Renin-angiotensin-aldosterone system inhibitors and covid-19 complications / Inibidores do sistema renina-angiotensina-aldosterona e complicações da covid-19

The world faces today a pandemic of unquestionable importance, caused by an infection with a new enveloped RNA virus that belongs to the Coronaviridae family. The new coronavirus (SARS-CoV 2) uses a glycoprotein present on its surface to bind to and infect host cells that express the angiotensin converting enzyme II (ACE-2). Although different tissues may be targeted by the virus, respiratory complications remain as the main cause of death. It has been demonstrated that Renin-Angiotensin-Aldosterone System (RAAS) inhibitors increase ACE-2 expression in animal models, raising the concern that patients under treatment with these drugs could become more susceptible to COVID-19 complications. Here, we discuss the impact of RAAS inhibitors on COVID-19 outcomes and show that no evidence so far supports that the use of these drugs could pose a risk to SARS-CoV 2-infected patients. In fact, clinical data suggest that RAAS inhibitors may even act in a protective way against COVID-19 complications and should not be discontinued.

MAIT cells are activated in acute Dengue virus infection and after in vitro Zika virus infection.

Dengue virus (DENV) and Zika virus (ZIKV) are members of the Flaviviridae and are predominantly transmitted via mosquito bites. Both viruses are responsible for a growing number of infections in tropical and subtropical regions. DENV infection can cause lethargy with severe morbidity and dengue shock syndrome leading to death in some cases. ZIKV is now linked with Guillain-Barré syndrome and fetal malformations including microcephaly and developmental disorders (congenital Zika syndrome). The protective and pathogenic roles played by the immune response in these infections is unknown. Mucosal-associated invariant T (MAIT) cells are a population of innate T cells with potent anti-bacterial activity. MAIT cells have also been postulated to play a role in the immune response to viral infections. In this study, we evaluated MAIT cell frequency, phenotype, and function in samples from subjects with acute and convalescent DENV infection. We found that in acute DENV infection, MAIT cells had elevated co-expression of the activation markers CD38 and HLA-DR and had a poor IFNγ response following bacterial stimulation. Furthermore, we found that MAIT cells can produce IFNγ in response to in vitro infection with ZIKV. This MAIT cell response was independent of MR1, but dependent on IL-12 and IL-18. Our results suggest that MAIT cells may play an important role in the immune response to Flavivirus infections

Evaluation of IL-10-producing regulatory B cells in patients with Common Variable Immunodeficiency (CVID)

A Imunodeficiência Comum Variável (ICV) é a imunodeficiência primária sintomática mais comum em adultos. Pacientes ICV frequentemente apresentam diversas alterações de linfócitos B, número reduzido de células Treg e ativação imune crônica, bem como infecções recorrentes, alta incidência de doenças autoimunes e um risco aumentado de doenças malignas. Testamos a hipótese de que a frequência de células B10 estaria diminuída nos pacientes ICV, já que elas desempenham um importante papel no desenvolvimento de células Treg, no controle da ativação de células T e na autoimunidade. Para tanto, nós avaliamos a frequência de células B10 em pacientes ICV buscando correlacioná-la com as diferentes manifestações clínicas e imunológicas associadas à doença. Quarenta e dois (42) pacientes com diagnóstico de ICV e 17 indivíduos saudáveis foram convidados a participar do estudo. A partir das CMSP criopreservadas foram realizados testes de perfil de ativação celular, presença de células T reguladoras (Treg) e caracterização das células B10. Os níveis de sCD14 no plasma foram determinados por ELISA. A produção de IL-10 foi determinada por ELISA em sobrenadante de cultura de células B. Pacientes ICV apresentam frequência diminuída de células B CD24hiCD38hi produtoras de IL-10 em diferentes condições de cultura celular e frequência diminuída de células B CD24hiCD27+ em cultura celular estimulada por CpG+PIB. No entanto, a produção de IL-10 por células B não demonstrou diferença significativa entre pacientes ICV e controles. A frequência de células B10 não teve correlação com a presença de autoimunidade, ativação celular ou frequência de células Treg em pacientes ICV. Este trabalho sugere que pacientes ICV têm um comprometimento na subpopulação de células B reguladoras, mas que não está correlacionado com as características clínicas e imunológicas apresentadas por esses indivíduosCommon variable immunodeficiency (CVID) is the most prevalent symptomatic primary immunodeficiency in adults. CVID patients often present changes in the frequency and function of B lymphocytes, reduced number of Treg cells, chronic immune activation, recurrent infections, high incidence of autoimmunity and increased risk for malignancies. We hypothesized that the frequency of B10 cells would be diminished in CVID patients because these cells play an important role in the development of Treg cells and in the control of T cell activation and autoimmunity. Therefore, we evaluated the frequency of B10 cells in CVID patients and correlated it with the different clinical and immunological characteristics of this disease. Forty-two CVID patients and 17 healthy controls were recruited for this study. Cryopreserved PBMCs were used for analysis of T cell activation, frequency of Treg cells and characterization of B10 cells by flow cytometry. Plasma sCD14 levels were determined by ELISA. IL-10 production was determined in supernatant by ELISA after culture of B cells. We found that CVID patients presented a decreased frequency of IL-10-producing CD24hiCD38hi B cells in different cell culture conditions and decreased frequency of IL-10-producing CD24hiCD27+ B cells stimulated with CpG+PIB. However, the B cells secretion of IL-10 was similar between CVID patients and healthy controls. The frequency of B10 cells had no correlation with autoimmunity, immune activation and Treg cells in CVID patients. This work suggests that CVID patients have a compromised regulatory B cell compartment which is not correlated with clinical and immunological characteristics presented by these individual

Inversion of the Vδ1 to Vδ2 γδ T cell ratio in CVID is not restored by IVIg and is associated with immune activation and exhaustion.

Common variable immunodeficiency (CVID) is defined by low levels of IgG and IgA, but perturbations in T cells are also commonly found. However, there is limited information on γδ T cells in CVID patients. Newly diagnosed CVID patients (n = 15) were enrolled before and after intravenous IgG (IVIg) replacement therapy. Cryopreserved peripheral blood mononuclear cells were then used to study γδ T cells and CVID patients were compared to healthy controls (n = 22). The frequency and absolute count of Vδ1 γδ T cells was found to be increased in CVID (median 0.60% vs 2.64%, P \u3c0.01 and 7.5 vs 39, P \u3c0.01 respectively), while they were decreased for Vδ2 γδ T cells (median, 2.36% vs 0.74%,P \u3c0.01 and 37.8 vs 13.9, P \u3c0.01 respectively) resulting in an inversion of the Vδ1 to Vδ2 ratio (0.24 vs 1.4, P \u3c0.001). Markers of immune activation were elevated on all subsets of γδ T cells, and HLA-DR expression was associated with an expansion of Vδ1 γδ T cells (r = 0.73, P = 0.003). Elevated PD-1 expression was found only on Vδ2 γδ T cells (median 1.15% vs 3.08%, P \u3c0.001) and was associated with the decrease of Vδ2 γδ T cells (r = −0.67, P = 0.007). IVIg had no effect on the frequency of Vδ1 and Vδ2 γδ T cells or HLA-DR expression, but alleviated CD38 expression on Vδ1 γδ T cells (median MFI 965 vs 736, P \u3c0.05). These findings suggest that immunological perturbations of γδ T cells are a general feature associated with CVID and are only partially reversed by IVIg therapy

MAIT cells are activated in acute Dengue virus infection and after <i>in vitro</i> Zika virus infection

<div><p>Dengue virus (DENV) and Zika virus (ZIKV) are members of the <i>Flaviviridae</i> and are predominantly transmitted via mosquito bites. Both viruses are responsible for a growing number of infections in tropical and subtropical regions. DENV infection can cause lethargy with severe morbidity and dengue shock syndrome leading to death in some cases. ZIKV is now linked with Guillain-Barré syndrome and fetal malformations including microcephaly and developmental disorders (congenital Zika syndrome). The protective and pathogenic roles played by the immune response in these infections is unknown. Mucosal-associated invariant T (MAIT) cells are a population of innate T cells with potent anti-bacterial activity. MAIT cells have also been postulated to play a role in the immune response to viral infections. In this study, we evaluated MAIT cell frequency, phenotype, and function in samples from subjects with acute and convalescent DENV infection. We found that in acute DENV infection, MAIT cells had elevated co-expression of the activation markers CD38 and HLA-DR and had a poor IFNγ response following bacterial stimulation. Furthermore, we found that MAIT cells can produce IFNγ in response to <i>in vitro</i> infection with ZIKV. This MAIT cell response was independent of MR1, but dependent on IL-12 and IL-18. Our results suggest that MAIT cells may play an important role in the immune response to <i>Flavivirus</i> infections.</p></div

Lower IFNγ production following <i>in vitro</i> stimulation with <i>E</i>. <i>coli</i> by MAIT cells in acute DENV infection.

<p>MAIT cells were stimulated with fixed <i>E</i>. <i>coli</i> (multiplicity of exposure 10) for 24h and IFNγ production by MAIT cells was evaluated by flow cytometry. Representative flow plots of IFNγ production by MAIT cells (A). IFNγ production by MAIT cells in response to <i>E</i>. <i>coli</i> stimulation in acute and convalescent DENV infection (n = 15, B). Association between the levels of sCD14 and MAIT cells IFNγ response to <i>E</i>. <i>coli</i> stimulation in acute DENV infection (C). * indicates p < 0.05.</p

MAIT cells have elevated expression of activation markers in acute DENV infection.

<p>Gating strategy and representative flow plots of MAIT cell frequency (A). MAIT cell frequency in acute and convalescent DENV infection (n = 25, B). MAIT cell count, (as determined by multiplying the lymphocyte count by the frequency of MAIT cells in lymphocytes), in acute and convalescent DENV infection (n = 24, C). Co-expression of CD38 and HLA-DR by MAIT cells in acute and convalescent DENV infection (n = 15, D). CD127 expression (MFI) by MAIT cells in acute and convalescent DENV infection (n = 15, E). PD-1 expression by MAIT cells in acute and convalescent DENV infection (n = 15, F). CCR6 expression (MFI) by MAIT cells in acute and convalescent DENV infection (n = 15, G). ** indicates p < 0.01, and *** indicates p < 0.001.</p

Increased levels of sCD14 in acute DENV infection.

<p>Plasma levels of sCD14 (A) and IL-7 (B) in acute and convalescent DENV infection were determined for subjects 1–10 (n = 10) and for healthy control (n = 5). The bars and whiskers represent the median and interquartile range respectively. ** indicates p < 0.01.</p

DENV patient demographics and cell count.

<p>DENV patient demographics and cell count.</p

MAIT cells response to <i>in vitro</i> ZIKV infection is dependent on IL-12 and IL-18.

<p>PBMCs were infected with ZIKV (MOI: 5) for 24h and IFNγ production by MAIT cells was evaluated by flow cytometry. Representative flow plots of IFNγ production by MAIT cells (A). MAIT cells IFNγ response to ZIKV infection (n = 9, B). PBMCs were incubated in presence of MR1 (n = 6), IL-12 (n = 4), IL-18 (n = 8), and IL-12 + IL-18 (n = 4) blocking antibodies and stimulated with <i>E</i>. <i>coli</i>, ZIKV, or heat inactivated ZIKV (n = 4) and IFNγ production by MAIT cells was measured (C). The results are presented as relative production of IFNγ by MAIT cells compared to the condition without any blocking antibody. Statistical analysis was performed before data normalization. PBMCs from HIV-1- (n = 8) and HIV-1+ (n = 6) subjects were infected with ZIKV (MOI: 5) and IFNγ production by MAIT cell was evaluated (D). PBMCs from HIV-1- (n = 6) and HIV-1+ (n = 6) subjects were treated with IL-12 and IL-18 (both at 50ng/ml) for 24 hours and IFNγ production by MAIT cell was evaluated (E). The bars and whiskers represent the median and interquartile range respectively. * indicates p < 0.05 and ** indicates p < 0.01.</p