in secondary analyses. Results: In SCAD patients with complete CBC and LVEF data (N=36; mean age 49.9 years at diagnosis, 28 female), peripheral eosinophil count was associated with significantly higher odds of systolic dysfunction [OR of LVEF<55% per every 1% higher eosinophil count = 1.87; 95% CI 1.04, 3.36; p=0.04]. NLR ratio was not associated with LV systolic dysfunction (OR 1.05; 95% CI 0.94, 1.18; p=0.35) nor were other circulating leukocyte fractions. Conclusion: Peripheral eosinophil count, but not other circulating leukocyte counts, was associated with LV systolic dysfunction as measured by LVEF <55%. These findings provide complementary support to pathology-based evidence of eosinophilia observed in SCAD lesions and require confirmation in future longitudinal studies of changes in LV function following SCAD events.

Impact of sleep deprivation on neurocognition and inflammation in rhesus macaques

Sleep deprivation in humans is associated with both cognitive impairment and immune dysregulation. An animal model of neuropathogenesis may provide insight to understand the effects of sleep deprivation on the brain. Human neurocognition is more closely mirrored by nonhuman primates (NHP) than other animals. As such, we developed an NHP model to assess the impact of sleep deprivation on neurocognition and markers of systemic immune activation. Six male rhesus macaques underwent three rounds of sleep deprivation (48 h without sleep) at days 0, 14, and 28. We performed domain specific cognitive assessments using the Cambridge Neuropsychological Test Automated Battery (CANTAB) via a touch screen before and after 24 and 48 h of sleep deprivation. Immune activation markers were measured in the blood by multiplex assay and flow cytometry. Although we observed variability in cognitive performance between the three rounds of sleep deprivation, cognitive impairments were identified in all six animals. We noted more cognitive impairments after 48 h than after 24 h of sleep deprivation. Following 48 h of sleep deprivation, elevations in markers of immune activation in the blood were observed in most animals. The observed impairments largely normalized after sleep. The co-occurrence of systemic immune alterations and cognitive impairment establishes this model as useful for studying the impact of sleep deprivation on neurobehavior and immune perturbations in rhesus macaques.

The Many Faces of Immune Activation in HIV-1 Infection: A Multifactorial Interconnection.

Chronic immune activation has a significant role in HIV-1 disease pathogenesis and CD4+ T-cell depletion. The causes of chronic inflammation and immune activation are incompletely understood, but they are likely multifactorial in nature, involving both direct and indirect stimuli. Possible explanations include microbial translocation, coinfection, and continued presence of competent replicating virus. In fact, long-term viral suppression treatments are unable to normalize elevated markers of systemic immune activation. Furthermore, high levels of pro-inflammatory cytokines increase susceptibility to premature aging of the immune system. The phenomenon of "inflammaging" has begun to be evident in the last decades, as a consequence of increased life expectancy due to the introduction of cART. Quality of life and survival have improved substantially; however, PLWH are predisposed to chronic inflammatory conditions leading to age-associated diseases, such as inflammatory bowel disease, neurocognitive disorders, cardiovascular diseases, metabolic syndrome, bone abnormalities, and non-HIV-associated cancers. Several approaches have been studied in numerous uncontrolled and/or randomized clinical trials with the aim of reducing immune activation/inflammatory status in PLWH, none of which have achieved consistent results.

Increased Macrophage-Specific Arterial Infiltration Relates to Noncalcified Plaque and Systemic Immune Activation in People With Human Immunodeficiency Virus.

Persistent immune activation is thought to contribute to heightened atherosclerotic cardiovascular disease (ASCVD) risk among people with human immunodeficiency virus (PWH). Participants (≥18 years) with or without human immunodeficiency virus (HIV) and without history of clinical ASCVD were enrolled. We hypothesized that increased macrophage-specific arterial infiltration would relate to plaque composition and systemic immune activation among PWH. We applied a novel targeted molecular imaging approach (technetium-99m [99mTc]-tilmanocept single photon emission computed tomography [SPECT]/CT) and comprehensive immune phenotyping. Aortic 99mTc-tilmanocept uptake was significantly higher among PWH (n = 20) than participants without HIV (n = 10) with similar 10-year ASCVD risk (P = .02). Among PWH, but not among participants without HIV, noncalcified aortic plaque volume related directly to aortic 99mTc-tilmanocept uptake at different uptake thresholds. An interaction (P = .001) was seen between HIV status and noncalcified plaque volume, but not calcified plaque (P = .83). Systemic levels of caspase-1 (P = .004), CD14-CD16+ (nonclassical/patrolling/homing) monocytes (P = .0004) and CD8+ T cells (P = .005) related positively and CD4+/CD8+ T-cell ratio (P = .02) inversely to aortic 99mTc-tilmanocept uptake volume. Macrophage-specific arterial infiltration was higher among PWH and related to noncalcified aortic plaque volume only among PWH. Key systemic markers of immune activation relating to macrophage-specific arterial infiltration may contribute to heightened ASCVD risk among PWH. NCT02542371.

Association of Microbial Tryptophan Metabolites and Indoleamine-2,3-Dioxygenase with Immune Activity in Healthy Adults

ObjectivesTryptophan (Trp) metabolites from intestinal bacteria, including indole, indole acetic acid (IAA) and indole propionic acid (IPA), and from the mammalian indoleamine 2,3-dioxygenase (IDO) pathway, including kynurenine (Kyn), can regulate immune activation. IDO activity in vivo is measured by the plasma Kyn/Trp ratio. In this study we hypothesized that (1) the plasma Kyn/Trp ratio, (2) plasma indole, IPA, and IAA concentrations, and (3) intestinal bacteria associated with indole metabolism, would all be associated with inflammation and immune activation markers in a study population of healthy adults.MethodsA group of 88 immune markers was assessed using plasma, flow cytometric analysis of whole blood and of peripheral blood mononuclear cells (PBMC), and ex vivo culture of PBMC, in 362 healthy, fasting adults. Plasma Trp metabolites were also measured. Bacterial taxa from stool were identified by 16S rRNA gene analysis and those associated with plasma Trp metabolites were identified. Multiple linear regression analysis was used to identify statistically significant associations (with p < .05 after adjustment for multiple comparisons) of these metabolites and taxa with immune markers.ResultsSeveral robust positive associations were found between Kyn/Trp and markers of inflammation including neopterin, IP-10, TNF-α, C-reactive protein, and the regulatory cytokine IL-10. A significant positive association was found between the sum of indole and IAA and natural killer T-cells. Three taxa associated with bacterial Trp metabolites were associated with elevated markers of immune activation: the family Lachnospiraceae with higher lymphocyte counts, the genus Dorea with higher production of the type 1 cytokine IFN-γ by T-cells in PBMC culture, the genus Ruminococcus with higher production of the inflammatory cytokine IL-6 in PBMC cultures stimulated with bacterial lipopolysaccharide.ConclusionsIDO activity, bacterial Trp metabolites and indole-associated commensal bacteria were all associated with markers of systemic immune activation, particularly involving inflammatory cytokines, the acute phase response and type 1 innate and adaptive immunity. These findings suggest sub-clinical levels of systemic and/or intestinal immune activity that might be precursors to adverse health outcomes.Funding SourcesUSDA/ARS 2032-51,530-026-00D.

A therapeutic HIV-1 vaccine reduces markers of systemic immune activation and latent infection in patients under highly active antiretroviral therapy

HIV infection is characterized by chronic immune activation and the establishment of a pool of latently infected cells. Antiretroviral therapy (ART) can suppress viral load to undetectable levels in peripheral blood by standard measure, however immune activation/chronic inflammation and latent infection persist and affect quality of life. We have now shown that a novel therapeutic HIV vaccine consisting of replication-defective HIV (HIVAX), given in the context of viral suppression under ART, can reduce both immune activation/chronic inflammation and latent infection. Immune activation, as measured by percent of CD8 + HLA-DR + CD38 + T cells, approached levels of healthy controls at week 16 following vaccination. Reduced immune activation was accompanied by a reduction in pro-inflammatory cytokines and peripheral α4β7 + plasmacytoid DC (a marker of mucosal immune activation). Levels of both HIV-1 DNA and 2-LTR circles were reduced at week 16 following vaccination, suggesting HIVAX can impact HIV-1 latency and reduce viral replication. Surprisingly, reduced immune activation/chronic inflammation was accompanied by an increase in the percent of memory CD4 + T cells expressing markers PD-1 and TIM-3. In addition, evaluation of HIV-1 Gag-specific CD4 + T cells for expression of 96 T cell related genes pre- and post-therapy revealed increased expression of a number of genes involved in the regulation of immune activation, T cell activation, and antiviral responses. Overall this study provides evidence that vaccination with HIVAX in subjects under long term antiviral suppression can reduce immune activation/chronic inflammation and latent infection (Clinicaltrials.gov, identifier NCT01428596).

Abstract P2-09-06: Safety and efficacy of stereotactic body radiotherapy and Pembrolizumab in advanced breast cancer patients with 1 to 5 metastases

Abstract Background Pre-clinical studies have demonstrated that stereotactic body radiotherapy (SBRT) induces immunogenic cell death and tumor antigen release promoting anti-tumor immunity. We hypothesized that the efficacy of SBRT could be improved with the addition of PD-1 blockade in advanced breast cancer (BC) patients with oligometastatic disease. Methods Advanced BC patients with 1 – 5 metastatic sites of disease received SBRT at a dose of 20Gy in 1 fraction to at least 1 metastasis followed by pembrolizumab 200mg IV (within 5 days of SBRT), once every 3 weeks for a total of 8 cycles. The primary endpoint was safety of the combination. The secondary endpoints were response using RECIST 1.1 and PERCIST 1.0 using 18F-Flurodeoxyglucose (FDG)- positron emission tomography (PET) scans as well as local progression-free survival and distant progression-free survival (d-PFS). Correlatives included deep sequencing of the T cell receptor (TCR) CDR3 regions of archival metastatic tumor material and in peripheral blood as well as evaluation of systemic markers of immune activation. Results 15 patients were enrolled between March 2016 and Nov 2017. The number of patients with 1, 2, 4 and 5 metastases treated with SBRT was 9 (60%), 3 (20%), 2 (13%) and 1 (7%), respectively. There were 3 (20%) TNBC, 2 (13%) HER2+ and 10 (67%) ER+/HER2- (Luminal) BC patients. Five (33%) patients experienced Grade 3 or higher Aes. Immune related Aes were reported in 10 (67%) patients, the most common being rash (n=4), thyroid (n=3) and pneumonitis (n=3) with pembrolizumab delayed in 3 (20%) patients and discontinued in 2 (13%) patients. Nine (60%) patients had a complete response or partial response according to RECIST 1.1 criteria and 13 (86%) patients had a complete metabolic response (CMR) or partial metabolic response (PMR) according to PERCIST 1.0 at the 3-month FDG-PET scan. At time of reporting (median follow-up 15 months; range 9-26 months) no deaths or local progression have been observed. Five patients (33%) progressed distantly at 3, 8, 8, 12 and 18 months: 2 of 3 (66%) TNBC, 2 of 10 (20%) Luminal and 1 of 2 (50%) HER2+. Estimated dPFS at 9 months was 80% (95% CI [62% – 100%]). Three patients have reached the 2-year mark without progression (all Luminal). In a patient who remained progression free at 24 months, TCR profiling showed that TCR sequences in a pre-treatment metastatic tumor biopsy were found in peripheral blood and became elevated after combination treatment, along with the emergence of new TCR sequences not seen in the tumor sample. Markers of increased CD8+ and CD4+ T cell activation using flow cytometry of peripheral blood lymphocytes were observed. This data suggests that the treatment induced peripheral expansion of tumor-specific T cells in this responding patient. Further correlatives are pending. Conclusion The combination of SBRT and 6 months of pembrolizumab in advanced breast cancer patients with 1-5 metastases showed an acceptable toxicity profile and promising clinical benefit especially in Luminal BC patients. Evidence of peripheral anti-tumor T cell responses was observed in a patient who remains progression free at 24 months. The potential synergy between these treatment modalities requires further study. Citation Format: David SP, Savas P, Neeson PJ, Luen SJ, Foroudi F, Siva S, Loi S. Safety and efficacy of stereotactic body radiotherapy and Pembrolizumab in advanced breast cancer patients with 1 to 5 metastases [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-09-06.

Abstract # 2069 Regional but not systemic immune parameters relate to neuropsychiatric morbidity in patients with genital herpes simplex virus (HSV) infection

Neuropsychiatric disturbances, including during the prodromal stage of infection, are common among patients with genital herpes simplex virus (HSV) infection. These disturbances are typically interpreted as signs of stress – in a stress-diathesis disease model. The role of immunological triggers in these manifestations is less explored. We examined a role for regional and systemic markers of immune activation in neuropsychiatric manifestations among patients with documented genital HSV infection. Twenty-two patients of an inner-city tertiary sexual health clinic were assessed when herpetic lesions were present, and again when lesions were absent. Measures were also obtained from healthy control subjects. Each assessment included a clinical examination, self-report measures, as well as a blood and urine collection. Markers of immune activation [neopterin and interleukin (IL)-6] in serum and urine were quantified by enzyme-linked immunoassay. Urinary, but not serum, levels of neopterin and/or IL-6 correlated significantly with a spectrum of neuropsychiatric and urogenital symptoms. Symptoms were significantly more severe during active clinical lesions (p

Exogenous carbohydrases added to a starter diet reduced markers of systemic immune activation and decreased Lactobacillus in weaned pigs1.

Although the impact of carbohydrases on performance and nutrient utilization has been well studied, their effects on immune status and intestinal microbiota are less known in pigs. This study aimed to evaluate the impact of xylanase (X) and a carbohydrase enzyme blend (EB; cellulase, ß-glucanase, and xylanase) on the immune profile of the intestine and peripheral system as well as intestinal microbes and microbial metabolites of weaned pigs fed higher fiber diets. Pigs (n = 460; 6.43 ± 0.06 kg BW; F25 × 6.0 Genetiporc) were blocked by initial BW. Pens (n = 48; 12 per treatment; 9 or 10 pigs per pen) were randomly assigned to 1 of 4 dietary treatments, including a higher fiber control diet (CON) and the CON supplemented with 0.01% X, 0.01% EB, or both enzymes (X + EB), arranged in a 2 × 2 factorial. The diets were based on corn, soybean meal, corn distillers dried grains with solubles, and wheat middlings. After 7-d adaptation to the environment, pigs were fed experimental diets ad libitum for 28 d. Blood samples were collected from the same pig within each pen on days 0, 7, 14, and 28. Intestinal tissues and digesta were collected on day 28. Bacteria 16S rRNA gene copy numbers were quantified using qPCR. The mRNA levels of colonic IL-17, occludin (OCLN), and claudin 3 (CLDN3) were greater in pigs fed diets with X + EB, but not X or EB, compared with those fed CON (P < 0.05). The EB in the diet reduced plasma IL-8 over the 28-d trial compared with diets without EB (P < 0.05). There was an X × EB interaction on plasma tumor necrosis factor α and IL-1ß (P < 0.05); their levels were decreased when X and EB were added together, but not individually, compared with CON. The EB decreased cecal propionate, butyrate, and total volatile fatty acids (P < 0.05). Pigs fed X had lower ileal Lactobacillus and greater ileal and cecal Enterobacteriaceae compared with those fed unsupplemented diets (P < 0.05). The EB decreased Lactobacillus (P < 0.05) and tended to decrease (P = 0.065) Enterobacteriaceae in the colon compared with diets without EB. In conclusion, the addition of X and EB together decreased systemic markers of immune activation, potentially diverting energy and nutrients towards growth. The EB reduced colonic Lactobacillus and cecal total volatile fatty acids, probably due to improved prececal fiber and starch degradation and thus reduced substrate availability in the large intestine. These data corroborated previously observed enhanced growth in pigs fed EB-supplemented diets.

Assessment of the Parameters of Adaptive Cell-Mediated Immunity in Naïve Common Marmosets (Callithrix jacchus)

Common marmosets are small New World primates that have been increasingly used in biomedical research. This report presents efficient protocols for assessment of the parameters of adaptive cell-mediated immunity in common marmosets, including the major subpopulations of lymphocytes and main markers of T- and B-cell maturation and activation using flow cytometry with a multicolor panel of fluorescently labelled antibodies. Blood samples from eight common marmosets were stained with fluorescently labeled monoclonal antibodies against their population markers (CD45, CD3, CD20, CD4, CD8) and lymphocyte maturation and activation markers (CD69, CD62L, CD45RO, CD107a and CD27) and analyzed by flow cytometry. Within the CD45+ population, 22.7±5.5% cells were CD3- CD20+ and 67.6±6.3% were CD3+CD20-. The CD3+ subpopulation included 55.7±5.5% CD3+CD4+CD8- and 34.3±3.7% CD3+CD4-CD8+ cells. Activation and maturation markers were expressed in the following lymphocyte proportions: CD62L on 54.0±10.7% of CD3+CD4+ cells and 74.4±12.1% of CD3+CD8+ cells; CD69 on 2.7±1.2% of CD3+CD4+ cells and 1.2±0.5% of CD3+CD8+ cells; CD45RO on 1.6±0.6% of CD3+CD4+ cells and 1.8±0.7% of CD3+CD8+ cells; CD107a on 0.7±0.5% of CD3+CD4+ cells and 0.5±0.3% of CD3+CD8+ cells; CD27 on 94.6±2.1% of CD3+ cells and 8.9±3.9% CD20+ cells. Female and male subjects differed in the percentage of CD3+CD4+CD45RO+ cells (1.9±0.5 in females vs 1.1±0.2 in males; p < 0.05). The percentage of CD20+CD27+ cells was found to highly correlate with animals' age (r = 0.923, p < 0.005). The basal parameters of adaptive cell-mediated immunity in naïve healthy marmosets without markers of systemic immune activation were obtained. These parameters and the described procedures are crucial in documenting the changes induced in common marmosets by prophylactic and therapeutic immune interventions.

Acute hyperinsulinemia effects on systemic markers of immune activation in HIV.

: The well treated HIV population remains at risk for insulin resistance and chronic immune activation. We tested the effects of acute hyperinsulinemia on inflammation in HIV. Twenty HIV-infected and 10 non-HIV-infected individuals well matched for BMI underwent oral glucose tolerance testing to stimulate insulin secretion and assess for changes in circulating soluble CD163, soluble CD14, and monocyte chemoattract protein 1. Soluble CD14 decreased significantly after stimulation of hyperinsulinemia and no significant changes in soluble CD163 or monocyte chemoattract protein 1 were demonstrated in HIV-infected and non-HIV-infected groups.

131 - Serologic Markers of Systemic Immune Activation and Intestinal Cell Damage in Non-Celiac Wheat Sensitivity

131 - Serologic Markers of Systemic Immune Activation and Intestinal Cell Damage in Non-Celiac Wheat Sensitivity

Lack of elevation in plasma levels of pro‐inflammatory cytokines in common rodent models of pulmonary arterial hypertension: questions of construct validity for human patients

Translational research depends on the relevance of animal models and how well they replicate human disease. Here, we investigated plasma levels of three important pro-inflammatory cytokines (TNFα, IL-6, and MCP-1), known to be elevated in human pulmonary arterial hypertension (PAH), and systematically assessed their levels in PAH patients compared to five different rodent models of pulmonary hypertension (PH). A consistent immunoassay platform (Luminex xMAP) and source (Millipore) was used to measure all specimens. PAH patients (n = 29) exhibited significant elevations in all three cytokines (median [IQR] pg/mL; TNFα, 7.0 [4.8–11.7]; IL-6, 9.2 [3.8–17.2]; MCP-1, 109 [65–142]) versus healthy participants (n = 20) (median [IQR] pg/mL; TNFα, 3.0 [2.0–3.6]; IL-6, 1.7 [0.5–7.2]; MCP-1, 79 [49–93]. In contrast, mice with PH established after three weeks of hypoxia (n = 18) or SU5416 plus hypoxia (n = 20) showed no significant change in their plasma cytokine levels versus controls (n = 16), based on three to four independent experiments per group. Similarly, plasma cytokine levels were not elevated in rats with PH established three weeks after monocrotaline (n = 23), eight weeks after SU5416 alone (n = 10) or six to eight weeks after SU5416 plus hypoxia (n = 21) versus controls (n = 36 rats), based on three to eight independent experiments per group. Positive biologic control specimens from sepsis patients (n = 9), cecal-ligation and puncture (CLP)-induced septic mice (n = 6), and lipopolysaccharide-induced septic rats (n = 4) showed robust elevations in all three cytokines. This study suggests that animal models commonly used for the development of novel diagnostic and therapeutic approaches for PAH may have limited construct validity with respect to markers of systemic immune activation seen in human patients.

Effects of pitavastatin and pravastatin on markers of immune activation and arterial inflammation in HIV.

Persistent immune activation is thought to contribute to increased cardiovascular disease risk in HIV and statins may help modulate systemic immune activation. We aimed to compare the effects of two key statins on markers of systemic immune activation and arterial inflammation in the HIV population. Double-blind, active-controlled, parallel-group comparative trial performed in 45 sites. Two hundred and fifty-two antiretroviral therapy-treated HIV-infected participants with dyslipidemia were randomized (1 : 1) to pitavastatin 4 mg daily vs. pravastatin 40 mg daily in the HIV-infected patieNts and TREatment with PItavastatin vs. pravastatin for Dyslipidemia (INTREPID) trial. In this analysis of the INTREPID trial, we assessed markers of immune activation and arterial inflammation using a modified intent-to-treat population. This trial is registered with ClinicalTrials.gov (NCT01301066). One hundred and twenty-six participants were randomized to receive pitavastatin and 126 to pravastatin. Ninety-nine participants in the pitavastatin group and 91 participants in the pravastatin group completed the study. Median age was 50 (45, 56) years [median (interquartile range)]. Baseline, low-density lipoprotein-cholestrol (LDL-C) was 153 (135, 171) mg/dl, log HIV-1 viral load was 1.1 ± 0.2 copies/ml, and CD4 cell count was 580 (439, 794) cells/μl. At week 52, the pitavastatin group had a significantly greater reduction (% change) compared with pravastatin in soluble CD14 (sCD14), (-10.0 vs. 0.6%, P = 0.02), oxidized LDL (oxLDL) (-26.9 vs. -17.5%, P = 0.02), and lipoprotein-associated phospholipase 2 (Lp-PLA2) (-26.6 vs. -15.5%, P = 0.005) (pitavastatin vs. pravastatin). Fifty-two weeks of pitavastatin 4 mg daily (vs. pravastatin 40 mg daily) led to a greater reduction in select markers of immune activation and arterial inflammation (sCD14, oxLDL, and LpPLA2) among HIV-infected participants. Further work is needed to assess whether immune-modulatory effects of pitavastatin reduce cardiovascular disease risk in HIV.

A Cross-Sectional Study of the Prevalence of Gastrointestinal Symptoms and Pathology in Patients With Common Variable Immunodeficiency.

The objective of this study was to study the prevalence of gastrointestinal (GI) symptoms and histopathology in patients with common variable immunodeficiency (CVID) as well as linking the findings to GI infections and markers of systemic immune activation. In this cross-sectional study, we addressed GI symptoms in 103 patients and GI histopathological findings in 53 patients who underwent upper and lower endoscopic examination. The most frequent histopathological findings were linked to GI symptoms, B-cell phenotype, and markers of systemic immune activation (soluble (s)CD14, sCD25, and sCD163). Microarray analysis compared "celiac-like disease" in CVID to celiac disease. Screening for selected bacterial and viral infections in fecal samples and gut mucosal biopsies was performed. The main findings of this study were as follows: most common GI symptoms were bloating (34%), pain (30%), and diarrhea (26%). The most frequent histopathological findings were increased intraepithelial lymphocytes in the descending part of the duodenum, i.e., "celiac-like disease" (46% of patients), decreased numbers of plasma cells in GI tract mucosa (62%), and lymphoid hyperplasia (38%), none of which were associated with GI symptoms. Reduced plasma cells in GI mucosa were associated with B-cell phenotypic characteristics of CVID, and increased serum levels of sCD14 (P=0.025), sCD25 (P=0.01), and sCD163 (P=0.04). Microarray analyses distinguished between CVID patients with "celiac-like disease" and celiac disease. Positive tests for bacterial and viral infections were scarce both in fecal samples and gut mucosal biopsies, including PCR test for norovirus in biopsy specimens (0 positive tests). In conclusion, GI pathology is common in CVID, but does not necessarily cause symptoms. However, reduced plasma cells in GI mucosa were linked to systemic immune activation, "celiac-like disease" in CVID and true celiac disease appear to be different disease entities, as assessed by gene expression, and infections (including norovirus) are rarely a cause of the CVID enteropathy.

Altered gut microbiota profile in common variable immunodeficiency associates with levels of lipopolysaccharide and markers of systemic immune activation.

Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency characterized by low immunoglobulin (Ig)G and IgA, and/or IgM. In addition to bacterial infections, a large subgroup has noninfectious inflammatory and autoimmune complications. We performed 16S ribosomal RNA-based profiling of stool samples in 44 CVID patients, 45 patients with inflammatory bowel disease (disease controls), and 263 healthy controls. We measured plasma lipopolysaccharide (LPS) and markers of immune cell activation (i.e., soluble (s) CD14 and sCD25) in an expanded cohort of 104 patients with CVID and in 30 healthy controls. We found a large shift in the microbiota of CVID patients characterized by a reduced within-individual bacterial diversity (alpha diversity, P<0.001) without obvious associations to antibiotics use. Plasma levels of both LPS (P=0.001) and sCD25 (P<0.0001) were elevated in CVID, correlating negatively with alpha diversity and positively with a dysbiosis index calculated from the taxonomic profile. Low alpha diversity and high dysbiosis index, LPS, and immune markers were most pronounced in the subgroup with inflammatory and autoimmune complications. Low level of IgA was associated with decreased alpha diversity, but not independently from sCD25 and LPS. Our findings suggest a link between immunodeficiency, systemic immune activation, LPS, and altered gut microbiota.

Probiotics Improve Inflammation-Associated Sickness Behavior by Altering Communication between the Peripheral Immune System and the Brain.

This research shows that probiotics, when eaten, can improve the abnormal behaviors (including social withdrawal and immobility) that are commonly associated with inflammation. Probiotics are able to cause this effect within the body by changing how the immune system signals the brain to alter brain function. These findings broaden our understanding of how probiotics may beneficially affect brain function in the context of inflammation occurring within the body and may open potential new therapeutic alternatives for the treatment of these alterations in behavior that can greatly affect patient quality of life.

Determinants of medium and high VACS index in HIV‐positive patients on effective HAART

Non‐AIDS events are the leading cause of death in HIV‐positive patients (pts) on effective HAART. The VACS index, composed by HIV‐RNA, CD4+, age, hemoglobin, FIB‐4, eGFR and HCV co‐infection, has been validated as 5‐year mortality index in HIV‐ positive pts [1]. The aim of our study was to evaluate the prevalence and any possible predictive factors of medium‐high VACS index in a cohort of HIV‐positive pts; we also evaluated whether it relates with markers of systemic immune activation. 501 consecutive HIV‐positive asymptomatic pts on effective HAART (HIV‐RNA &lt;40 cp/ml) were enrolled. T‐cell activation (CD38+, CD8+45R0, CD8+38R0) and differentiation (CD127+) was assessed by flow cytometry; VACS index was calculated closest to the sample timepoint. Comparisons were assessed by Chi‐square test. Factors associated with VACS index equal or greater than 10% (gender, time on HAART, CD4+nadir, AIDS diagnosis, previous or current IDU, immune‐activation markers) in univariate model entered the multivariate logistic regression. Of the 501 patients enrolled, 350 (70%) had a low VACS index (VACS &lt;10%), 143 (28%) a medium index (VACS 10–30%) and 8 (1%) an high one (VACS &gt;30%). Groups (pts with low and medium‐high VACS index) were comparable for CD4+ nadir, AIDS diagnosis, CD8+45RO%, CD8+38RO%, CD127+%. Females, active or previous IDU, pts with shorter HAART exposure showed more frequently medium‐high VACS index (table 1). In the multivariable model, female sex (AOR 6.26, 95% CI 3.45‐11.38, p&lt;0.000), IDU history (AOR 2.409, 95% CI 1.31–4.422, p=0.0045) and current CD38+/CD8% (each% more: AOR 1.122, 95% CI 1.03‐1.21, p=0.004) were all independent predictors of VACS ≥10%. Our data suggest that a persistently‐activated immune profile despite virologically‐suppressive HAART may contribute to all‐cause mortality risk, possibly through its role in accelerating degenerative disease. Possible determinants of gender differences in VACS index (such as hemoglobin) need to be further studied. Variable associated with medium‐high VACS index in univariate model Pts with low (&lt;10%) VACS index (n=350) Pts with medium‐high (&gt;10%) VACS index (n=151) p Female sex ° 69 (19%) 66 (43%) 0.0001 AIDS° 75 (21%) 50 (33%) 0.38 Nadir CD4+ T cells/mmc* 211 (7–600) 183 (4–489) 0.75 HAART duration, years* 8.1 (1–21) 7.9 (1–20) 0.01 IDU° 74 (21%) 50 (33%) 0.004 CD127/CD4 + %* 35 (0–63) 35 (0–58) 0.81 CD127/CD8 + %* 44 (0–55) 45 (0–46) 0.70 CD8 + 45/RO%* 13 (0–43) 14 (0–61) 0.7 CD8 + 38/RO%* 1,5 (0–27) 1,6 (0–13) 0.85 CD8 + CD38 + %* 3.01 (0–23) 4.09 (0–23) 0.004 Data are presented as mean (range) Data are presented as the number (percentage)

Randomized pilot trial of a synbiotic dietary supplement in chronic HIV-1 infection

BackgroundInfection with HIV-1 results in marked immunologic insults and structural damage to the intestinal mucosa, including compromised barrier function. While the development of highly active antiretroviral therapy (HAART) has been a major advancement in the treatment of HIV-1 infection, the need for novel complementary interventions to help restore intestinal structural and functional integrity remains unmet. Known properties of pre-, pro-, and synbiotics suggest that they may be useful tools in achieving this goal.MethodsThis was a 4-week parallel, placebo-controlled, randomized pilot trial in HIV-infected women on antiretroviral therapy. A synbiotic formulation (Synbiotic 2000®) containing 4 strains of probiotic bacteria (1010 each) plus 4 nondigestible, fermentable dietary fibers (2.5 g each) was provided each day, versus a fiber-only placebo formulation. The primary outcome was bacterial translocation. Secondary outcomes included the levels of supplemented bacteria in stool, the activation phenotype of peripheral T-cells and monocytes, and plasma levels of C-reactive protein and soluble CD14.ResultsMicrobial translocation, as measured by plasma bacterial 16S ribosomal DNA concentration, was not altered by synbiotic treatment. In contrast, the synbiotic formulation resulted in significantly elevated levels of supplemented probiotic bacterial strains in stool, including L. plantarum and P. pentosaceus, with the colonization of these two species being positively correlated with each other. T-cell activation phenotype of peripheral blood lymphocytes showed modest changes in response to synbiotic exposure, with HLA-DR expression slightly elevated on a minor population of CD4+ T-cells which lack expression of HLA-DR or PD-1. In addition, CD38 expression on CD8+ T-cells was slightly lower in the fiber-only group. Plasma levels of soluble CD14 and C-reactive protein were unaffected by synbiotic treatment in this study.ConclusionsSynbiotic treatment for 4 weeks can successfully augment the levels of probiotic species in the gut during chronic HIV-1 infection. Associated changes in microbial translocation appear to be absent, and markers of systemic immune activation appear largely unchanged. These findings may help inform future studies aimed at testing pre- and probiotic approaches to improve gut function and mucosal immunity in chronic HIV-1 infection.Trial registrationClinical Trials.gov: NCT00688311