Hydroxychloroquine is associated with lower seroconversion upon 17DD-Yellow fever primovaccination in patients with primary Sjögren's syndrome.

The present study aimed at investigating whether the hydroxychloroquine (HCQ) treatment would impact the neutralizing antibody production, viremia levels and the kinetics of serum soluble mediators upon planned 17DD-Yellow Fever (YF) primovaccination (Bio-Manguinhos-FIOCRUZ) of primary Sjögren's syndrome (pSS). A total of 34 pSS patients and 23 healthy controls (HC) were enrolled. The pSS group was further categorized according to the use of HCQ (HCQ and Non-HCQ). The YF-plaque reduction neutralization test (PRNT ≥1:50), YF viremia (RNAnemia) and serum biomarkers analyses were performed at baseline and subsequent time-points (Day0/Day3-4/Day5-6/Day7/Day14-D28). The pSS group showed PRNT titers and seropositivity rates similar to those observed for HC (GeoMean = 238 vs 440, p = .11; 82% vs 96%, p = .13). However, the HCQ subgroup exhibited lower seroconversion rates as compared to HC (GeoMean = 161 vs 440, p = .04; 69% vs 96%, p = .02) and Non-HQC (GeoMean = 161 vs 337, p = .582; 69% vs 94%, p = .049). No differences in YF viremia were observed amongst subgroups. Serum biomarkers analyses demonstrated that HCQ subgroup exhibited increased levels of CCL2, CXL10, IL-6, IFN-γ, IL1-Ra, IL-9, IL-10, and IL-2 at baseline and displayed a consistent increase of several biomarkers along the kinetics timeline up to D14-28. These results indicated that HCQ subgroup exhibited a deficiency in assembling YF-specific immune response elicited by 17DD-YF primovaccination as compared to Non-HCQ subgroup. Our findings suggested that hydroxychloroquine is associated with a decrease in the humoral immune response after 17DD-YF primovaccination.

Performance of immunological assays for universal and differential diagnosis of HTLV-1/2 infection in candidates for blood donations from the Brazilian Amazon.

The present study compares the ability of distinct immunological assays (chemiluminescence immunoassay-CLIA, western blot-WB and flow cytometry-FC-Simplex and Duplex) to detect anti-HTLV (human T-lymphotropic virus) antibodies in candidates for blood donations at the Amazonas State Blood Center (Brazil) between January 2018 and December 2022. Overall, 257,942 samples from candidates for blood donations were screened using CLIA, which led to 0.15% seropositivity for HTLV (409 samples). A total of 151 candidates for blood donations were enrolled for retesting with CLIA followed by additional testing using WB and FC-Simplex and Duplex analysis. Our results demonstrated that 62% (93/151), 20% (30/151) and 17% (26/151) of the samples presented positive results with retesting using CLIA, WB and FC-Simplex analysis, respectively. Additional analysis of the CLIA, WB and FC-Simplex results revealed an overall agreement of 56% for CLIA and WB (22 co-negative; 30 co-positive samples), 48% for CLIA and FC-Simplex (21 co-negative; 24 co-positive samples) and 80% for WB and FC-Simplex (51 co-negative; 23 co-positive samples). Considering the WB as the reference standard for the diagnosis of infection with HTLV-1/2, we observed that the CLIA results of ≤3.0 RLU and >10.0 RLU in the retest can be used define a negative or positive result, respectively, and could be used as new specific cut-off values. The overall agreement between WB and FC-Duplex for accomplishing the differential diagnosis was evaluated and demonstrated 100% correspondence for the diagnosis of HTLV-1 (15/15) and HTLV-2 (7/7). Our findings demonstrate that gaps in the diagnosis of infection with HTLV-1/2 could be overcome by the simultaneous use of distinct immunological assays during retesting of candidates for blood donations.

Sofosbuvir Off-label Treatment of Yellow Fever Patients During an Outbreak in Brazil, 2018: A Cohort Study.

We enrolled 21 patients with laboratory-confirmed yellow fever (YF), hospitalized at Eduardo de Menezes Hospital, Brazil, to be treated with sofosbuvir, a drug approved for hepatitis C. Given the absence of specific YF antiviral treatments, the off-label nonrandomized sofosbuvir treatment aimed to address high disease severity and the risk of fatal outcomes. Patients received a daily dose of 400 mg sofosbuvir from 4 to 10 days post-symptom onset. YF viral load (VL) comparisons were made between treated and nontreated patients who either survived or died. The genomic VL for the treated group steadily decreased after day 7 post-symptom onset, suggesting that sofosbuvir might reduce YF VL. This study underscores the urgent need for YF antiviral therapies, advocating for randomized clinical trials to further explore sofosbuvir's role in YF treatment.

Impact of Neurological Complications on Long-Term Outcomes in Patients with Infective Endocarditis.

Neurological complications are frequent during the active course of infective endocarditis (IE), and they are associated with high in-hospital mortality rates. However, limited data exist on the prognostic value of these complications for late outcomes. This study aimed to assess the long-term impact of neurological complications in patients surviving an IE episode. A total of 263 consecutive IE patients admitted to a tertiary care center between 2007 and 2022 were prospectively included. Neurological complications at admission included transient ischemic attack (TIA), ischemic stroke, hemorrhagic stroke, intracerebral abscess, and meningitis. The primary outcome was a composite of overall mortality or heart valve surgery. Of the patients, 34.2% died in the hospital, leaving 173 survivors for long-term follow-up. Over a median of 3.5 years, 29 patients died, and 13 (9%) underwent cardiac surgery, resulting in an overall adverse event rate of 30%. Neurological complications independently predicted long-term adverse outcomes (hazard ratio (HR) 2.237; 95% CI 1.006-4.976), after adjusting for age, chronic kidney disease (CKD), and heart failure (HF) development. In an IE patient cohort, neurological complications at admission, which is a complication directly related to the IE process, were independent predictors of long-term outcomes.

Signatures of CD4+ T and B cells are associated with distinct stages of chronic chagasic cardiomyopathy.

Introduction: Chagas disease is a neglected parasitic disease caused by Trypanosoma cruzi. While most patients are asymptomatic, around 30% develop Chronic Chagasic Cardiomyopathy (CCC). Methods: Here, we employed high-dimensional flow cytometry to analyze CD4+ T and B cell compartments in patients during the chronic phase of Chagas disease, presenting the asymptomatic and mild or moderate/severe cardiac clinical forms. Results: Effector CD27-CD4+ T cells were expanded in both CCC groups, and only mild CCC patients showed higher frequencies of effector memory and T follicular helper (Tfh) cells than healthy donors (CTL) and asymptomatic patients. Unsupervised analysis confirmed these findings and further revealed the expansion of a specific subpopulation composed of Tfh, transitional, and central memory CD4+ T cells bearing a phenotype associated with strong activation, differentiation, and exhaustion in patients with mild but not moderate/severe CCC. In contrast, patients with mild and moderate/severe CCC had lower frequencies of CD4+ T cells expressing lower levels of activation markers, suggesting resting status, than CTL. Regarding the B cell compartment, no alterations were found in naïve CD21-, memory cells expressing IgM or IgD, marginal zone, and plasma cells in patients with Chagas disease. However, expansion of class-switched activated and atypical memory B cells was observed in all clinical forms, and more substantially in mild CCC patients. Discussion: Taken together, our results showed that T. cruzi infection triggers changes in CD4+ T and B cell compartments that are more pronounced in the mild CCC clinical form, suggesting an orchestrated cellular communication during Chagas disease. Conclusion: Overall, these findings reinforce the heterogeneity and complexity of the immune response in patients with chronic Chagas disease and may provide new insights into disease pathology and potential markers to guide clinical decisions.

A single dose of angiotensin-(1-7) resolves eosinophilic inflammation and protects the lungs from a secondary inflammatory challenge.

OBJECTIVE: Angiotensin-(1-7) [Ang-(1-7)] is a pro-resolving mediator. It is not known whether the pro-resolving effects of Ang-(1-7) are sustained and protect the lung from a subsequent inflammatory challenge. This study sought to investigate the impact of treatment in face of a second allergic or lipopolysaccharide (LPS) challenge. METHODS: Mice, sensitized and challenged with ovalbumin (OVA), received a single Ang-(1-7) dose at the peak of eosinophilic inflammation, 24 h after the final OVA challenge. Subsequently, mice were euthanized at 48, 72, 96, and 120 h following the OVA challenge, and cellular infiltrate, inflammatory mediators, lung histopathology, and macrophage-mediated efferocytic activity were evaluated. The secondary inflammatory stimulus (OVA or LPS) was administered 120 h after the last OVA challenge, and subsequent inflammatory analyses were performed. RESULTS: Treatment with Ang-(1-7) resulted in elevated levels of IL-10, CD4+Foxp3+, Mres in the lungs and enhanced macrophage-mediated efferocytic capacity. Moreover, in allergic mice treated with Ang-(1-7) and then subjected to a secondary OVA challenge, inflammation was also reduced. Similarly, in mice exposed to LPS, Ang-(1-7) effectively prevented the lung inflammation. CONCLUSION: A single dose of Ang-(1-7) resolves lung inflammation and protect the lung from a subsequent inflammatory challenge highlighting its potential therapeutic for individuals with asthma.

New insights into Trypanosoma cruzi genetic diversity, and its influence on parasite biology and clinical outcomes.

Chagas disease, caused by Trypanosoma cruzi, remains a serious public health problem worldwide. The parasite was subdivided into six distinct genetic groups, called "discrete typing units" (DTUs), from TcI to TcVI. Several studies have indicated that the heterogeneity of T. cruzi species directly affects the diversity of clinical manifestations of Chagas disease, control, diagnosis performance, and susceptibility to treatment. Thus, this review aims to describe how T. cruzi genetic diversity influences the biology of the parasite and/or clinical parameters in humans. Regarding the geographic dispersion of T. cruzi, evident differences were observed in the distribution of DTUs in distinct areas. For example, TcII is the main DTU detected in Brazilian patients from the central and southeastern regions, where there are also registers of TcVI as a secondary T. cruzi DTU. An important aspect observed in previous studies is that the genetic variability of T. cruzi can impact parasite infectivity, reproduction, and differentiation in the vectors. It has been proposed that T. cruzi DTU influences the host immune response and affects disease progression. Genetic aspects of the parasite play an important role in determining which host tissues will be infected, thus heavily influencing Chagas disease's pathogenesis. Several teams have investigated the correlation between T. cruzi DTU and the reactivation of Chagas disease. In agreement with these data, it is reasonable to suppose that the immunological condition of the patient, whether or not associated with the reactivation of the T. cruzi infection and the parasite strain, may have an important role in the pathogenesis of Chagas disease. In this context, understanding the genetics of T. cruzi and its biological and clinical implications will provide new knowledge that may contribute to additional strategies in the diagnosis and clinical outcome follow-up of patients with Chagas disease, in addition to the reactivation of immunocompromised patients infected with T. cruzi.

A nationwide study on immunosenescence biomarkers profile in older adults: ELSI-Brazil.

Immunosenescence is a phenomenon caused by changes in the immune system, and part of these changes involves an increase in circulating immunological biomarkers, a process known as "Inflammaging." Inflammaging can be associated with many diseases related to older people. As the older population continues to grow, understanding changes in the immune system becomes essential. While prior studies assessing these alterations have been conducted in countries with Caucasian populations, this investigation marks a pioneering effort. The object of the study is to describe for the first time that the distribution of cytokines, chemokines, and growth factors serum levels, assessed by Luminex platform, has been examined in a Brazilian population-based study of older adult females and males by age. Blood samples from 2111 participants (≥50 years old) were analyzed at the baseline (2015/2016) of the ELSI-Brazil study. The exploratory variables considered in the study were age, sex, educational level, residence area, geographic region, alcohol and smoking consumption, physical activity, and self-reported medical diagnoses of hypertension, diabetes, asthma, arthritis, and cancer. The association between serum biomarker levels and age was assessed by a quantile regression model adjusted in the total population and stratified by sex. The significance level considered in the analysis was 0.05. The mean age of the participants was 62.9 years, with a slight majority of female (52.7 %). Differences were found between the sexes in the median circulating levels of the CCL11, CXCL10, and FGF biomarkers. Eight biomarkers showed significant associations with age, including the pro-inflammatory CXCL10, TNF-α, IL-6, IL-17, and IL-2; and type 2/regulatory CCL11 and IL-4, showing positive associations, and anti-inflammatory IL-1Ra showing a negative association. The results suggest similar associations between the sexes, revealing an inflammatory profile characterized by types 1 and 2. Remarkably, these findings reinforce the concept of the Inflammaging process in Brazilian population. These findings add novel insights to about the immunosenescence aspects in middle-income countries and help define biomarkers capable of monitoring inflammation in older adults.

Comprehensive landscape of neutralizing antibody and cell-mediated response elicited by the 1/5 fractional dose of 17DD-YF primary vaccination in adults.

The present study aimed at evaluating the YF-specific neutralizing antibody profile besides a multiparametric analysis of phenotypic/functional features of cell-mediated response elicited by the 1/5 fractional dose of 17DD-YF vaccine, administered as a single subcutaneous injection. The immunological parameters of each volunteer was monitored at two time points, referred as: before (Day 0) [Non-Vaccinated, NV(D0)] and after vaccination (Day 30-45) [Primary Vaccinees, PV(D30-45)]. Data demonstrated high levels of neutralizing antibodies for PV(D30-45) leading to a seropositivity rate of 93%. A broad increase of systemic soluble mediators with a mixed profile was also observed for PV(D30-45), with IFN-γ and TNF-α presenting the highest baseline fold changes. Integrative network mapping of soluble mediators showed increased correlation numbers in PV(D30-45) as compared to NV(D0) (532vs398). Moreover, PV(D30-45) exhibited increased levels of Terminal Effector (CD45RA+CCR7-) CD4+ and CD8+ T-cells and Non-Classical memory B-cells (IgD+CD27+). Dimensionality reduction of Mass Cytometry data further support these findings. A polyfunctional cytokine profile (TNF-α/IFN-γ/IL-10/IL-17/IL-2) of T and B-cells was observed upon in vitro antigen recall. Mapping and kinetics timeline of soluble mediator signatures for PV(D30-45) further confirmed the polyfunctional profile upon long-term in vitro culture, mediated by increased levels of IFN-γ and TNF-α along with decreased production of IL-10. These findings suggest novel insights of correlates of protection elicited by the 1/5 fractional dose of 17DD-YF vaccine.

Immune response induced by standard and fractional doses of 17DD yellow fever vaccine.

The re-emergence of yellow fever (YF) urged new mass vaccination campaigns and, in 2017, the World Health Organization approved the use of the fractional dose (FD) of the YF vaccine due to stock shortage. In an observational cross-sectional investigation, we have assessed viremia, antibodies, soluble mediators and effector and memory T and B-cells induced by primary vaccination of volunteers with FD and standard dose (SD). Similar viremia and levels of antibodies and soluble markers were induced early after immunization. However, a faster decrease in the latter was observed after SD. The FD led to a sustained expansion of helper T-cells and an increased expression of activation markers on T-cells early after vaccination. Although with different kinetics, expansion of plasma cells was induced upon SD and FD immunization. Integrative analysis reveals that FD induces a more complex network involving follicular helper T cells and B-cells than SD. Our findings substantiate that FD can replace SD inducing robust correlates of protective immune response against YF.

Evaluation of humoral immune response after yellow fever infection: an observational study on patients from the 2017-2018 sylvatic outbreak in Brazil.

Between 2016 and 2018, Brazil experienced major sylvatic yellow fever (YF) outbreaks that caused hundreds of casualties, with Minas Gerais (MG) being the most affected state. These outbreaks provided a unique opportunity to assess the immune response triggered by the wild-type (WT) yellow fever virus (YFV) in humans. The plaque reduction neutralization test (PRNT) is currently the standard method to assess the humoral immune response to YFV by measuring neutralizing antibodies (nAbs). The present study aimed to evaluate the humoral immune response of patients from the 2017-2018 sylvatic YF outbreak in MG with different disease outcomes by using PRNTs with a WT YFV strain, isolated from the 2017-2018 outbreak, and a vaccine YFV strain. Samples from naturally infected YF patients were tested, in comparison with healthy vaccinees. Results showed that both groups presented different levels of nAb against the WT and vaccine strains, and the levels of neutralization against the strains varied homotypically and heterotypically. Results based on the geometric mean titers (GMTs) suggest that the humoral immune response after a natural infection of YFV can reach higher levels than that induced by vaccination (GMT of patients against WT YFV compared to GMT of vaccinees, P < 0.0001). These findings suggest that the humoral immune responses triggered by the vaccine and WT strains of YFV are different, possibly due to genetic and antigenic differences between these viruses. Therefore, current means of assessing the immune response in naturally infected YF individuals and immunological surveillance methods in areas with intense viral circulation may need to be updated.IMPORTANCEYellow fever is a deadly febrile disease caused by the YFV. Despite the existence of effective vaccines, this disease still represents a public health concern worldwide. Much is known about the immune response against the vaccine strains of the YFV, but recent studies have shown that it differs from that induced by WT strains. The extent of this difference and the mechanisms behind it are still unclear. Thus, studies aimed to better understand the immune response against this virus are relevant and necessary. The present study evaluated levels of neutralizing antibodies of yellow fever patients from recent outbreaks in Brazil, in comparison with healthy vaccinees, using plaque reduction neutralization tests with WT and vaccine YFV strains. Results showed that the humoral immune response in naturally infected patients was higher than that induced by vaccination, thus providing new insights into the immune response triggered against these viruses.

Correlation of blood-based immune molecules with cardiac gene expression profiles reveals insights into Chagas cardiomyopathy pathogenesis.

Introduction: Understanding compartmentalized immune responses in target organs is crucial for elucidating the pathogenesis of various diseases. However, obtaining samples from affected vital organs often poses safety challenges. In this study, we aimed to investigate potential correlations between the levels of disease-associated immune molecules in the bloodstream with their gene expression profiles in the hearts of patients suffering from Chagas Cardiomyopathy (CCC). This debilitating and often fatal condition is caused by infection with the protozoan Trypanosoma cruzi. Methods: Blood samples were analyzed using the Bio-Plex platform. Gene Expression Omnibus (GEO) database was used to determine gene expression profile in heart tissue from CCC and non-Chagas controls (CTRL). Results: Elevated levels of inflammatory cytokines were detected in the plasma of CCC patients, and these levels correlated with clinical indicators of deteriorating cardiac function. Notably, 75% of the soluble factors assessed in the plasma exhibited a consistent relationship with their gene expression levels in the cardiac tissue of CCC patients. Analysis of interactions and signaling pathways related to these molecules revealed an overrepresentation of inflammatory pathways in both blood and heart compartments. Moreover, we identified that differentially expressed genes in CCC cardiac tissue were primarily associated with T-cell signaling pathways and correlated with the presence of CD8+ T cells in the myocardium. Discussion: Our findings establish a strong correlation between relevant immune molecules and their signaling pathways in both the blood and heart tissue in CCC. This validates the use of blood as a non-invasive medium for understanding immunopathology and identifying markers for cardiac dysfunction in Chagas disease.

Different profiles of chemokines, cytokines and cell growth factors in plasma samples from patients with leprosy, leprosy reactions and households contacts.

BACKGROUND: Leprosy is a highly neglected disease that is considered a serious public health problem in many countries. This illness is characterised by a variety of clinical and histopathological manifestations that are related to the patient immune response. OBJECTIVES: This work aimed evaluate the profile of circulating immune mediators in the plasma from patients classified clinically as paucibacillary (PB), multibacillary (MB), households contacts (HHC), type1 leprosy reaction (T1R), type2 leprosy reaction (T2R) and control individuals without medical history of leprosy (CTL). METHODS: To assessment of the plasma immune mediators was used multiplex microbeads immunoassay "Luminex". FINDINGS: The results showed that patients (PB) had a regulatory-biased profile, while MB revealed a pro-inflammatory trend of highly expressed biomarkers. HHC display conspicuously increased levels in the plasma of the chemokines (CCL2, CCL3, CCL4, CCL5 and CXCL8), pro-inflammatory cytokines (IFN-γ,TNF and IL-1ß), modulating cytokines (IL-9 and IL-1Ra) and growth factors (PDGF, G-CSF and IL-2). Interestingly, HHC displayed superior production of IFN-γ as compared to other leprosy groups, indicating a putative protective role for this cytokine during chronic Mycobacterium leprae exposure. MAIN CONCLUSION: Further investigations are currently underway to elucidate the potential of these mediators as biomarkers applicable to the diagnosis/prognosis of leprosy and also T1R and T2R leprosy reactions.

Plaque Reduction Neutralization Test (PRNT) Accuracy in Evaluating Humoral Immune Response to SARS-CoV-2.

Massive vaccination positively impacted the SARS-CoV-2 pandemic, being a strategy to increase the titers of neutralizing antibodies (NAbs) in the population. Assessing NAb levels and understanding the kinetics of NAb responses is critical for evaluating immune protection. In this study, we optimized and validated a PRNT50 assay to assess 50% virus neutralization and evaluated its accuracy to measure NAbs to the original strain or variant of SARS-CoV-2. The optimal settings were selected, such as the cell (2 × 105 cells/well) and CMC (1.5%) concentrations and the viral input (~60 PFU/well) for PRNT-SARS-CoV-2 with cut-off point = 1.64 log5 based on the ROC curve (AUC = 0.999). The validated PRNT-SARS-CoV-2 assay presented high accuracy with an intraassay precision of 100% for testing samples with different NAb levels (low, medium, and high titers). The method displays high selectivity without cross-reactivity with dengue (DENV), measles (MV), zika (ZIKV), and yellow fever (YFV) viruses. In addition, the standardized PRNT-SARS-CoV-2 assay presented robustness when submitted to controlled variations. The validated PRNT assay was employed to test over 1000 specimens from subjects with positive or negative diagnoses for SARS-CoV-2 infection. Patients with severe COVID-19 exhibited higher levels of NAbs than those presenting mild symptoms for both the Wuhan strain and Omicron. In conclusion, this study provides a detailed description of an optimized and validated PRNT50 assay to monitor immune protection and to subsidize surveillance policies applied to epidemiologic studies of COVID-19.

Nanoparticle-based DNA vaccine protects against SARS-CoV-2 variants in female preclinical models.

A safe and effective vaccine with long-term protection against SARS-CoV-2 variants of concern (VOCs) is a global health priority. Here, we develop lipid nanoparticles (LNPs) to provide safe and effective delivery of plasmid DNA (pDNA) and show protection against VOCs in female small animal models. Using a library of LNPs encapsulating unique barcoded DNA (b-DNA), we screen for b-DNA delivery after intramuscular administration. The top-performing LNPs are further tested for their capacity of pDNA uptake in antigen-presenting cells in vitro. The lead LNP is used to encapsulate pDNA encoding the HexaPro version of SARS-CoV-2 spike (LNP-HPS) and immunogenicity and protection is tested in vivo. LNP-HPS elicit a robust protective effect against SARS-CoV-2 Gamma (P.1), correlating with reduced lethality, decreased viral load in the lungs and reduced lung damage. LNP-HPS induce potent humoral and T cell responses against P.1, and generate high levels of neutralizing antibodies against P.1 and Omicron (B.1.1.529). Our findings indicate that the protective efficacy and immunogenicity elicited by LNP-HPS are comparable to those achieved by the approved COVID-19 vaccine from Biontech/Pfizer in animal models. Together, these findings suggest that LNP-HPS hold great promise as a vaccine candidate against VOCs.

Expression of SmATPDases 1 and 2 in Schistosoma mansoni eggs favours IL-10 production in infected individuals.

A role of IL-10 is down-regulating T-cell responses to schistosome antigens. Since SmATPDases can be correlated to modulation of the immune response, we evaluated the expression of enzymes in S. mansoni eggs. Faecal samples were collected from 40 infected individuals to detect coding regions of the SmATPDases. The cytokines were measured in supernatants of PBMC. The analysis was performed by the global median determination and set up high producers (HP) of cytokines. Six individuals expressed SmATPDase1, six expressed SmATPDase2 and six expressed both enzymes. The group who expressed only SmATPDase1 showed a high frequency of IFN-γ, TNF IL-4 HP; individuals who expressed only SmATPDase2 showed a high frequency of IFN-γ, IL-6 and IL-4 HP; and individuals who expressed both enzymes showed a high frequency of IL-10 HP. The comparison of the IFN-γ/IL-10 ratio presented higher indices in the group who had SmATPDase 2 expression than those who had the expression of both enzymes. The positive correlation between infection intensity and IL-10 levels remained only in the positive SmATPDase group. The IL-10 is the only cytokine induced by the expression of both enzymes. Our data suggest that the expression of both enzymes seems to be a factor that modulates the host immune response by inducing high IL-10 production.

Different profiles of chemokines, cytokines and cell growth factors in plasma samples from patients with leprosy, leprosy reactions and households contacts

BACKGROUND Leprosy is a highly neglected disease that is considered a serious public health problem in many countries. This illness is characterised by a variety of clinical and histopathological manifestations that are related to the patient immune response. OBJECTIVES This work aimed evaluate the profile of circulating immune mediators in the plasma from patients classified clinically as paucibacillary (PB), multibacillary (MB), households contacts (HHC), type1 leprosy reaction (T1R), type2 leprosy reaction (T2R) and control individuals without medical history of leprosy (CTL). METHODS To assessment of the plasma immune mediators was used multiplex microbeads immunoassay "Luminex". FINDINGS The results showed that patients (PB) had a regulatory-biased profile, while MB revealed a pro-inflammatory trend of highly expressed biomarkers. HHC display conspicuously increased levels in the plasma of the chemokines (CCL2, CCL3, CCL4, CCL5 and CXCL8), pro-inflammatory cytokines (IFN-γ,TNF and IL-1β), modulating cytokines (IL-9 and IL-1Ra) and growth factors (PDGF, G-CSF and IL-2). Interestingly, HHC displayed superior production of IFN-γ as compared to other leprosy groups, indicating a putative protective role for this cytokine during chronic Mycobacterium leprae exposure. MAIN CONCLUSION Further investigations are currently underway to elucidate the potential of these mediators as biomarkers applicable to the diagnosis/prognosis of leprosy and also T1R and T2R leprosy reactions.

Microparticles and cardiotoxicity secondary to doxorubicin-based chemotherapy in breast cancer patients.

Doxorubicin (DOXO)-cardiotoxicity is a limiting factor for breast cancer chemotherapy. The relationship between microparticles (MPs) and cardiotoxicity remains unclear. MPs can be released under varying pathophysiological conditions. Thereby, this study aimed to assess MPs derived from cardiomyocytes (CardioMPs), platelets (PMPs) and those that expresses tissue factor (TFMPs) in 80 women with breast cancer undergoing DOXO-based chemotherapy, with or without cardiotoxicity in a one-year follow-up. We observed in the cardiotoxicity group higher count of total-MPs at T0 (prior chemotherapy) (p = 0.034), CardioMPs at T0 and T1 (just after chemotherapy) (p = 0.009 and p = 0.0034) and TFMPs at T0 (p = 0.011) compared to non-cardiotoxicity group. The results suggest that MPs could be associated to cardiotoxicity due to DOXO treatment in breast cancer patients.

Airway epithelial cells and macrophages trigger IL-6-CD95/CD95L axis and mediate initial immunopathology of COVID-19.

Airway epithelial cells (AEC) infected with SARS-CoV-2 may drive the dysfunction of macrophages during COVID-19. We hypothesized that the direct interaction of AEC with macrophages mediated by CD95/CD95L or indirect interaction mediated by IL-6 signaling are key steps for the COVID-19 severe acute inflammation. The interaction of macrophages with apoptotic and infected AEC increased CD95 and CD163 expression, and induced macrophage death. Macrophages exposed to tracheal aspirate with high IL-6 levels from intubated patients with COVID-19 or to recombinant human IL-6 exhibited decreased HLA-DR expression, increased CD95 and CD163 expression and IL-1ß production. IL-6 effects on macrophages were prevented by both CD95/CD95L antagonist and by IL-6 receptor antagonist and IL-6 or CD95 deficient mice showed significant reduction of acute pulmonary inflammation post-infection. Our findings show a non-canonical CD95L-CD95 pathway that simultaneously drives both macrophage activation and dysfunction and point to CD95/CD95L axis as therapeutic target.

Systemic immunological profile of children with B-cell acute lymphoblastic leukemia: performance of cell populations and soluble mediators as serum biomarkers.

Background: Children with B-cell acute lymphoblastic leukemia (B-ALL) have an immune imbalance that is marked by remodeling of the hematopoietic compartment, with effects on peripheral blood (PB). Although the bone marrow (BM) is the main maintenance site of malignancy, the frequency with which immune cells and molecules can be monitored is limited, thus the identification of biomarkers in PB becomes an alternative for monitoring the evolution of the disease. Methods: Here, we characterize the systemic immunological profile in children undergoing treatment for B-ALL, and evaluate the performance of cell populations, chemokines and cytokines as potential biomarkers during clinical follow-up. For this purpose, PB samples from 20 patients with B-ALL were collected on diagnosis (D0) and during induction therapy (days 8, 15 and 35). In addition, samples from 28 children were used as a control group (CG). The cellular profile (NK and NKT-cells, Treg, CD3+ T, CD4+ T and CD8+ T cells) and soluble immunological mediators (CXCL8, CCL2, CXCL9, CCL5, CXCL10, IL-6, TNF, IFN-γ, IL-17A, IL- 4, IL-10 and IL-2) were evaluated via flow cytometry immunophenotyping and cytometric bead array assay. Results: On D0, B-ALL patients showed reduction in the frequency of cell populations, except for CD4+ T and CD8+ T cells, which together with CCL2, CXCL9, CXCL10, IL-6 and IL-10 were elevated in relation to the patients of the CG. On D8 and D15, the patients presented a transition in the immunological profile. While, on D35, they already presented an opposite profile to D0, with an increase in NKT, CD3+ T, CD4+ T and Treg cells, along with CCL5, and a decrease in the levels of CXCL9, CXCL10 and IL-10, thus demonstrating that B-ALL patients present a complex and dynamic immune network during induction therapy. Furthermore, we identified that many immunological mediators could be used to classify the therapeutic response based on currently used parameters. Conclusion: Finally, it is noted that the systemic immunological profile after remission induction still differs significantly when compared to the GC and that multiple immunological mediators performed well as serum biomarkers.