Lack of differences in outcomes between three immunosuppression protocols in the first year post pediatric liver transplantation. A multicenter study.

INTRODUCTION: Advances in immunosuppression have extended patient and graft survival rates after solid organ transplantation; however, this is not free of side effects. Balancing safety and efficacy is of paramount importance, particularly in the pediatric setting. Current literature comparing different protocols is scarce, and decisions are mostly guided by physician preference. We aimed to compare three different protocols from four different centers to identify differences in outcomes after one year of follow-up. MATERIALS AND METHODS: A retrospective analysis of the databases of the participating centers was performed. Consecutive patients aged <18 years with a first liver-only transplant and no other underlying congenital or acquired immunodeficiency were included. Patients were classified according to the immunosuppression protocol as follows: Group A (Prednisone + Tacrolimus + Basiliximab), Group B (Prednisone + Tacrolimus + Basiliximab + anti-thymocyte globulin), and Group C (Prednisone + Tacrolimus). Differences in survival, frequency of rejection, infections, and other complications were analyzed in the entire group (n=97) and in the group with biliary atresia (n=48). RESULTS: After one year of follow-up, no differences in patient or graft survival were observed when comparing either the entire group (n=97) or patients with biliary atresia only (n=48). The frequencies of rejection and episodes of infection were similar. Renal function showed no differences either before or after transplantation or between the groups. CONCLUSION: Immunosuppression protocols used in this study appeared to be equally safe and effective. This could offer the opportunity to tailor them to the patient's individual characteristics without compromising the outcome.

The relationship between host defense peptides and adrenal steroids. An account of reciprocal influences.

AIM: ß-defensins 2 and -3 (HBD-2 and HBD-3) and cathelicidin LL-37 are host defense peptides (HDPs) that play a crucial role in the immune response against mycobacteria. Given our former studies in tuberculosis patients wherein their plasma levels of such peptides correlated with steroid hormone concentrations, we now studied the reciprocal influence of cortisol and/or dehydroepiandrosterone (DHEA) on HDPs biosynthesis and LL-37 on adrenal steroidogenesis. MAIN METHODS: Cultures of macrophages derived from the THP-1 line were treated with cortisol (10-6M) and/or DHEA (10-6M and 10-7M) and stimulated with irradiated M. tuberculosis (Mi) or infected M. tuberculosis strain H37Rv to assess cytokine production, HDPs, reactive oxygen species (ROS) and colony forming units. Cultures of NCI-H295-R adrenal line were treated with LL37 (5, 10, and 15 µg/ml) for 24 h to further measure cortisol and DHEA levels together with steroidogenic enzyme transcripts. KEY FINDINGS: In macrophages, M. tuberculosis produced an increase of IL-1ß, TNFα, IL-6, IL-10, LL-37, HBD-2, and HBD-3 levels, irrespective of DHEA treatment. Adding cortisol to M. tuberculosis-stimulated cultures (with or without DHEA) decreased the amounts of these mediators, compared to only stimulated cultures. Although M. tuberculosis reduced ROS levels, DHEA increased these values in addition to diminishing intracellular mycobacterial growth (no matter cortisol treatment). In turn, studies on adrenal cells showed that LL-37 reduced the production of cortisol and DHEA besides modifying transcripts for some steroidogenic enzymes. SIGNIFICANCE: while adrenal steroids seem to influence the production of HDPs, the former compounds are also likely to modulate adrenal biogenesis.

Evidence that changes in antimicrobial peptides during tuberculosis are related to disease severity, clinical presentation, specific therapy and levels of immune-endocrine mediators.

Given the role of host defense peptides (HDPs) in the defensive response against mycobacteria, we analyzed the circulating levels of LL-37, ß-defensin-2 and -3 in newly diagnosed patients with pulmonary (PTB) or pleural tuberculosis (PLTB) in whom measurements of pleural fluids were also performed. Severe PTB patients displayed higher circulating amounts of ß-defensin-3, statistically different from controls, further decreasing upon antimycobacterial treatment. LL-37 concentrations appeared within the normal range at diagnosis, but tended to increase during treatment, becoming statistically upon its completion in moderate cases. PLTB patients revealed decreased levels of ß-defensin-2 in presence of increased amounts of ß-defensin-3 and LL-37; in their plasma or pleural fluids. Considering the immune-endocrine dysregulation of tuberculosis, we also performed correlation analysis detecting positive associations between levels of cortisol, IL-6 and ß-defensin-3 in plasma from untreated severe patients as did their dehydroepiandrosterone and LL-37 values. Increased presence of ß-defensins, may represent an attempt to improve defensive mechanisms; which also take part in the inflammatory reaction accompanying TB, reinforced by the association with immune-endocrine mediators. The divergent profile of PLTB patients, decreased ß-defensin-2 but increased ß-defensin-3 and LL-37 levels, suggests a differential role of these HDPs in a situation characterized for its better protective response.

Local Regulation of Adrenal Steroidogenesis: Subtle in vitro Effects of IL-1ß on the Human Cell Line NCI-H295R Steroid Production along with Changes in MicroRNA Profile and Orphan Nuclear Receptors NR4As.

INTRODUCTION: IL-1ß, a cytokine from the innate immune response, is well known for its proinflammatory effects and stimulating activity on the hypothalamus-pituitary-adrenal axis, leading to the pituitary synthesis of adrenocorticotropic hormone followed by cortisol (and dehydroepiandrosterone - DHEA) release by the adrenal gland. While IL-1ß modulates the adrenal steroidogenesis at the central level, it is unclear whether it also exerts an effect on the adrenal gland. METHOD: We studied the effect of IL-1ß on adrenal steroid production and steroidogenic enzyme RNA expression in the human cell line NCI-H295R. We also explored eventual changes in the microRNA (miRNA) profile from IL-1ß-treated NCI-H295R cells. RESULTS: Transcripts encoding IL-1ß receptors 1 and 2 were noticeable in the cell line, with cortisol and DHEA production showing a subtle increase after cytokine treatment. Transcripts from key enzymes in the steroidogenic pathway were analyzed, with no noticeable changes on them. The miRNA profile was modified by IL-1ß treatment to an extent which bears some relationship with the regulatory mechanisms underlying adrenal steroid production. Since orphan nuclear receptors NR4As have emerged as potential key factors for coordinating inflammatory and metabolic responses, cell expression studies were also carried out to show an NR4As transcript augmentation following IL-1ß treatment. DISCUSSION/CONCLUSIONS: The subtle increase in adrenal steroid production in response to IL-1ß stimulation without any modification in the transcription of the steroidogenic enzymes analyzed suggests an additional inflammatory/anti-inflammatory loop, wherein NR4As receptors may participate. Besides its physiological role, this process might be implied in pathological states accompanied by an unbalanced immune-endocrine relationship.

Immune response triggered by Trypanosoma cruzi infection strikes adipose tissue homeostasis altering lipid storage, enzyme profile and adipokine expression.

Adipose tissue is a target of Trypanosoma cruzi infection being a parasite reservoir during the chronic phase in mice and humans. Previously, we reported that acute Trypanosoma cruzi infection in mice is linked to a severe adipose tissue loss, probably triggered by inflammation, as well as by the parasite itself. Here, we evaluated how infection affects adipose tissue homeostasis, considering adipocyte anabolic and catabolic pathways, the immune-endocrine pattern and the possible repercussion upon adipogenesis. During in vivo infection, both lipolytic and lipogenic pathways are profoundly affected, since the expression of lipolytic enzymes and lipogenic enzymes was intensely downregulated. A similar pattern was observed in isolated adipocytes from infected animals and in 3T3-L1 adipocytes infected in vitro with Trypanosoma cruzi. Moreover, 3T3-L1 adipocytes exposed to plasmas derived from infected animals also tend to downregulate lipolytic enzyme expression which was less evident regarding lipogenic enzymes. Moreover, in vivo-infected adipose tissue reveals a pro-inflammatory profile, with increased leucocyte infiltration accompanied by TNF and IL-6 overexpression, and adiponectin downregulation. Strikingly, the nuclear factor PPAR-γ is strongly decreased in adipocytes during in vivo infection. Attempts to favor PPAR-γ-mediated actions in the adipose tissue of infected animals using agonists failed, indicating that inflammation or parasite-derived factors are strongly involved in PPAR-γ inhibition. Here, we report that experimental acute Trypanosoma cruzi infection disrupts both adipocyte catabolic and anabolic metabolism secondary to PPAR-γ robust downregulation, tipping the balance towards to an adverse status compatible with the adipose tissue atrophy and the acquisition of an inflammatory phenotype.

Diminished Prolinemia in Chronic Chagasic Patients: A New Clue for Disease Pathology?

Trypanosoma cruzi, the etiological agent of Chagas disease, is dependent on proline for a variety of processes, such as energy metabolism, host cell invasion, differentiation, and resistance to osmotic, metabolic, and oxidative stress. On this basis, we investigated a possible relationship between prolinemia and severity of T. cruzi infection in chronic patients, as reported here. The study population consisted of 112 subjects, separated into 83 chronically T. cruzi-infected patients and 29 age-matched healthy volunteers (control) of both sexes, recruited at the Chagas Disease Service from the Department of Cardiology, Hospital Provincial del Centenario de Rosario (Rosario, Argentina). Chagasic patients were separated into three groups: chronic asymptomatic, mild/moderate, and severe chronic chagasic cardiomyopathy (CCC) subjects. We observed a significant decrease of 11.7% in prolinemia in chagasic patients when compared to controls. Further analysis within the three groups of chagasic patients also revealed a statistically significant decrease of prolinemia in severe CCC patients compared to controls, showing a relative difference of 13.6% in proline concentrations. These data point to the possibility that collagen-which participates in the healing process of cardiac tissue-and proline metabolism in the myocardium could constitute new factors affecting the evolution of Chagas disease.

Dysregulated Network of Immune, Endocrine and Metabolic Markers is Associated to More Severe Human Chronic Chagas Cardiomyopathy.

Individuals who are infected with Trypanosoma cruzi develop chronic Chagas cardiomyopathy (CCC), which is a complication involving a series of immune pathogenetic mechanisms, although an association between immune and metabolic alterations was more recently proposed. Accordingly, we investigated the immuno-metabolic response in chagasic patients and their possible influence on CCC pathogenesis. To this end, T. cruzi-seropositive (asymptomatic or with CCC) and sero-negative individuals were studied. Serum tumour necrosis factor (TNF)-α, interleukin (IL)-6, adipocytokines and the expression of their receptors in peripheral blood mononuclear cell (PBMC) were evaluated, together with other factors influencing the immune response. CCC patients showed major metabolic and hormonal abnormalities, in parallel with increased IL-6 and leptin serum levels. TNF-α receptor s, leptin and adiponectin receptors (ObR and Adipo-Rs respectively), as well as PPAR-γ expression in PBMCs from CCC patients were compatible with a counteracting response leading to an unfavourable immune-metabolic profile. These results suggest that persistently increased levels of immune-metabolic pro-inflammatory mediators along with the adverse endocrine anti-inflammatory response of CCC individuals, may contribute to the underlying mechanisms dealing with myocardial tissue damage.

Death of adrenocortical cells during murine acute T. cruzi infection is not associated with TNF-R1 signaling but mostly with the type II pathway of Fas-mediated apoptosis.

Earlier studies from our laboratory demonstrated that acute experimental Trypanosoma cruzi infection promotes an intense inflammation along with a sepsis-like dysregulated adrenal response characterized by normal levels of ACTH with raised glucocorticoid secretion. Inflammation was also known to result in adrenal cell apoptosis, which in turn may influence HPA axis uncoupling. To explore factors and pathways which may be involved in the apoptosis of adrenal cells, together with its impact on the functionality of the gland, we carried out a series of studies in mice lacking death receptors, such as TNF-R1 (C57BL/6-Tnfrsf1a tm1Imx or TNF-R1-/-) or Fas ligand (C57BL/6 Fas-deficient lpr mice), undergoing acute T. cruzi infection. Here we demonstrate that the late hypercorticosterolism seen in C57BL/6 mice during acute T. cruzi infection coexists with and hyperplasia and hypertrophy of zona fasciculata, paralleled by increased number of apoptotic cells. Apoptosis seems to be mediated mainly by the type II pathway of Fas-mediated apoptosis, which engages the mitochondrial pathway of apoptosis triggering the cytochrome c release to increase caspase-3 activation. Fas-induced apoptosis of adrenocortical cells is also related with an exacerbated production of intra-adrenal cytokines that probably maintain the late supply of adrenal hormones during host response. Present results shed light on the molecular mechanisms dealing with these phenomena which are crucial not only for the development of interventions attempting to avoid adrenal dysfunction, but also for its wide occurrence in other infectious-based critical illnesses.

HIV-TB coinfection impairs CD8(+) T-cell differentiation and function while dehydroepiandrosterone improves cytotoxic antitubercular immune responses.

Tuberculosis (TB) is the leading cause of death among HIV-positive patients. The decreasing frequencies of terminal effector (TTE ) CD8(+) T cells may increase reactivation risk in persons latently infected with Mycobacterium tuberculosis (Mtb). We have previously shown that dehydroepiandrosterone (DHEA) increases the protective antitubercular immune responses in HIV-TB patients. Here, we aimed to study Mtb-specific cytotoxicity, IFN-γ secretion, memory status of CD8(+) T cells, and their modulation by DHEA during HIV-TB coinfection. CD8(+) T cells from HIV-TB patients showed a more differentiated phenotype with diminished naïve and higher effector memory and TTE T-cell frequencies compared to healthy donors both in total and Mtb-specific CD8(+) T cells. Notably, CD8(+) T cells from HIV-TB patients displayed higher Terminal Effector (TTE ) CD45RA(dim) proportions with lower CD45RA expression levels, suggesting a not fully differentiated phenotype. Also, PD-1 expression levels on CD8(+) T cells from HIV-TB patients increased although restricted to the CD27(+) population. Interestingly, DHEA plasma levels positively correlated with TTE in CD8(+) T cells and in vitro DHEA treatment enhanced Mtb-specific cytotoxic responses and terminal differentiation in CD8(+) T cells from HIV-TB patients. Our data suggest that HIV-TB coinfection promotes a deficient CD8(+) T-cell differentiation, whereas DHEA may contribute to improving antitubercular immunity by enhancing CD8(+) T-cell functions during HIV-TB coinfection.

Combined analysis of cross-reacting antibodies anti-ß1AR and anti-B13 in advanced stages of Chagas heart disease.

OBJECTIVE: Autoantibodies cross-reacting with the ß1 adrenergic receptor (anti-ß1AR and anti-p2ß) and cardiac myosin antigens (anti-B13) have been related to the pathogenesis of chronic Chagas heart disease (CCHD). Studies exploring their levels in different stages are scarce. We aimed to evaluate the relationship of these autoantibodies with the clinical profile of chronic patients, especially regarding their classificatory accuracy in severe presentation with heart failure. METHODS AND RESULTS: We conducted a cross-sectional study of 155 T. cruzi-seropositive patients and 26 age- and gender-matched healthy controls. They were categorised in three stages of CCHD. Serum antibodies were measured by specific immunoassays. Symptomatic individuals showed increased levels of anti-ß1AR and anti-B13, while anti-p2ß antibodies were similar between groups. A composite logistic regression model including anti-B13, anti-ß1AR antibody levels and age was able to predict systolic heart failure yielding an area under the curve of 83% (sensitivity of 67% and specificity of 89%). CONCLUSIONS: In our study, anti-ß1AR and anti-B13 antibodies were higher in individuals with chronic Chagas heart disease stage III, mainly in those with dilated cardiomyopathy associated with systolic heart failure. Logistic regression analysis showed that both antibodies were good predictors of severe CCHD. As well as being involved in disease progression, anti-ß1AR and anti-B13 antibodies may be used as a serum marker of poor prognosis in terms of heart compromise.

IgG Autoantibodies Induced by T. cruzi During Pregnancy: Correlation with Gravidity Complications and Early Outcome Assessment of the Newborns.

Objective The aim of the present research was to evaluate the correlation of vertically transmitted IgG antibodies induced by T. cruzi and newborn early outcome assessment, mainly birth weight and gestational age. Methods We performed a cross-sectional study with 183 pregnant women (64 with asymptomatic Chagas disease) and their newborns. Both were subjected to complete clinical examination. Peripheral parasitemia was assessed in mother and neonates by parasite detection through microscopic examination of the buffycoat from mother's peripheral and cord blood. Antibodies induced by T. cruzi, such as anti-FRA, anti-B13, anti-p2ß and anti-T. cruzi were assessed by immunoassay. Birth weight, general condition evaluation by APGAR Score and gestational age by Capurro Score, were determined in newborns. Results The rate of stillbirth background and pregnancy-induced hypertension were higher in patients with Chagas disease (p = 0.01 and p = 0.02, respectively). Parasitemia was detectable in 17 mothers and 4 newborns. The newborns of mothers with detectable parasitemia presented decreased gestational age (p = 0.006) and body weight (p = 0.04). Mostly all the mothers with Chagas disease and all their newborns have positive values of antibodies induced by T. cruzi; however, only anti-p2ß showed to be related to the presence of complication during pregnancy (OR 2.35, p = 0.036), and to low birth weight (OR 1.55, p = 0.02). Conclusions Low birth weight and decreased postnatal estimation of maturity were related to detectable parasitemia in the mother. Also, vertical transmission of T. cruzi-induced autoantibodies might have clinical implication in newborns given the negative association between anti-p2ß values and weight.

Immunoendocrine dysbalance during uncontrolled T. cruzi infection is associated with the acquisition of a Th-1-like phenotype by Foxp3(+) T cells.

We previously showed that Trypanosomacruzi infection in C57BL/6 mice results in a lethal infection linked to unbalanced pro- and anti-inflammatory mediators production. Here, we examined the dynamics of CD4(+)Foxp3(+) regulatory T (Treg) cells within this inflammatory and highly Th1-polarized environment. Treg cells showed a reduced proliferation rate and their frequency is progressively reduced along infection compared to effector T (Teff) cells. Also, a higher fraction of Treg cells showed a naïve phenotype, meanwhile Teff cells were mostly of the effector memory type. T. cruzi infection was associated with the production of pro- and anti-inflammatory cytokines, notably IL-27p28, and with the induction of T-bet and IFN-γ expression in Treg cells. Furthermore, endogenous glucocorticoids released in response to T. cruzi-driven immune activation were crucial to sustain the Treg/Teff cell balance. Notably, IL-2 plus dexamethasone combined treatment before infection was associated with increased Treg cell proliferation and expression of GATA-3, IL-4 and IL-10, and increased mice survival time. Overall, our results indicate that therapies aimed at specifically boosting Treg cells, which during T. cruzi infection are overwhelmed by the effector immune response, represent new opportunities for the treatment of Chagas disease, which is actually only based on parasite-targeted chemotherapy.

Modulation of the phenotype and function of Mycobacterium tuberculosis-stimulated dendritic cells by adrenal steroids.

Cell-mediated immunity, cytokines induced during the specific immune response and T-cell populations are crucial factors for containing Mycobacterium tuberculosis infection. Recent reports suggest a cross-regulation between adrenal steroids (glucocorticoids and dehydroepiandrosterone, DHEA) and the function of antigen-presenting cells (APCs). Therefore, we investigated the role of adrenal hormones on the functional capacity of M. tuberculosis-induced dendritic cells (DCs). Cortisol significantly inhibited the functions of M. tuberculosis-induced DCs. Interestingly, the presence of DHEA enhanced the M. tuberculosis-induced expression of MHC I, MHC II and CD86 and also increased ERK1/2 phosphorylation. Moreover, DHEA improved the production of IL-12 in response to M. tuberculosis stimulation, diminished IL-10 secretion and could not modify TNF-α synthesis. Importantly, we observed that DHEA enhanced the antigen-specific T-cell proliferation and IFN-γ production induced by M. tuberculosis-stimulated DC. These data show for the first time the relevance of the adrenal axis (especially of DHEA) in the modulation of DC function in the context of tuberculosis, a disease where the induction of a Th1 environment by APCs is crucial for the development of an effective immune response to the mycobacteria.

Decreased level of antibodies and cardiac involvement in patients with chronic Chagas heart disease vaccinated with BCG.

Studies indicate that Trypanosoma cruzi is capable of inducing immunological disturbances such as decreased expression of molecules involved in T-cell survival and costimulation for antigen-driven T-cell responses. On the other hand, several reports have described that BCG vaccination induces a T-helper 1-type immune response with protective effects in different pathologies. In this regard, we evaluated whether BCG vaccination coexists with a better clinical and immunological profile of chronic Chagas heart disease (CCHD). We performed a cross-sectional study in T. cruzi seropositive patients categorized according the BCG vaccine background and to the well-established CCHD classification provided by Storino et al. All individuals were subjected to a complete clinical examination. All patients presented detectable levels of autoantibodies anti-p2ß, anti-B13, anti-FRA and antiparasite homogenate immunoglobulins, which were unrelated to age and sex distribution or blood pressure values. Comparisons according to BCG vaccination revealed that individuals who had not been vaccinated presented higher values of antibodies, and patients without BCG vaccine had an OR of 6.1 (95 % CI 1.23-29.25, p = 0.02) for globally dilated cardiomyopathy with reduced ejection fraction (Hosmer and Lemeshow test of 5.2 p = 0.73). Our results suggest that BCG vaccination coexists with a better clinical and immunological profile of CCHD, associated with lower cardiac involvement.

Adverse neuro-immune-endocrine interactions in patients with active tuberculosis.

The nervous, endocrine and immune systems play a crucial role in maintaining homeostasis and interact with each other for a successful defensive strategy against injurious agents. However, the situation is different in long-term diseases with marked inflammation, in which defensive mechanisms become altered. In the case of tuberculosis (TB), this is highlighted by several facts: an imbalance of plasma immune and endocrine mediators, that results in an adverse environment for mounting an adequate response against mycobacteria and controlling inflammation; the demonstration that dehidroepiandrosterone (DHEA) secretion by a human adrenal cell line can be inhibited by culture supernatants from Mycobacterium tuberculosis-stimulated peripheral blood mononuclear cells - PBMC - of TB patients, with this effect being partly reverted when neutralizing transforming growth factor-ß in such supernantants; the in vitro effects of adrenal steroids on the specific immune response of PBMC from TB patients, that is a cortisol inhibition of mycobacterial antigen-driven lymphoproliferation and interferon-γ production as well as a suppression of TGF-ß production in DHEA-treated PBMC; and lastly the demonstration that immune and endocrine compounds participating in the regulation of energy sources and immune activity correlated with the consumption state of TB patients. Collectively, immune-endocrine disturbances of TB patients are involved in critical components of disease pathology with implications in the impaired clinical status and unfavorable disease outcome. This article is part of a Special Issue entitled 'Neuroinflammation in neurodegeneration and neurodysfunction'.

Discovery of circulating miRNAs as biomarkers of chronic Chagas heart disease via a small RNA-Seq approach.

Chagas disease affects approximately 7 million people worldwide in Latin America and is a neglected tropical disease. Twenty to thirty percent of chronically infected patients develop chronic Chagas cardiomyopathy decades after acute infection. Identifying biomarkers of Chagas disease progression is necessary to develop better therapeutic and preventive strategies. Circulating microRNAs are increasingly reliable biomarkers of disease and therapeutic targets. To identify new circulating microRNAs for Chagas disease, we performed exploratory small RNA sequencing from the plasma of patients and performed de novo miRNA prediction, identifying potential new microRNAs. The levels of the new microRNAs temporarily named miR-Contig-1519 and miR-Contig-3244 and microRNAs that are biomarkers for nonchagasic cardiomyopathies, such as miR-148a-3p and miR-224-5p, were validated by quantitative reverse transcription. We found a specific circulating microRNA signature defined by low miR-Contig-3244, miR-Contig-1519, and miR-148a-3 levels but high miR-224-5p levels for patients with chronic Chagas disease. Finally, we predicted in silico that these altered circulating microRNAs could affect the expression of target genes involved in different cellular pathways and biological processes, which we will explore in the future.

Reciprocal influences between leptin and glucocorticoids during acute Trypanosoma cruzi infection.

Leptin and glucocorticoids (GCs) are involved in metabolic functions, thymic homeostasis and immune activity through complex interactions. We recently showed that C57BL/6 mice infected with Trypanosoma cruzi revealed a fatal disease associated with a dysregulated immune-endocrine response characterized by weight loss, deleterious synthesis of pro-inflammatory cytokines and GCs-driven thymus atrophy. Extending this study, we now explored the relationship between leptin and GCs, in terms of infection outcome, thymic and metabolic changes. T. cruzi-infected mice showed a food intake reduction, together with hypoglycemia and lipolysis-related changes. Infected animals also displayed a reduction in systemic and adipose tissue levels of leptin, paralleled by a down-regulation of their receptor (ObR) in the hypothalamus. Studies in infected mice subjected to adrenalectomy (Adx) showed a worsened course of infection accompanied by even more diminished systemic and intrathymic leptin levels, for which GCs are necessary not only to decrease inflammation but also to sustain leptin secretion. Adx also protected from thymic atrophy, independently of the reduced leptin contents. Leptin administration to infected mice aggravated inflammation, lowered parasite burden and attenuated GCs release, but did not normalize thymic atrophy or metabolic parameters. Acute T. cruzi infection in C57BL/6 mice coexists with a dysregulation of leptin/hypothalamic ObR circuitry dissociated from body weight and food intake control. Endogenous GCs production attempted to reestablish systemic leptin concentrations, but failed to improve leptin-protective activities at the thymic level, suggesting that the leptin/GCs intrathymic relationship is also altered during this infection.

Antibodies to SARS-CoV2 induced by vaccination and infection correlate with protection against the infection.

The COVID-19 pandemic remained worldwide for almost three years, but little is known about the dynamics of humoral immune response to the third dose over time and its protection from infection. Our aim was to assess the humoral immune response after the third dose of the different vaccines administered to SARS-CoV-2 naive and previously infected individuals, and its correlation with protection in an academic community. For each person studied (185), three blood samples were taken between December 2021 and July 2022, one month apart. Anti-S antibodies were quantified by ELISA, while anti-N antibody levels were determined by ECLIA. Most of the participants had received two doses of viral vector-based, mRNA-based and virus-inactivated vaccines. Although anti-N antibody levels revealed that 80% of the individuals had been exposed to the virus before or during the study, only 42% reported having been diagnosed. When anti-S IgG levels were measured 3-5 months after the second dose of any vaccine, they were higher in those previously infected individuals. The same results were observed for anti-N IgG levels in those who received 2 doses of the virus-inactivated vaccine. When analyzing the dynamics of anti-S antibodies we observed that, although positive IgG antibody levels were detected 5-6 months after the second dose administration, those observed 30-60 days after the third dose were significantly higher and remained so for at least 8 months. Higher levels of anti-S IgG antibodies at the first sampling were associated with a lower incidence of subsequent infection. The same association was seen in people who received the booster compared with those who received two doses. This study provides further evidence that anti-S IgG antibodies remained at high levels over time, and both anti-S levels and the third dose of anti-SARS-CoV-2 vaccine correlate with protection against the infection. It also shows that infection acts as a booster of immunization, increasing levels of both anti-N and anti-S IgG.

Studies on the contribution of PPAR Gamma to tuberculosis physiopathology.

Introduction: Tuberculosis (TB) is a major health problem characterized by an immuno-endocrine imbalance: elevated plasma levels of cortisol and pro- and anti-inflammatory mediators, as well as reduced levels of dehydroepiandrosterone. The etiological agent, Mycobacterium tuberculosis (Mtb), is captured by pulmonary macrophages (Mf), whose activation is necessary to cope with the control of Mtb, however, excessive activation of the inflammatory response also leads to tissue damage. Glucocorticoids (GC) are critical elements to counteract the immunoinflammatory reaction, and peroxisome proliferator-activated receptors (PPARs) are also involved in this regard. The primary forms of these receptors are PPARϒ, PPARα, and PPARß/δ, the former being the most involved in anti-inflammatory responses. In this work, we seek to gain some insight into the contribution of PPARϒ in immuno-endocrine-metabolic interactions by focusing on clinical studies in pulmonary TB patients and in vitro experiments on a Mf cell line. Methods and results: We found that TB patients, at the time of diagnosis, showed increased expression of the PPARϒ transcript in their peripheral blood mononuclear cells, positively associated with circulating cortisol and related to disease severity. Given this background, we investigated the expression of PPARϒ (RT-qPCR) in radiation-killed Mtb-stimulated human Mf. The Mtb stimulation of Mf derived from the human line THP1 significantly increased the expression of PPARϒ, while the activation of this receptor by a specific agonist decreased the expression of pro- and anti-inflammatory cytokines (IL-1ß and IL-10). As expected, the addition of GC to stimulated cultures reduced IL-1ß production, while cortisol treatment together with the PPARϒ agonist lowered the levels of this proinflammatory cytokine in stimulated cultures. The addition of RU486, a glucocorticoid receptor antagonist, only reversed the inhibition produced by the addition of GC. Conclusion: The current results provide a stimulating background for further analysis of the interconnection between PPARs and steroid hormones in the context of Mtb infection.

The long-term antibody response after SARS-CoV-2 prime-boost vaccination in healthy individuals. The positive influence of extended between-dose intervals and heterologous schedule.

Introduction: Anti-COVID vaccination in Argentina was carried out using different protocols and variations in periods between administrations, as well as combinations of different vaccine platforms. Considering the relevance of the antibody response in viral infections, we analyzed anti-S antibodies in healthy people at different points of time following the Sputnik immunization procedure. Methods: We attended the vaccination centers in the city of Rosario, which had shorter versus longer intervals between both doses. A total of (1021) adults with no COVID-compatible symptoms (throughout the study period) were grouped according to the gap between both vaccine doses: 21 (Group A, n=528), 30 (Group B, n=147), and 70 days (Group C, n=82), as well as an additional group of individuals with heterologous vaccination (Sputnik/Moderna, separated by a 107-day interval, group D, n=264). Results and conclusions: While there were no between-group differences in baseline levels of specific antibodies, data collected several weeks after administering the second dose showed that group D had the highest amounts of specific antibodies, followed by values recorded in Groups C, B, and A. The same pattern of group differences was seen when measuring anti-S antibodies at 21 or 180 days after the first and second doses, respectively. Delayed between-dose intervals coexisted with higher antibody titers. This happened even more when using a prime-boost heterologous schedule.