Plasmatic Levels Of Cytokines Research Articles

Genetic, Clinical, Epidemiological, and Immunological Profiling of IgG Response Duration after SARS-CoV-2 Infection.

The IgG response against SARS-CoV-2 infection can persist for over six months (long response; LR). However, among 30% of those infected, the duration can be as short as three months or less (short response; SR). The present study assembled serological data on the anti-SARS-CoV-2 IgG response duration of two previous studies and integrated these results with the plasmatic cytokine levels and genetic profile of 10 immune-relevant SNPs that were also previously published, along with the plasmatic total IgG, IgA, and IgM levels, allowing for the genetic, clinical, immunological, and epidemiological aspects of the post-COVID-19 IgG response duration to be understood. The SR was associated with previous mild acute COVID-19 and with an SNP (rs2228145) in IL6R related to low gene expression. Additionally, among the SR subgroup, no statistically significant Spearman correlations were observed between the plasma levels of IL-17A and the Th17 regulatory cytokines IFN-γ (rs = 0.2399; p = 0.1043), IL-4 (rs = 0.0273; p = 0.8554), and IL-2 (rs = 0.2204; p = 0.1365), while among the LR subgroup, weaker but statistically significant Spearman correlations were observed between the plasma levels of IL-17A and IFN-γ (rs = 0.3873; p = 0.0016), IL-4 (rs = 0.2671; p = 0.0328), and IL-2 (rs = 0.3959; p = 0.0012). These results suggest that the Th17 response mediated by the IL-6 pathway has a role in the prolonged IgG response to SARS-CoV-2 infection.

Brief Report: In cART-Treated HIV-Infected Patients, Immunologic Failure Is Associated With a High Myeloid-Derived Suppressor Cell Frequency.

During HIV infection, effective combined antiretroviral therapy suppresses viral replication and restores the number of circulating CD4+ T cells. However, 15%-30% of treated patients show a discordant response to combined antiretroviral therapy. Myeloid-derived suppressor cells (MDSC) are expanded in HIV+ patients; to better understand the role of MDSC on CD4 T-cell recovery, we evaluated the frequency of MDSC in HIV+ patients under combined antiretroviral therapy and its association with immunologic response. We enrolled 60 HIV+ patients, including complete responders (R, n = 44), virologic nonresponders (VNR, n = 5), and immunologic nonresponders (INR, n = 11). The frequency of circulating MDSC and the percentage of activated and naïve CD4 T cells were evaluated by flow cytometry. Plasmatic cytokine levels were analyzed by automated ELISA. As previously observed, polymorphonuclear MDSC (PMN-MDSC) frequency was higher in HIV+ patients compared with healthy donors. Furthermore, PMN-MDSC percentage was higher in INR than R patients, and a significant association between MDSC frequency and immunologic failure was confirmed by a receiver operator characteristic analysis. Accordingly, an inverse correlation was found between the percentages of PMN-MDSC and naïve CD4 T cells. A positive correlation was observed between PMN-MDSC frequency and the percentage of human leucocyte antigen locus DR + CD4 T cells and the plasmatic level of IL-1β and IL-8. Our results show that a high frequency of PMN-MDSC persists in INR, possibly because of immune activation, contributing to CD4 T-cell recovery failure. These findings further highlight the detrimental role of MDSC during HIV infection, suggesting these cells as a possible new therapeutic target.

Exploring cytokine dynamics in tuberculosis: A comparative analysis of patients and controls with insights from three-week antituberculosis intervention.

Despite developing new diagnostics, drugs, and vaccines, treating tuberculosis (TB) remains challenging. Monitoring inflammatory markers can contribute to more precise diagnostics of TB, identifying its active and latent forms, or monitoring its treatment success. We assessed alterations in plasma levels of 48 cytokines in 20 patients (17 males) with active pulmonary TB compared to age-matched healthy controls (n = 18). Blood samples were collected from individuals hospitalised with TB prior to commencing antibiotic therapy, after the first week, and following the third week. The majority of patients received treatment with a combination of four first-line antituberculosis drugs: rifampicin, isoniazid, ethambutol, and pyrazinamide. Plasmatic cytokine levels from patients three times and controls were analyzed using a Bio-Plex Pro Human Cytokine Screening Panel. The results showed significantly higher levels of 31 cytokines (p<0.05) than healthy controls. Three-week therapy duration showed significantly decreased levels of nine cytokines: interferon alpha-2 (IFN-α2), interleukin (IL) 1 alpha (IL-1α), IL-1 receptor antagonist (IL-1ra), IL-6, IL-10, IL-12 p40, IL-17, leukemia inhibitory factor (LIF), and tumor necrosis factor alpha (TNF-α). Out of these, only levels of IL-1α and IL-6 remained significantly elevated compared to controls. Moreover, we have found a negative correlation of 18 cytokine levels with BMI of the patients but no correlation with age. Our results showed a clinical potential for monitoring the levels of specific inflammatory markers after a short treatment duration. The reduction in cytokine levels throughout the course of therapy could indicate treatment success but should be confirmed in studies with more individuals involved and a longer observation period.

Liver fibrotic development is reduced through inflammation prevention by an adenosine derivative compound

BackgroundLiver fibrosis is a global health problem, and studying its development provides important information to address its treatment. Here, we characterized the effects of an adenosine compound (IFC-305) on preventing fibrosis and liver inflammation. Methods: We studied the impact of IFC-305 on a carbon tetrachloride-induced liver fibrosis model in Wistar male rats at 4, 6, and 8 weeks. The effects were characterized by liver tissue histology, macrophages identification by flow cytometry with CD163+/CD11b/c+ antibodies, hepatic and plasmatic cytokine levels employing MILLIPLEX MAP and ELISA, Col1a1 and Il6 gene expression by RTqPCR, lipoperoxidation by TBARS reaction, and reactive oxygen species using 2'−7'dichlorofluorescin diacetate. Results: CCl4-induced liver fibrosis and inflammation were significantly reduced in rats treated with IFC-305 at 6 and 8 weeks. In addition, we observed diminished expression of Col1a1; a decrease in the inflammatory cytokines IL-1β, IL-6, MCP-1, TNF-α, and IL-4 a; reduction in inflammatory macrophages; inhibition of lipoperoxidation; and ROS production in Kupffer cells. Conclusion: This study showed that IFC-305 can inhibit liver fibrosis establishment by regulating the immune response during CCl4-induced damage. The immunomodulatory action of IFC-305 supports its use as a potential therapeutic strategy for preventing liver fibrosis.

Exopolysaccharide Producing Bifidobacterium animalis subsp. lactis Strains Modify the Intestinal Microbiota and the Plasmatic Cytokine Levels of BALB/c Mice According to the Type of Polymer Synthesized.

Bacteria-host interactions are mediated by different microbial associated molecular patterns which are most often surface structures such as, among others, exopolysaccharides (EPSs). In this work, the capability of two isogenic EPS-producing Bifidobacterium animalis subsp. lactis strains to modulate the gut microbiota of healthy mice, was assessed. Each strain produces a different type of polymer; the ropy strain S89L synthesized a rhamnose-rich, high-molecular weight EPS in highest abundance than the non-ropy DMS10140 one. BALB/c mice were orally fed for 10 days with milk-bifidobacterial suspensions and followed afterward for 7 post-intervention days (wash-out period). The colonic content of mice was collected in several sampling points to perform a metataxonomic analysis. In addition, the influence of specific microbial clades, apparently stimulated by the ropy and non-ropy strains, on mouse plasmatic cytokine levels was investigated through hierarchical association testing. Analysis of 16S rRNA gene sequences showed that the abundance of Firmicutes phylum significantly increased 7 days after cessing the treatment with both strains. The relative abundance of Alloprevotella genus also rose, but after shorter post-treatment times (3 days for both DMS10140 and S89L strains). Some bacterial clades were specifically modulated by one or another strain. As such, the non-ropy DMS10140 strain exerted a significant influence on Intestinomonas genus, which increased after 4 post-administration days. On the other hand, feeding with the ropy strain S89L led to an increase in sequences of Faecalibaculum genus at 4 post-treatment days, while the abundance of Erysipelotrichaceae and Lactobacillaceae families increased for prolonged times. Association testing revealed that several lactobacilli and bifidobacterial significantly stimulated by ropy S89L strain were positively associated with the levels of certain cytokines, including IL-5 and IL-27. These results highlight relevant changes in mice gut microbiota produced after administration of the ropy S89L strain that were associated to a potential immune modulation effect.

Impaired Thymic Output Can Be Related to the Low Immune Reconstitution and T Cell Repertoire Disturbances in Relapsing Visceral Leishmaniasis Associated HIV/AIDS Patients

Background: Visceral leishmaniasis/HIV-co-infected patients (VL/HIV) accounts for around 8% of VL reported cases in Brazil. Relapses of Leishmania infection after anti-leishmanial treatment constitute a great challenge in the clinical practice because of the disease severity and drug resistance. We have shown that non-relapsing-VL/HIV (NR-) evolved with increase of CD4+ T-cell counts and reduction of activated CD4+ and CD8+ T cells after anti-leishmanial treatment. This immune profile was not observed in relapsing-VL/HIV patients (R-), indicating a more severe immunological compromising degree. Elevated activation status may be related to a deficient immune reconstitution and could help to explain the frequent relapses in VL/HIV co-infection. Our aim was to evaluate if this gain of T cells was related to changes in the peripheral TCRVβ repertoire and inflammatory status, as well as the possible thymus involvement in the replenishment of these newly formed T lymphocytes.Methods: VL/HIV patients, grouped into non-relapsing (NR- = 6) and relapsing (R- = 12) were evaluated from the active phase up to 12 months post-treatment (mpt). HIV-infected patients (non-VL) and healthy subjects (HS) were included. The TCRVβ repertoire was evaluated ex vivo by flow cytometry, whereas the plasmatic cytokine levels were assessed by Luminex assay. To evaluate the thymic output, DNA was extracted from PBMCs for TCR rearrangement excision circles (TREC) quantification by qPCR.Results: VL/HIV cases presented an altered mobilization profile (expansions or retractions) of the TCRVβ families when compared to HS independent of the follow-up phase (p < 0.05). TCRVβ repertoire on CD4+ T-cells was more homogeneous in the NR-VL/HIV cases, but heterogeneous on CD8+ T-cells, since different Vβ-families were mobilized. NR-VL/HIV had the inflammatory pattern reduced after 6 mpt. Importantly, VL/HIV patients showed number of TREC copies lower than controls during all follow-up. An increase of recent thymic emigrants was observed in NR-VL/HIV individuals at 10 mpt compared to R- patients (p < 0.01), who maintained lower TREC contents than the HIV controls.Conclusions: VL/HIV patients that maintain the thymic function, thus generating new T-cells, seem able to replenish the T lymphocyte compartment with effector cells, then enabling parasite control.

Cytokines Genotype-Phenotype Correlation in Nonalcoholic Steatohepatitis.

NASH consists in lipid accumulation in hepatocytes that trigger oxidative stress, secretion of proinflammatory cytokines leading to steatohepatitis (NASH). The study aimed to investigate the levels of proinflammatory (TNF-α and IL-6) along with anti-inflammatory cytokine IL-10 in patients with NASH and to correlate the cytokines' level with their polymorphism. Sixty-six patients with NASH and 30 healthy volunteers were included in the study. The plasmatic level of IL-6, IL-10, and TNF-α were determined by ELISA. IL-10 -1082 G/A, IL-6 -174 G/C, and TNF-α -308 G/A polymorphisms were determined using the PCR-RFLP technique. IL-6, TNF-α, and CRP levels were significantly higher in patients with NASH. There was a positive correlation between proinflammatory cytokines and a negative correlation between IL-10 and proinflammatory markers. The G allele and GG genotype of IL-6 -174 G/C polymorphism were more frequently noticed in NASH patients. Regarding IL-10 -1082 G/A polymorphism, the AA genotype was correlated with NASH and with a low plasmatic level of IL-10. The A allele in position 308 of the TNF-α gene was associated with high level of cytokine. In conclusion, there was an imbalance between pro- and anti-inflammatory cytokines in NASH patients. IL-10 -1082 G/A and TNF-α -308 G/A genotypes were correlated with the plasmatic levels of cytokines.

Immune response pattern in recurrent Plasmodium vivax malaria.

BackgroundPlasmodium vivax is the causative agent of human malaria of large geographic distribution, with 35 million cases annually. In Brazil, it is the most prevalent species, being responsible by around 70 % of the malaria cases.MethodsA cross-sectional study was performed in Manaus (Amazonas, Brazil), including 36 adult patients with primary malaria, 19 with recurrent malaria, and 20 endemic controls. The ex vivo phenotypic features of circulating leukocyte subsets (CD4+ T-cells, CD8+ T-cells, NK, NKT, B, B1 and Treg cells) as well as the plasmatic cytokine profile (IL-2, IL-4, IL-6, IL-10, TNF and IFN-γ) were assessed, aiming at establishing patterns of immune response characteristic of primary malaria vs recurrent malaria as compared to endemic controls.ResultsThe proportion of subjects with high levels of WBC was reduced in malaria patients as compared to the endemic control. Monocytes were diminished particularly in patients with primary malaria. The proportion of subjects with high levels of all lymphocyte subsets was decreased in all malaria groups, regardless their clinical status. Decreased proportion of subjects with high levels of CD4+ and CD8+ T-cells was found especially in the group of patients with recurrent malaria. Data analysis indicated significant increase in the proportion of the subjects with high plasmatic cytokine levels in both malaria groups, characterizing a typical cytokine storm. Recurrent malaria patients displayed the highest plasmatic IL-10 levels, that correlated directly with the CD4+/CD8+ T-cells ratio and the number of malaria episodes.ConclusionThe findings confirm that the infection by the P. vivax causes a decrease in peripheral blood lymphocyte subsets, which is intensified in the cases of “recurrent malaria”. The unbalanced CD4+/CD8+ T-cells ratio, as well as increased IL-10 levels were correlated with the number of recurrent malaria episodes. These results suggest that the gradual remodelling of the immune response is dependent on the repeated exposure to the parasite, which involves a strict control of the immune response mediated by the CD4+/CD8+ T-cell unbalance and exacerbated IL-10 secretion.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-016-1501-5) contains supplementary material, which is available to authorized users.

Increased Levels of IL-17, IL-23, MIP-1α, MCP-1 and Global Leukocytes in Fibromyalgia Patients

Objectives: To evaluate and compare the blood leukocytes and plasmatic levels of cytokines [IL-17, IL-23, MIP-1α and MCP-1] found in patients with fibromyalgia [FM] and healthy controls.Methods: Fo...

Plasmatic Cytokine Levels in Lung Cancer Patients Undergoing Definitive Radiation Therapy

To assess the kinetics of plasmatic cytokines during the course of definitive radiation therapy (RT) for locally-advanced or early-stage Non-Small Cell Lung Cancer (NSCLC). This prospective study was conducted with the approval of our Institutional Review Board, and was conducted on 28 lung cancer patients: 15 early-stage NSCLC patients underwent to Stereotactic Body RT (SBRT) consisting of 52 Gy in 8 fractions; 13 locally-advanced NSCLC patients underwent to radical Intensity Modulated Radiation Therapy (IMRT) consisting of 60 Gy in 25 fractions. All patients were treated with helical tomotherapy. For patients undergoing to SBRT, EDTA-peripheral blood samples were collected at the following time: first day of SBRT (TFd), last day of SBRT (TLd) and 45 days (T45d) after the end of SBRT. For patients undergoing IMRT, blood samples were collected at the following time: first day (TFd), at two weeks (T2w), at four weeks (T4w), last day (TLd), and 45 days (T45d) after the completion of RT course. A multiplex parametric technology was used for quantification of the following cytokines: IL-1, IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-15, IL-17A, EGF, FGF-2, INF-γ, MIP-1α, MIP-1β, TGF-α, TNF-α, VEGF, PDGF-α, and PDGF-β. Cytokine levels measured at different RT time were compared using a two-tailed Student's t test; statistical significance was claimed for p < 0.05. No difference in baseline levels of cytokines was documented between SBRT (early-stage) patients and IMRT (locally-advanced) patients. For SBRT patients, a mean IL-10 and IL-7 plasma level reduction of 5 pg/mL (p < 0.05) and 2 pg/mL (p < 0.05), respectively, was noted between TLd and TFd. IL-10 and IL-17 returned to pre-RT levels 45 days after completion of SBRT. For IMRT patients, a statistically significant (p < 0.05) mean plasma level reduction was noted between T4w and TFd for all the following cytokines: IL-1 (4 pg/mL), IL-1ra (33 pg/mL), IL-2 (5 pg/mL), IL-12 (35 pg/mL), IL-13 (4 pg/mL), FGF-2 (42 pg/mL), MIP-1α (2 pg/mL), MIP-1β (13 pg/mL), TGF-α (2 pg/mL), TNF-α (7 pg/mL), VEGF (105 pg/mL), PDGF-α (3784 pg/mL), and PDGF-β (47875 pg/mL). All theses cytokines returned to pre-RT levels the last day (TLd) of IMRT, and stayed stable 45 days after the completion of RT. The present study was conducted to examine the effect of different schedule of radiation therapy on levels of inflammatory markers in NSCLC patients. We have shown that several cytokines are sensitive to irradiation. A reduction of plasmatic cytokine levels during the course of radiation therapy both for early-stage and locally advanced NSCLC patients was documented. If such cytokine kinetics might have an impact in outcome or in radiation-related toxicity has to be investigated.

Apoptosis of non-parasitised red blood cells in Plasmodium yoelii malaria

Recently, while studying erythrocytic apoptosis during Plasmodium yoelii infection, we observed an increase in the levels of non-parasitised red blood cell (nRBC) apoptosis, which could be related to malarial anaemia. Therefore, in the present study, we attempted to investigate whether nRBC apoptosis is associated with the peripheral RBC count, parasite load or immune response. To this end, BALB/c mice were infected with P. yoelii 17XL and nRBC apoptosis, number of peripheral RBCs, parasitaemia and plasmatic levels of cytokines, nitric oxide and anti-RBC antibodies were evaluated at the early and late stages of anaemia. The apoptosis of nRBCs increased at the late stage and was associated with parasitaemia, but not with the intensity of the immune response. The increased percentage of nRBC apoptosis that was observed when anaemia was accentuated was not related to a reduction in peripheral RBCs. We conclude that nRBC apoptosis in P. yoelii malaria appears to be induced in response to a high parasite load. Further studies on malaria models in which acute anaemia develops during low parasitaemia are needed to identify the potential pathogenic role of nRBC apoptosis.

1222 Assessment of the Contribution of Cytokine Plasmatic Levels to Detect Retinopathy of Prematurity

Objective: To evaluate the association of plasmatic levels of IL-6, IL-8, IL-10, IL-1 β, and TNF- α with the presence of any stage of ROP or with ROP stages 3 or more in very low birth weight preterm infants with clinical early-onset sepsis. Design Methods: From July 2005 to October 2007, inborn preterm infants with birth weight ≤ 1500 grams and gestational age ≤32 weeks with clinical early-onset sepsis were included in a prospective cohort study. We excluded patients that died before 6 weeks of life, had major malformations or congenital infections. Plasma was assayed for IL-6, IL-8, IL-10, IL-1 β, and TNF- α in the same sample collected for sepsis work up. ROP was diagnosed in screening assessments in NICU. The highest stage of ROP was considered. Results: We enrolled 74 patients (mean gestational age: 29.5 ±0.2 weeks; mean birth weight:1110 ±230 grams) that were followed from birth to hospital discharge; 49 (66.2%) had no ROP and 25 (33.8%) had any stage ROP(17 had stages 1 or 2, and 8 had stage 3 or more). All median cytokine plasmatic levels were similar between no ROP and ROP patients. Only low birth weight and low gestational age were significantly associated with any stage and severe ROP. Conclusions: There was no association between altered plasmatic levels of cytokines with any stage of ROP or with ROP stages 3 or more in very low birth weight infants with early-onset sepsis. Low birth weight and gestational age were important factors for ROP occurrence.

An early inflammatory response to oesophagectomy predicts the occurrence of pulmonary complications☆

Respiratory complications are the most frequent concern following oesophagectomy. We aimed to assess the postoperative inflammatory response after oesophagectomy and to determine its reliability to predict the occurrence of pulmonary complications. A total of 97 patients were enrolled in this prospective observational study. All patients underwent a transthoracic oesophagectomy for cancer. From D0 to D3, plasmatic cytokine levels (interleukin (IL)-1, IL-6, IL-8, IL-10, tumour necrosis factor (TNF)-alpha), short synacthen test (SST), PaO(2)/FiO(2) ratio and clinical factors determining the systemic inflammatory response syndrome (SIRS) were monitored and compared between patients who experienced pulmonary complications (group I) and those who did not (group II). The overall in-hospital mortality was 5%. Postoperative pulmonary complications occurred in 33 patients (34%). Sputum retention was the first step of pulmonary complications in 26 patients (occurring at a mean of 2.8+/-1 days after the operation), leading to pneumonia in 22 patients (4.7+/-1 days) and acute respiratory distress syndrome (ARDS) in 10 (6.9+/-3 days). At day 2, group I patients had significantly higher plasmatic levels of IL-6, IL-10 and TNF-alpha than group II patients. PaO(2)/FiO(2) was impaired accordingly (215 vs 348; p=0.006). SST was negative in 38% of group I patients and in 30% of group II patients (p=0.51). SIRS was present in 33% and 6% of group I and group II patients, respectively (p< or =0.01). At multivariate analysis, early occurrence of SIRS was the sole significant predictor of pulmonary complications (p=0.005; odds ratio (OR):11.4, confidence interval (CI): 2-63). The vast majority of postoperative pulmonary complications after oesophagectomy occur after the 4th postoperative day. The earlier detection (first 48 h) of SIRS, high plasmatic cytokine levels and impairment of PaO(2)/FiO(2) predicts the onset of these complications. This finding suggests that early pharmacological intervention may have a beneficial impact.

Mixed inflammatory/regulatory cytokine profile marked by simultaneous raise of interferon-γ and interleukin-10 and low frequency of tumour necrosis factor-α+ monocytes are hallmarks of active human visceral Leishmaniasis due toLeishmania chagasiinfection

Considering the complexity of the immunological events triggered during active visceral Leishmaniasis (VL), the relevance of the segregation of the immune response during human VL into type 1 and type 2 still remains unclear. For this purpose, in individuals living in risk areas for VL, we have evaluated especially asymptomatic individuals and patients with active VL, the plasmatic levels of cytokines and reactive nitrogen species under ex vivo conditions. In addition, we have also performed an analysis of intracellular cytokine patterns of circulating leucocytes after short-term culture, particularly in the absence of antigenic-specific stimulation, in order to reflect dynamic events of immune response in vivo during Leishmania chagasi infection. Although asymptomatic individuals and non-infected subjects presented a similar immunological profile, an outstanding inflammatory/regulatory profile, based on higher plasmatic levels of cytokines such as interleukin (IL)-8, interferon (IFN)-gamma, tumour necrosis factor (TNF)-alpha, IL-6 and IL-10, was associated with clinical status observed in active VL. In this context, we hypothesize that IL-10, through its ability to inhibit anti-leishmanial macrophage activation, associated with the lower frequency of TNF-alpha(+) monocytes and ordinary levels of nitrite and nitrate are the major mechanisms associated with disease onset.

BCAA SUPPLEMENTATION AND THE IMMUNE RESPONSE IN TRIATHLETES

703 Intense long-duration exercise could lead to immune suppression through a decrease in plasma glutamine level. In this study we evaluated lymphocyte proliferation, plasmatic levels of cytokines and glutamine and in vitro production of cytokines by peripheral blood lymphocytes before and after an Olympic Triathlon and the incidence of infection, by the use of a questionnaire. Twelve elite male triathletes (25.5±3.2 y.old) received 6.0g BCAA daily, for one month prior to competition. BCAA supplementation avoided a decrease in plasma glutamine after the trial observed in the placebo group 22.8%. Changes in the proliferative response of peripheral blood lymphocytes were accompanied by a reduction in IL-1 production after exercise (22.2%), that was reversed by BCAA supplementation (20.3%), and no changes in IL-2 production. Athletes from the BCAA group also showed a decrease in the incidence of infections, paralleled by an increased response of lymphocytes to ConA and LPS, as well as an increased production of IL-1 and 2, TNF and IFN. These data showed that, by avoiding plasma glutamine reduction during exercise, BCAA supplementation enhances immune response in triathletes. Acknowledgements - FAPESP 98/07141-7 and TWINLAB