scholarly journals Functional Autoreactive Anti-β2 Adrenergic Antibodies May Contribute to Insulin Resistance Profile in Patients with Chronic Chagas Disease

Pathogens ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 378
Author(s):  
Luz María Rodeles ◽  
Miguel Hernán Vicco ◽  
Álvaro Siano ◽  
Leonardo Andrés Fuchs ◽  
Luz María Peverengo ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Chagas Disease ◽  
Neuroendocrine Cells ◽  
Risk Scores ◽  
Atherogenic Dyslipidemia ◽  
Metabolic Disturbances ◽  
Metabolic Evaluation ◽  
Resistance Profile ◽  
Chronic Chagas Disease

Potential activation of β2 adrenergic receptors (β2AR) by specific autoreactive antibodies (Abs) that arise during the host reaction to Trypanosoma cruzi, could contribute to the elevated prevalence of metabolic disturbances described in patients with chronic Chagas disease (CCD). This study aimed to determine the prevalence of anti-β2AR Abs in patients with CCD, as well as the correlation of these Abs with the presence of glucose and lipid metabolism disturbances, in order to explore their association with an insulin resistance profile. Additionally, we tested the functional effects of anti-β2AR Abs employing an in vitro bioassay with neuroendocrine cells expressing β2AR. A clinical and metabolic evaluation including an OGTT was performed in 80 CCD patients and 40 controls. Anti-β2AR Abs were measured by an in-house-developed ELISA, and the β2 adrenergic activity of affinity-purified IgG fractions from patient’ sera were assayed in CRE-Luc and POMCLuc transfected AtT-20 cells. A higher proportion of dysglycemia (72.5% vs. 37.5%; p = 0.001) was observed in the CCD group, accompanied by increased HOMA2-IR (p = 0.019), especially in subjects with Abs (+). Anti-β2AR Abs reactivity (7.01 (2.39–20.5); p = 0.0004) and age >50 years (3.83 (1.30–11.25); p = 0.014) resulted as relevant for IR prediction (AUC: 0.786). Concordantly, Abs (+) CCD patients showed elevated metabolic risk scores and an increased prevalence of atherogenic dyslipidemia (p = 0.040), as compared to Abs (−) patients and controls. On functional bioassays, Abs exerted specific and dose-dependent β2-agonist effects. Our findings suggest that anti-β2AR Abs may induce the activation of β2AR in other tissues besides the heart; furthermore, we show that in patients with CCD these Abs are associated with an insulin resistance profile and atherogenic dyslipidemia, providing biological plausibility to the hypothesis that adrenergic activation by anti-β2AR Abs could contribute to the pathogenesis of metabolic disturbances described in CCD patients, increasing their cardiovascular risk.

scholarly journals IL-10 and IFN-γ gene expression in chronic Chagas disease patients after in vitro stimulation with recombinant antigens of Trypanosoma cruzi

Cytokine ◽  
2012 ◽  
Vol 58 (2) ◽  
pp. 207-212 ◽  
Author(s):  
Adriene Siqueira de Melo ◽  
Virginia Maria Barros de Lorena ◽  
Suellen Carvalho de Moura Braz ◽  
Cássia Docena ◽  
Yara de Miranda Gomes
Keyword(s):  
Gene Expression ◽  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Recombinant Antigens ◽  
Ifn Γ ◽  
Chronic Chagas Disease

The immune response against Trypanosoma cruzi in the human placenta

2017 ◽  
Vol 1 (6) ◽  
pp. 573-577
Author(s):  
Ulrike Kemmerling ◽  
Christian Castillo ◽  
Ana Liempi ◽  
Lisvaneth Medina ◽  
Ileana Carrillo ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Immune Responses ◽  
Chagas Disease ◽  
Defense Mechanisms ◽  
Complex Interaction ◽  
Chorionic Villi ◽  
Congenital Transmission ◽  
Intracellular Parasites ◽  
Chronic Chagas Disease

Congenital Chagas disease, caused by Trypanosoma cruzi (T. cruzi), is partially responsible for the increasing globalization of Chagas disease despite its low transmission. During congenital transmission, the parasite reaches the fetus by crossing the placental barrier. However, the success or impairment of congenital transmission of the parasite is the product of a complex interaction between the parasite, the maternal and fetus/newborn immune responses and placental factors. There is other evidence apart from the low congenital transmission rates, which suggests the presence of defense mechanisms against T. cruzi. Thus, the typical amastigote nests (intracellular parasites) cannot be observed in placentas from mothers with chronic Chagas disease nor in human placental chorionic villi explants infected in vitro with the parasite. In the latter, only a few parasite antigens and DNA are identified. Accordingly, other infections of the placenta are not commonly observed. All these evidences suggest that the placenta can mount defense mechanisms against T. cruzi.

scholarly journals Evaluation of CD4+CD25+ T lymphocyte response time kinetics in patients with chronic Chagas disease after in vitro stimulation with recombinant Trypanosoma cruzi antigens

2013 ◽  
Vol 46 (3) ◽  
pp. 362-366 ◽  
Author(s):  
Suellen Carvalho de Moura Braz ◽  
Virginia Maria Barros de Lorena ◽  
Adriene Siqueira Melo ◽  
Maria da Gloria Aureliano Melo Cavalcanti ◽  
Yara de Miranda Gomes
Keyword(s):  
Trypanosoma Cruzi ◽  
Response Time ◽  
Chagas Disease ◽  
T Lymphocyte ◽  
Lymphocyte Response ◽  
Chronic Chagas Disease

scholarly journals A case report of long treatment with Itraconazole in a patient with chronic Chagas disease

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Pau Bosch-Nicolau ◽  
Fernando Salvador ◽  
Adrián Sánchez-Montalvá ◽  
Elena Sulleiro ◽  
Joaquín Burgos ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Chagas Disease ◽  
Treatment Strategies ◽  
Chronic Phase ◽  
Rt Pcr ◽  
Ergosterol Synthesis ◽  
Contradictory Evidence ◽  
Chronic Chagas Disease

Abstract Background Current available treatments (benznidazole and nifurtimox) for Chagas disease (CD) show limited efficacy in chronic phase and frequent undesirable effects. Ergosterol synthesis inhibitors (ESI) had been considered as promising drugs for CD treatment and despite its recent poor results in several clinical trials, different strategies have been proposed to optimize its role in this infection. Case presentation We present a case of chronic Chagas disease in patient diagnosed with HIV who received treatment for histoplasmosis with itraconazol during twelve months. Even though T. cruzi rt-PCR was persistently negative during treatment, when itraconazol was stopped she presented with a positive blood rt-PCR. Conclusion Several studies using different ESI had been published for CD treatment. Either in vitro or in vivo assays demonstrated activity against T. cruzi of the different triazole derivatives so different clinical trials had been carried out to evaluate its efficacy and safety. Despite contradictory evidence in the animal model, longer treatments along with other treatment strategies previously proposed suggests that ESI failure rates in positive peripheral blood rt-PCR are higher than that obtained with the current treatments of choice.

scholarly journals New Biomarker in Chagas Disease: Extracellular Vesicles Isolated from Peripheral Blood in Chronic Chagas Disease Patients Modulate the Human Immune Response

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Rafael Pedro Madeira ◽  
Lavínia Maria Dal’Mas Romera ◽  
Paula de Cássia Buck ◽  
Charles Mady ◽  
Barbara Maria Ianni ◽  
...  
Keyword(s):  
Chagas Disease ◽  
Extracellular Vesicles ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Public Health Problem ◽  
Major Public Health Problem ◽  
Cytokine Detection ◽  
Potential Biomarker ◽  
Chronic Chagas Disease

Chagas disease, a neglected tropical disease (NTD) caused by the flagellated protozoan Trypanosoma cruzi (T. cruzi), is a major public health problem. It was initially restricted to Latin America, but it is now expanding globally. Host and pathogen interactions are crucial in the establishment of disease, and since 1970, it has been known that eukaryotic cells release extracellular vesicles (EVs), which in turn have an important role in intercellular communication in physiological and pathological conditions. Our study proposed to characterize and compare circulating EVs isolated from the plasma of chronic Chagas disease (CCD) patients and controls. For this, peripheral blood was collected from patients and controls, and mononuclear cells (PBMCs) were isolated and stimulated with parasite EVs, showing that patient cells released fewer EVs than control cells. Then, after plasma separation followed by EV total shedding enrichment, the samples were subjected to ultracentrifugation to isolate the circulating EVs, which then had their size and concentration characterized by nanoparticle tracking analysis (NTA). This showed that patients had a lower concentration of circulating EVs while there were no differences in size, corroborating the in vitro data. Additionally, circulating EVs were incubated with THP-1 cells (macrophages) that, after the interaction, had their supernatant analyzed by ELISA for cytokine detection. In relation to their ability to induce cytokine production, the CCD patient EVs were able to induce a differential production of IFN-γ and IL-17 in relation to controls, with differences being more evident in earlier/less severe stages of the disease. In summary, a decreased concentration of circulating EVs associated with differential activation of the immunological system in patients with CCD is related to parasite persistence and the establishment of chronic disease. It is also a potential biomarker for monitoring disease progression.

scholarly journals Cellular immunity in chronic Chagas' disease

1977 ◽  
Vol 5 (4) ◽  
pp. 401-404
Author(s):  
O M Montufar ◽  
C C Musatti ◽  
E Mendes ◽  
N F Mendes
Keyword(s):  
Immune Response ◽  
Chagas Disease ◽  
Cellular Immunity ◽  
Cellular Immune Response ◽  
Specific Antigen ◽  
Lymphocyte Function ◽  
Cell Reactivity ◽  
Cellular Immune ◽  
Chronic Chagas Disease

The cellular immune response was assessed in 20 patients with chronic Chagas' disease (American trypanosomiasis). Thymus-derived lymphocyte function was determined in vivo by cutaneous reactivity to several antigens including a soluble preparation derived from Trypanosoma cruzi and sensitization to 2,4-dinitrochlorobenzene. The in vitro T-cell reactivity was investigated by the proliferative response to phytohemagglutinin and to T. cruzi antigen and by inhibition of leukocyte migration with the specific antigen. In addition, the proportion and absolute numbers of peripheral blood T and B-lymphocytes were determined by rosette formation. This research indicates that the general and specific cellular immune response, evaluated by the tests herein mentioned, is well preserved in patients, with Chagas' disease. We conclude that chronic Chagas' disease is not associated with deficiency in cellular immunity, nor does it lead to it. Conceivably, the active participation of delayed hypersensitivity may play an important role in the expression of the human chagasic lesions.

scholarly journals Trypanosoma cruzi Induces Regulatory B Cell Alterations in Patients With Chronic Chagas Disease

2021 ◽  
Vol 11 ◽  
Author(s):  
Magalí C. Girard ◽  
Micaela S. Ossowski ◽  
Arturo Muñoz-Calderón ◽  
Marisa Fernández ◽  
Yolanda Hernández-Vásquez ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Chagas Disease ◽  
Ex Vivo ◽  
Production Capacity ◽  
Cell Phenotype ◽  
Regulatory B Cell ◽  
B10 Cells ◽  
Chronic Chagas Disease

The clinical evolution of patients with chronic Chagas disease (CCD) is mainly associated with an excessive inflammation and a defective immunomodulatory profile caused by the interaction between T. cruzi and the host. Regulatory B (Breg) cells exert immune suppression mostly through IL-10 production (B10 cells), but also through IL-10-independent mechanisms. Previously, we demonstrated that CCD patients with cardiomyopathy show changes in the ex vivo Breg cell phenotypic distribution although maintain IL-10 production capacity. Here, we sought to identify potential alterations on Breg cells upon in vitro stimulation. Isolated B cells from CCD patients with or without cardiomyopathy and non-infected (NI) donors were stimulated with T. cruzi lysate or CpG + CD40L, and characterized by flow cytometry based on the expression of CD24, CD27, CD38, and the regulatory molecules IL-10 and PD-L1. IL-10 and IL-17 secretion in the supernatant of B cells was evaluated by ELISA. Data showed that T. cruzi stimulation diminished the expression of CD24 and CD38 on CD27− B cells while reducing the percentage of CD24high inside CD27+ B cells. Furthermore, T. cruzi induced a regulatory B cell phenotype by increasing B10 cells and IL-10 secretion in all the groups. The innate-like B10 cells expansion observed in patients with cardiomyopathy would be associated with CD27− B10 cell subsets, while no predominant phenotype was found in the other groups. Patients with cardiomyopathy also displayed higher IL-17 secretion levels in T. cruzi–activated B cells. CpG + CD40L stimulation revealed that B cells from CCD patients and NI donors had the same ability to differentiate into B10 cells and secrete IL-10 in vitro. Additionally, CCD patients showed an increased frequency of CD24−CD27− B cells and a reduction in the percentage of CD24highCD27+ Breg cells, which appeared to be inversely correlated with the presence of T. cruzi DNA in blood. Finally, CCD patients exhibited a higher frequency of PD-L1+ B cells in T. cruzi–stimulated samples, suggesting that IL-10-independent mechanisms could also be tangled in the control of inflammation. Altogether, our results provide evidence about the potential role of Breg cells in the immune response developed against T. cruzi and its contribution to chronic Chagas cardiomyopathy.

scholarly journals Immune exhaustion in chronic Chagas disease: Pro-inflammatory and immunomodulatory action of IL-27 in vitro

2021 ◽  
Vol 15 (6) ◽  
pp. e0009473
Author(s):  
María Ailén Natale ◽  
Todd Minning ◽  
María Cecilia Albareda ◽  
Melisa Daiana Castro Eiro ◽  
María Gabriela Álvarez ◽  
...  
Keyword(s):  
T Cells ◽  
Heart Disease ◽  
T Cell ◽  
Chagas Disease ◽  
Cell Function ◽  
Immune Exhaustion ◽  
T Cell Function ◽  
And Function ◽  
Chronic Chagas Disease

In chronic Chagas disease, Trypanosoma cruzi-specific T-cell function decreases over time, and alterations in the homeostatic IL-7/IL-7R axis are evident, consistent with a process of immune exhaustion. IL-27 is an important immunoregulatory cytokine that shares T-cell signaling with IL-7 and other cytokines of the IL-12 family and might be involved in the transcriptional regulation of T-cell function. Here, we evaluated the expression and function of IL-27R in antigen-experienced T cells from subjects with chronic Chagas disease and assessed whether in vitro treatment with IL-27 and IL-7 might improve T. cruzi-specific polyfunctional T-cell responses. In vitro exposure of PBMCs to T. cruzi induced a downregulation of IL-27R in CD4+ T cells and an upregulation in CD8+ T cells in subjects without heart disease, while IL-27R expression remained unaltered in subjects with more severe clinical stages. The modulation of IL-27R was associated with functional signaling through STAT3 and STAT5 and induction of the downstream genes TBX21, EOMES and CXCL9 in response to IL-27. In vitro treatment of PBMCs with IL-27 and IL-7 improved monofunctional and polyfunctional Th1 responses, accompanied by the induction of IL-10 and Bcl-2 expression in subjects without heart disease but did not improve those in subjects with cardiomyopathy. Our findings support the process of desensitization of the IL-27/IL-27R pathway along with disease severity and that the pro-inflammatory and immunomodulatory mechanisms of IL-27 might be interconnected.

scholarly journals CD4+ T cells from chronic Chagas disease patients with different degrees of cardiac compromise exhibit distinct expression patterns of inhibitory receptors TIGIT, Tim-3 and Lag-3

2019 ◽  
Author(s):  
Paula B. Alcaraz ◽  
Magali C. Girard ◽  
M. Paula Beati ◽  
Raul Chadi ◽  
Marisa Fernandez ◽  
...  
Keyword(s):  
T Cells ◽  
Chagas Disease ◽  
Immune Modulation ◽  
Expression Patterns ◽  
T Cell Response ◽  
Antigenic Stimulation ◽  
Inhibitory Receptors ◽  
Therapeutic Success ◽  
Chronic Chagas Disease

AbstractT cells are central to adaptive immune response against T. cruzi infection. In the chronic stage of Chagas disease, circulating parasite-specific memory T cells show reduced functionality and increased expression of inhibitory receptors, possibly as a result of persistent antigenic stimulation. This exhausted phenotype has been linked to progression of cardiac pathology while, contrariwise, the presence of polyfunctional T cells shows association with therapeutic success and more efficient control of infection. Given this, we hypothesized that inhibitory receptors TIGIT, Tim-3 and Lag-3 may be involved in immune modulation of anti-T. cruzi T cell response, and therefore may play a role in the containment or the unleashing of inflammatory phenomena that ultimately lead to tissue damage and pathology. In this preliminary study, we assess the frequency of CD4+ T cells expressing each of these receptors and their relation to cellular activation. Samples from chronic Chagas disease patients with different degrees of cardiac compromise, and non-infected donors were analyzed under different stimulation conditions. Our results show that the frequency of TIGIT+ CD4+ T cells is increased in Chagas patients, while Tim-3+ cells are more abundant in patients with signs of cardiac alterations. In addition, the frequency of Lag-3+ cells increases in non-activated CD4+ T cells from Chagas patients without demonstrable cardiopathy upon pathogen-specific in vitro antigenic stimulation.

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