Levels Of Immune Activation Markers Research Articles

Jaundice in relation to immune activation during Epstein-Barr virus-induced infectious mononucleosis

BackgroundLiver involvement during infectious mononucleosis is common, but jaundice is considered rare. This study aimed to investigate serum bilirubin concentrations in patients with infectious mononucleosis and immune abnormalities associated with jaundice. MethodsWe report on an adult patient with monoclonal B lymphocytosis and IgM-lambda gammopathy who developed a severe icteric hepatitis during infectious mononucleosis. We then reviewed the clinical records of 389 patients admitted to the hospital with infectious mononucleosis between 1995 and 2018 (51.7% male patients; median age, 19 years; range, 15-87 years) with focus on liver abnormalities and associated factors. ResultsFifty-nine patients (15.1%) had serum bilirubin concentrations between 1.5 and 3 mg/dL, and 47 patients (12.0%) had serum bilirubin >3 mg/dL. Patients with increased bilirubin concentrations had a distinct clinical presentation, with more frequent abdominal pain, nausea and vomiting, and less frequent sore throat than patients with normal bilirubin. Age and sex were not significantly different for the patients with increased and normal serum bilirubin concentrations. The patients with increased serum bilirubin concentrations showed higher levels of immune activation markers than the patients with normal bilirubin, including blood lymphocyte counts, serum IgM, and β2-microglobulin concentrations. Heterophile antibody-positive patients (88.6%) showed similar bilirubin concentrations but higher aspartate aminotransferase and alkaline phosphatase levels than their heterophile-negative counterparts. Serum bilirubin elevations normalized quickly during follow-up. ConclusionsTransient hyperbilirubinemia is common during severe (in-hospital) infectious mononucleosis in adult patients. Patients with hyperbilirubinemia have less frequent pharyngitis symptoms and more frequent abdominal symptoms. Hyperbilirubinemia during infectious mononucleosis is associated with immune activation markers.

Possible role of plasma Galectin-9 levels as a surrogate marker of viremia in HIV infected patients on antiretroviral therapy in resource-limited settings

BackgroundEarly detection of viremia in HIV infected patients on anti-retroviral therapy (ART) is important to prevent disease progression as well as accumulation of drug resistance mutations. This makes HIV viral load (VL) monitoring indispensable in HIV infected patients on ART. However VL, being an expensive test, results in heavy financial burden on health services. Hence, cheaper surrogate markers of viremia are desired to reduce overall cost of management of HIV infected patients.MethodsWe enrolled aviremic (n = 63, M:F = 31:32) and viremic (n = 43, M:F = 21:22) HIV infected patients at 1 year after ART initiation. Viremic individuals were identified as those having a plasma VL of more than 1000 copies/µl and aviremic individuals as less than 40 copies/µl. The study participants also included immuno-virologically discordant patients as they demonstrate differential degrees of immune-reconstitution and are likely to harbour concomitant infections influencing levels of immune-activation markers screened as the surrogate markers. Immune activation markers viz. plasma hs-CRP, soluble-CD14 and Galectin-9 levels were estimated by ELISA, IL-6 by luminex assay and percentages of CD38+ CD8+ cells were determined by flow cytometry. The levels were compared between viremic and aviremic patients and correlated with plasma viral load. Receiver operated curve (ROC) analysis was done for plasma Galectin-9 levels.ResultsViremic patients had significantly higher levels of Galectin-9 and %CD38+ CD8+ cells (p values < 0.0001) than aviremic patients. Levels of the other activation markers did not differ between viremic and aviremic individuals. Galectin-9 levels (r = 0.76) and %CD38+ CD8+ cells (r = 0.39) correlated positively with VL. Area under curve for Galectin-9 levels for distinguishing between viremic and aviremic individuals was 0.98. Youden index, sensitivity, specificity, positive predictive value and negative predictive value for Galectin-9 levels were 0.87, 0.97, 0.90, 0.87 and 0.98, respectively, at the cut-off value of 5.79 ng/ml.ConclusionsPlasma Galectin-9 levels could identify viremic individuals with sensitivity and specificity of more than 90%. Thus, they showed a potential to serve as a surrogate marker of viremia in HIV infected patients on ART and would have cost implications on HIV management especially in resource-limited settings. However, the findings need to be confirmed in the patients on ART for different durations of time.

Very Early Initiation of Antiretroviral Therapy During Acute HIV Infection Is Associated With Normalized Levels of Immune Activation Markers in Cerebrospinal Fluid but Not in Plasma.

Chronic immune activation in the blood and central nervous system is a consequence of human immunodeficiency virus (HIV) infection that contributes to disease morbidity and can occur despite virally suppressive antiretroviral therapy (ART). The trajectory of HIV-related inflammation may vary with the timing of ART initiation. We examined immune activation markers in cerebrospinal fluid (CSF) and blood specimens collected over 96 weeks from participants who initiated ART during acute HIV infection (AHI). RV254/SEARCH010 study participants with AHI underwent CSF (n = 89) and plasma (n = 146) sampling before initiating ART and at weeks 24 and 96 of treatment. A majority participants (64.4%) received a standard ART regimen (hereafter, "standard ART"), with some (34.7%) also receiving maraviroc and raltegravir for the first 24 weeks (hereafter, "ART plus"). We compared neopterin, CXCL10, CCL2, and interleukin 6 (IL-6) levels in the AHI group to those in 18 healthy, uninfected controls. Following 24 and 96 weeks of treatment, levels of all CSF markers normalized while levels of several plasma markers remained elevated in the AHI group (P < .001). Participants receiving the ART-plus regimen had lower median plasma CCL2 levels at week 24 and lower plasma neopterin levels at week 96. ART initiation during AHI differentially impacts the brain compartment, with markers of inflammation returning to normal levels in the CSF, where they were sustained at week 96, but not in plasma.

Eradication of Hepatitis C Virus (HCV) Reduces Immune Activation, Microbial Translocation, and the HIV DNA Level in HIV/HCV-Coinfected Patients.

There are contradictory data about the influence that hepatitis C virus (HCV) has on immune activation and inflammation in patients coinfected with human immunodeficiency virus (HIV) and HCV. HIV/HCV-coinfected patients receiving antiretroviral treatment who achieved a sustained virological response with interferon-free regimens were consecutively enrolled in a prospective study. The following factors were assessed before, immediately after the end of, and 1 month after the end of therapy: expression of HLA-DR/CD38, PD-1, and CD57 on CD4+ and CD8+ T-cells; measurement of the total HIV DNA load in peripheral blood mononuclear cells; and determination of plasma levels of soluble CD14 (sCD14), lipopolysaccharide (LPS), 16S ribosomal DNA (rDNA), interleukin 6 (IL-6), D-dimers, and high-sensitivity C-reactive protein (hsCRP). Ninety-seven patients were consecutively included. At the end of therapy and 1 month later, there were significant reductions in the expression of HLA-DR and CD38 in CD4+ and CD8+ T cells, as well as levels of proviral HIV DNA, sCD14, LPS, 16S rDNA, and D-dimer (P < .001). By contrast, the expression of PD-1 and CD57 in CD4+ and CD8+ T cells and levels of IL-6 and hsCRP did not change. The improvement in levels of immune activation markers, proviral HIV DNA, and microbial translocation markers did not translate into an increased CD4+ T-cell count or increased ratio of the CD4+ T-cell count to the CD8+ T-cell count. HCV eradication in HIV/HCV-coinfected patients results in significant decreases in levels of immune activation markers, proviral HIV DNA load, microbial translocation markers, and D-dimers. These findings support the use of HCV treatment for all HIV/HCV-coinfected patients, even those with low-grade fibrosis.

Immune Activation by Mycobacterium tuberculosis in HIV-Infected and -Uninfected Subjects.

This study investigates the influence of Mycobacterium tuberculosis infection on immune activation biomarkers, both in HIV-infected and -uninfected subjects. Forty-eight treatment-naive HIV-infected patients and 74 HIV-uninfected subjects were recruited and divided into groups according to their M. tuberculosis infection status: latent tuberculosis infection (LTBI), active tuberculosis (TB), and no evidence of M. tuberculosis infection. The expression of cellular markers CD38 and HLA-DR on circulating CD8 T lymphocytes and the plasmatic levels of soluble markers interleukin-6, sCD14, and D-Dimer were measured and compared between groups. The HIV-infected patients with no evidence of M. tuberculosis or with LTBI who initiated antiretroviral treatment were tested again for these biomarkers once viral suppression was reached. In both HIV-infected and -uninfected groups, patients with TB had higher levels of immune activation markers than subjects with LTBI and with no evidence of M. tuberculosis. Among the HIV-uninfected subjects, no significant difference in biomarker level was found between those presenting LTBI and those with no evidence of M. tuberculosis. The effect of LTBI on activation biomarkers in the HIV-infected groups was inconclusive because of the small number of individuals in the HIV+/LTBI group. sCD14 and D-Dimer levels were significantly higher in the TB-only group than in the HIV-only group. Although TB is associated with an increase in biomarkers of immune activation, the effect of LTBI is less evident. Further investigation is warranted, and according to our results, soluble markers may offer greater sensitivity for the evaluation of M. tuberculosis-associated immune activation than cellular markers.

Probiotics Differently Affect Gut-Associated Lymphoid Tissue Indolamine-2,3-Dioxygenase mRNA and Cerebrospinal Fluid Neopterin Levels in Antiretroviral-Treated HIV-1 Infected Patients: A Pilot Study.

Recently the tryptophan pathway has been considered an important determinant of HIV-1 infected patients’ quality of life, due to the toxic effects of its metabolites on the central nervous system (CNS). Since the dysbiosis described in HIV-1 patients might be responsible for the microbial translocation, the chronic immune activation, and the altered utilization of tryptophan observed in these individuals, we speculated a correlation between high levels of immune activation markers in the cerebrospinal fluid (CSF) of HIV-1 infected patients and the over-expression of indolamine-2,3-dioxygenase (IDO) at the gut mucosal surface. In order to evaluate this issue, we measured the levels of neopterin in CSF, and the expression of IDO mRNA in gut-associated lymphoid tissue (GALT), in HIV-1-infected patients on effective combined antiretroviral therapy (cART), at baseline and after six months of probiotic dietary management. We found a significant reduction of neopterin and IDO mRNA levels after the supplementation with probiotic. Since the results for the use of adjunctive therapies to reduce the levels of immune activation markers in CSF have been disappointing so far, our pilot study showing the efficacy of this specific probiotic product should be followed by a larger confirmatory trial.

Kidney Dysfunction and Markers of Inflammation in the Multicenter AIDS Cohort Study.

Human immunodeficiency virus (HIV)-infected individuals are at higher risk for chronic kidney disease than HIV-uninfected individuals. We investigated whether the inflammation present in treated HIV infection contributes to kidney dysfunction among HIV-infected men receiving highly active antiretroviral therapy. The glomerular filtration rate (GFR) was directly measured (using iohexol) along with 12 markers of inflammation in Multicenter AIDS Cohort Study participants. Exploratory factor analysis was used to identify inflammatory processes related to kidney dysfunction. The estimated levels of these inflammatory processes were used in adjusted logistic regression analyses evaluating cross-sectional associations with kidney function outcomes. There were 434 HIV-infected men receiving highly active antiretroviral therapy and 200 HIV-uninfected men. HIV-infected men were younger (median age, 51 vs 53 years) and had higher urine protein-creatinine ratios (median, 98 vs 66 mg/g) but comparable GFRs (median, 109 vs 106 mL/min|1.73 m(2)). We found an inflammatory process dominated by markers: soluble tumor necrosis factor receptor 2, soluble interleukin 2 receptor α, soluble gp130, soluble CD27, and soluble CD14. An increase of 1 standard deviation in that inflammatory process was associated with significantly greater odds of GFR ≤90 mL/min/1.73 m(2) (odds ratio, 2.0) and urine protein >200 mg/g (odds ratio, 2.3). Higher circulating levels of immune activation markers among treated HIV-infected men may partially explain their higher burden of kidney dysfunction compared with uninfected men.

Older HIV-infected patients on antiretroviral therapy have B-cell expansion and attenuated CD4 cell increases with immune activation reduction

The contribution of immune activation to accelerated HIV-disease progression in older individuals has not been delineated. Prospective multicenter cohort of older (≥45 years) and younger (18-30 years) HIV-infected adults initiating 192 weeks of antiretroviral therapy (ART). Longitudinal models of CD4 cell restoration examined associations with age-group, thymic volume, immune activation, and viral load. Forty-five older and 45 younger adults (median age 50 and 26 years, respectively) were studied. Older patients had fewer naive CD4 cells (P<0.001) and higher HLA-DR/CD38 expression on CD4 (P=0.05) and CD8 cells (P=0.07) than younger patients at any time on ART. The rate of naive and total CD4 cell increase was similar between age groups, but older patients had a faster mean rate of B-cell increase (by +0.7 cells/week; P=0.01), to higher counts than healthy controls after 192 weeks (P=0.003). Naive CD4 increases from baseline were associated with immune activation reductions (as declines from baseline of %CD8 cells expressing HLA-DR/CD38; P<0.0001), but these increases were attenuated in older patients, or in those with small thymuses. A 15% reduction in activation was associated with naive gains of 29.9 and 6.2 cells/μl in younger, versus older patients, or with gains of 25.7, 23.4, and 2.1 cells/μl in patients with the largest, intermediate, and smallest thymuses, respectively (P<0.01 for interactions between activation reduction and age-group or thymic volume). Older patients had significant B-cell expansion, higher levels of immune activation markers, and significantly attenuated naive CD4 cell gains associated with activation reduction.

Immune Activation in HIV-Infected Aging Women on Antiretrovirals—Implications for Age-Associated Comorbidities: A Cross-Sectional Pilot Study

BackgroundPersistent immune activation and microbial translocation associated with HIV infection likely place HIV-infected aging women at high risk of developing chronic age-related diseases. We investigated immune activation and microbial translocation in HIV-infected aging women in the post-menopausal ages.MethodsTwenty-seven post-menopausal women with HIV infection receiving antiretroviral treatment with documented viral suppression and 15 HIV-negative age-matched controls were enrolled. Levels of immune activation markers (T cell immune phenotype, sCD25, sCD14, sCD163), microbial translocation (LPS) and biomarkers of cardiovascular disease and impaired cognitive function (sVCAM-1, sICAM-1 and CXCL10) were evaluated.ResultsT cell activation and exhaustion, monocyte/macrophage activation, and microbial translocation were significantly higher in HIV-infected women when compared to uninfected controls. Microbial translocation correlated with T cell and monocyte/macrophage activation. Biomarkers of cardiovascular disease and impaired cognition were elevated in women with HIV infection and correlated with immune activation.ConclusionsHIV-infected antiretroviral-treated aging women who achieved viral suppression are in a generalized status of immune activation and therefore are at an increased risk of age-associated end-organ diseases compared to uninfected age-matched controls.

Amelioration of Idiopathic Pneumonia Syndrome (IPS) and GVHD by KGF-Pretreatment Is Partly Mediated Via a STAT-6-Dependent Pathway in the Host.

KGF (FGF-7), an epithelial cell growth factor, can lessen the injurious effects of post-BMT lung injury (IPS) and GVHD when given prior to conditioning of the recipient. We reported that mice treated with KGF pre-conditioning had elevated systemic levels of Th2-type cytokines at the time of BM infusion which was associated with less GVHD. In non-conditioned SCID mice that developed lethal GVHD from allogeneic T cells, KGF pretreatment also increased Th2 cytokines implying that KGF alone was responsible for the systemic Th2 milieu and not a response that was dependent on conditioning. In the post-BMT lung, KGF pretreatment did not alter the cellular composition of the inflammatory infiltrate but resulted in decreased levels of immune activation markers compared to non-treated control IPS mice. The mechanism of this immunomodulatory effect is unknown. Since Th2 responses are dependent on the STAT-6 transcription factor, we studied the effects of KGF in our established murine IPS model using lethally-conditioned STAT-6−/− mice (B6 background) as recipients of allogeneic B10.BR BM and T cells and compared to WT hosts. STAT-6−/− mice pretreated with KGF (5 mg/kg s.c. for 3 days) had an accelerated mortality rate and poorer survival compared to WT recipients. Examination of GVHD target organs revealed that KGF pretreatment ameliorated liver GVHD in WT and STAT-6−/− recipients. In contrast, the benefit of KGF for GVHD of the colon was only seen in the WT but not in STAT-6−/− recipients, consistent with post-BMT body weights and survival. Whole body plethysmograph was done to evaluate lung function at 30 cm water pressure on day 7 post-BMT, a time when acute IPS is manifested in this model. WT but not STAT-6−/− mice pretreated with KGF had improved lung compliance compared to their non-treated counterparts (p<0.05). KGF-pretreated STAT-6−/− recipients also had increased lung weights compared to control- or KGF-treated WT mice with IPS (p<0.05). Histological analysis of lung cryosections taken on day 7 post-BMT showed that all recipients of allogeneic BM and T cells had increased inflammatory cells in their lungs, consistent with acute IPS. However, STAT-6−/− hosts with IPS had elevated numbers of CD4+ T cells in their lungs compared to WT hosts with IPS (18.3%±1.5 vs 11.6%±2.7, p=0.01). Other cell phenotypes did not differ. However, KGF-pretreated STAT-6−/− mice had significantly elevated levels (10-fold) of IL-17, CCL2 and CCL8 in their bronchoalveolar lavage fluid on day 7 post-BMT compared to their WT KGF-treated counterparts implying a skewing to a Th17 inflammatory response in STAT-6−/− mice. These data indicate that the STAT-6 pathway plays a role in the cytoprotective function of KGF and this STAT-6-dependency is tissue-specific. To achieve the full benefits of KGF and other cytoprotective agents, it will be important to take into account the immune modulatory mechanisms operative in individual GVHD target organs.

Changes in HIV RNA viral load, CD4+ T‐cell counts, and levels of immune activation markers associated with anti‐tuberculosis therapy and cotrimoxazole prophylaxis among HIV‐infected tuberculosis patients in Abidjan, Côte d'Ivoire

We analyzed changes in plasma human immunodeficiency virus (HIV)-1 viral load, CD4+ T-cell count, and markers of immune activation markers at start of treatment of tuberculosis and 12 months after among 44 HIV-1-infected patients with newly diagnosed, sputum-smear positive for Mycobacterium tuberculosis pulmonary infection. All patients received a standard regimen of 6 months of rifampicin and isoniazid with first 2 months of pyrazinamid with or without cotrimoxazole. Compared with values at start of treatment, median viral load increased by a median of 0.64 log10 copies/ml after 12 months of follow-up (P=0.0002). Median CD4+ T-cell counts were 393 cells/L at start of treatment and 370 cells/L after 12 months of follow-up (P=0.61). Levels of serum activation markers decreased significantly at 12 months of follow-up of the patients for both patients on standard and cotrimoxazole treatment. Levels of viral load, CD4+ T-cell counts, and markers of immune activation were not different for patients on standard treatment of tuberculosis compared with those on standard and cotrimoxazole treatment. Levels of serum activation markers decreased significantly at 12 months of follow-up of the patients for both patients on standard and cotrimoxazole treatment. Because viral load is a predictor of disease progression, its persistent elevated levels in blood of HIV-infected patients co-infected with tuberculosis, who successfully complete TB treatment, may account for the high mortality observed in this population.

Suppression of human immunodeficiency virus replication during acute measles.

To determine the effect of measles virus coinfection on plasma human immunodeficiency virus (HIV) RNA levels, a prospective study of hospitalized children with measles was conducted between January 1998 and October 2000 in Lusaka, Zambia. Plasma HIV RNA levels were measured during acute measles and 1 month after hospital discharge. The median plasma HIV RNA level in 33 children with measles who were followed longitudinally was 5339 copies/mL at study entry, 60,121 copies/mL at hospital discharge, and 387,148 copies/mL at 1-month follow-up. The median plasma HIV RNA level in children without acute illness was 228,454 copies/mL. Plasma levels of immune activation markers were elevated during the period of reduced plasma HIV RNA. Plasma levels of several potential HIV suppressive factors also were elevated during acute measles. HIV replication is transiently suppressed during acute measles at a time of intense immune activation.

Highly active antiretroviral therapy (HAART) and circulating markers of immune activation: specific effect of HAART on neopterin.

The circulating levels of immune activation markers, including neopterin, tumor necrosis factor receptor type II, and interleukin-2 receptors, are increased in human immunodeficiency virus-infected patients. We show here that highly active antiretroviral therapy significantly decreased neopterin levels. This effect is reversible, since neopterin levels increased after the arrest of treatment. Their determination may be useful in the evaluation of the efficacy of antiretroviral therapy.

Associations between maternal and fetal serum levels of immune activation markers and fetal growth.

During pregnancy, signs of maternal immunologic sensitization to fetal HLA and other fetoplacental alloantigens are often detectable in peripheral blood. Presumbly, this in part reflects immune activity at the maternal-fetal interface. This response may involve activation of maternal T cells, which stimulate placental growth via lymphokine production. To shed light on this mechanism, data on placental weight, neonatal anthropometry, gestational age, fetomaternal HLA relationships (reflecting a potential for HLA allosensitization), and serum levels of three immune activation markers in maternal and cord blood were collected in a sample of 61 primiparous women and their neonates. The activation markers were soluble CD8 antigen (sCD8), interleukin-2 receptor (sIL-2R), and beta-2 microglobulin (β2 m). Mean fetal and maternal sCD8 and β2 m levels, and mean fetal sIL-2R levels were significantly higher than published norms. Fetal means for all three markers exceeded maternal means, and both sIL-2R and β2 m were highly correlated between mother and fetus. This suggests that fetal sIL-2R and β2 m levels result in part from transport or diffusion from the maternal compartment. No associations were found between fetomaternal HLA relationships, activation markers, and placental weight. The difference between the fetal and maternal β2 m value was significantly correlated with birth weight, controlling for chest circumference and crown-heel length. Associations between birth weight and fetomaternal HLA relationships could not be interpreted with certainty. These findings suggest that maternal immune activation and diffusion or transport of β2 m into fetal compartment enhances fetal growth in fat-free body mass. © 1995 Wiley-Liss, Inc.