Enhanced Migratory Capacity of T Lymphocytes in Severe Chagasic Patients Is Correlated With VLA-4 and TNF-α Expression.

Trypanosoma cruzi infection in humans leads to progression to chronic chagasic myocarditis (CCM) in 30% of infected individuals, paralleling T cell inflammatory infiltrates in the heart tissue. T-cell trafficking into the hearts of CCM patients may be modulated by in situ expression of chemotactic or haptotactic molecules, as the chemokine CXCL12, the cytokine tumor necrosis factor-alpha (TNF-α), and extracellular matrix proteins (ECM), such as fibronectin. Herein we evaluated the expression of fibronectin, CXCL12, and TNF-α in the myocardial tissue of T. cruzi seropositive (asymptomatic or with CCM), as well as seronegative individuals as healthy controls. Hearts from CCM patients exhibited enhanced expression of these three molecules. CXCL12 and TNF-α serum levels were also increased in CCM individuals. We then evaluated T lymphocytes from chronic chagasic patients by cytofluorometry, in terms of membrane expression levels of molecules involved in cell activation and cell migration, respectively, HLA-DR and the VLA-4 (very late antigen-4, being one integrin-type fibronectin receptor). Indeed, the expression of HLA-DR and VLA-4 was enhanced on T lymphocytes from chagasic patients, especially in the CCM group. To further approach the dynamics of T cell migratory events, we performed fibronectin-, TNF-α-, and CXCL12-driven migration. Peripheral blood mononuclear cells (PBMCs) and T cells from CCM patients presented an ex vivo enhanced migratory capacity driven by fibronectin alone when this ECM protein was placed in the membrane of transwell migration chambers. When TNF-α was previously placed upon fibronectin, we observed a further and significant increase in the migratory response of both PBMCs and T lymphocytes. Overall, these data suggest the existence in patients with chronic Chagas disease of a cardiac inflammatory infiltrate vector that promotes the recruitment and accumulation of activated T cells, driven in part by enhanced tissue expression of fibronectin and TNF-α, as well as the respective corresponding VLA-4 and TNF receptors.

Chagas disease reactivation in rheumatologic patients: association with immunosuppressive therapy and humoral response.

Evidence for Chagas disease reactivation (CDR) in rheumatologic patients under rheumatologic treatments (RTs) is scarce. To screen and follow-up patients with rheumatic diseases and concomitant Chagas disease under RT to detect CDR and to describe a possible relationship between CDR and specific RT. An observational, longitudinal, prospective, consecutive study was carried out between 2018 and 2020. Included patients were evaluated during the follow-up for clinical and laboratorial manifestations of CDR. Direct blood parasitological examination (Strout method) and polymerase chain reaction (PCR) were employed to diagnose CDR. The dynamic of anti-T. cruzi-specific antibodies was also assessed by IHA and ELISA (total IgG and Anti-SAPA). Fifty-one patients were included (86% women). Rheumatoid arthritis was the predominant disease (57%). Classic DMARDs (86.3%) and corticosteroids (61%) were the most frequent RT. CDR was developed in 6 patients (11.7%), exhibiting both positive Strout and PCR. Symptomatic reactivation of CD (fever, asthenia, arthralgias, myalgias) occurred in two patients who had previously been diagnosed with it. Regardless of the different RT, all patients who experienced CDR had previously received more than ≥ 20 mg/day of prednisone equivalent. Despite immunosuppression, patients with CDR exhibited increased levels of specific anti-T. cruzi and anti-SAPA antibodies, which decreased after anti-parasitic treatment. CDR is possible in rheumatologic patients, especially after receiving high doses of corticosteroids. Since CDR symptoms may mimic rheumatic disease activity, monitoring of Chagas disease is highly recommended before, during and after immunosuppression. Key Points • Chagas disease reactivation (CDR) in the context of rheumatological treatment was associated to high doses of corticosteroids. • CDR was associated with an increase in anti-T. cruzi antibodies despite the immunosuppressive treatment. • Suspecting and anticipating CDR is mandatory in this patient population to diagnose and treat it.

The Role of High Mobility Group Box 1 Protein (HMGB1) in the Immunopathology of Experimental Pulmonary Tuberculosis.

BACKGROUND: The high mobility group box 1 (HMGB1) is the prototype of alarmin protein released by stressed or dying cells. The redox state of this protein confers different functions in the regulation of inflammation and immune response. AIM: Determine the kinetics, cellular sources and function of HMGB1 in experimental tuberculosis. METHODS: BALB/c mice were infected with Mycobacterium tuberculosis strain H37Rv. At different time points, HMGB1 was quantified in bronchial lavage fluid (BALF) and in lungs was determined its cellular sources by immunohistochemistry. HMGB1 was blocked with specific antibodies or recombinant HMGB1 was administered during early or late infection. Bacilli burdens, inflammation and cytokines expression were determined. RESULTS: The maximal concentration of HMGB1 in BALF was at day one of infection. Bronchial epithelium and macrophages were the most important sources. At day 7 to 21 the oxidized HMGB1 was predominant, while during late infection only the reduced form was seen. Blocking HMGB1 during early infection produced significant decrease of bacilli burdens and high production of pro-inflammatory cytokines, while the opposite was seen when HMGB1 was administered. Blocking HMGB1 activity or administrated it in high amounts during late infection worsening the disease. CONCLUSIONS: HMGB1 is liberated during experimental tuberculosis and promotes or suppress the immune response and inflammation depending on the redox state.

Immunoendocrine interactions during HIV-TB coinfection: implications for the design of new adjuvant therapies.

Worldwide, around 14 million individuals are coinfected with both tuberculosis (TB) and human immunodeficiency virus (HIV). In coinfected individuals, both pathogens weaken immunological system synergistically through mechanisms that are not fully understood. During both HIV and TB infections, there is a chronic state of inflammation associated to dramatic changes in immune cytokine and endocrine hormone levels. Despite this, the relevance of immunoendocrine interaction on both the orchestration of an effective immune response against both pathogens and the control of the chronic inflammation induced during HIV, TB, or both infections is still controversial. The present study reviews immunoendocrine interactions occurring during HIV and TB infections. We also expose our own findings on immunoendocrine cross talk in HIV-TB coinfection. Finally, we evaluate the use of adrenal hormones and their derivatives in immune-therapy and discuss the use of some of these compounds like the adjuvant for the prevention and treatment of TB in HIV patients.

Impaired neutrophil function in patients with pulmonary tuberculosis and its normalization in those undergoing specific treatment, except the HIV-coinfected cases.

Our study investigated whether the respiratory burst (RB) of polymorphonuclear neutrophils from tuberculosis (TB) patients was related with the disease severity or treatment, as well as the circulating levels of TNF-alpha. The sample comprised 57 patients with moderate (n=21) or advanced disease (n=36, 13 of them with HIV coinfection, TB-HIV) and 12 controls. Patients were newly diagnosed (n=27) or under treatment (moderate=14, advanced=10, TB-HIV=6). Cytometric analysis showed that untreated patients had a depressed RB in response to Candida albicans, being more pronounced in the advanced group and nearly absent in TB-HIV cases. A recovered RB was observed in treated patients, except for the TB-HIV cases that continued to show a poor response. TNF-alpha serum levels were increased in untreated patients, mostly in the advanced and TB-HIV groups, and showed an inverse and significant correlation with the RB. Disease severity and anti-TB therapy exerted negative and positive influences on the reactive oxygen intermediates production, respectively.