Blocking the CTLA-4 and PD-1 pathways during pulmonary paracoccidioidomycosis improves immunity, reduces disease severity, and increases the survival of infected mice.

Immune checkpoint pathways, i.e., coinhibitory pathways expressed as feedback following immune activation, are crucial for controlling an excessive immune response. Cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed cell death protein-1 (PD-1) are the central classical checkpoint inhibitory (CPI) molecules used for the control of neoplasms and some infectious diseases, including some fungal infections. As the immunosuppression of severe paracoccidioidomycosis (PCM), a chronic granulomatous fungal disease, was shown to be associated with the expression of coinhibitory molecules, we hypothesized that the inhibition of CTLA-4 and PD-1 could have a beneficial effect on pulmonary PCM. To this end, C57BL/6 mice were infected with Paracoccidioides brasiliensis yeasts and treated with monoclonal antibodies (mAbs) α-CTLA-4, α-PD-1, control IgG, or PBS. We verified that blockade of CTLA-4 and PD-1 reduced the fungal load in the lungs and fungal dissemination to the liver and spleen and decreased the size of pulmonary lesions, resulting in increased survival of mice. Compared with PBS-treated infected mice, significantly increased levels of many pro- and anti-inflammatory cytokines were observed in the lungs of α-CTLA-4-treated mice, but a drastic reduction in the liver was observed following PD-1 blockade. In the lungs of α-CPI and IgG-treated mice, there were no changes in the frequency of inflammatory leukocytes, but a significant reduction in the total number of these cells was observed. Compared with PBS-treated controls, α-CPI- and IgG-treated mice exhibited reduced pulmonary infiltration of several myeloid cell subpopulations and decreased expression of costimulatory molecules. In addition, a decreased number of CD4+ and CD8+ T cells but sustained numbers of Th1, Th2, and Th17 T cells were detected. An expressive reduction in several Treg subpopulations and their maturation and suppressive molecules, in addition to reduced numbers of Treg, TCD4+, and TCD8+ cells expressing costimulatory and coinhibitory molecules of immunity, were also detected. The novel cellular and humoral profiles established in the lungs of α-CTLA-4 and α-PD-1-treated mice but not in control IgG-treated mice were more efficient at controlling fungal growth and dissemination without causing increased tissue pathology due to excessive inflammation. This is the first study demonstrating the efficacy of CPI blockade in the treatment of pulmonary PCM, and further studies combining the use of immunotherapy with antifungal drugs are encouraged.

Transcriptional profiling of a fungal granuloma reveals a low metabolic activity of Paracoccidioides brasiliensis yeasts and an actively regulated host immune response.

Granulomas are important immunological structures in the host defense against the fungus Paracoccidioides brasiliensis, the main etiologic agent of Paracoccidioidomycosis (PCM), a granulomatous systemic mycosis endemic in Latin America. We have performed transcriptional and proteomic studies of yeasts present in the pulmonary granulomas of PCM aiming to identify relevant genes and proteins that act under stressing conditions. C57BL/6 mice were infected with 1x106 yeasts and after 8- and 12-weeks of infection, granulomatous lesions were obtained for extraction of fungal and murine RNAs and fungal proteins. Dual transcriptional profiling was done comparing lung cells and P. brasiliensis yeasts from granulomas with uninfected lung cells and the original yeast suspension used in the infection, respectively. Mouse transcripts indicated a lung malfunction, with low expression of genes related to muscle contraction and organization. In addition, an increased expression of transcripts related to the activity of neutrophils, eosinophils, macrophages, lymphocytes as well as an elevated expression of IL-1ß, TNF-α, IFN-γ, IL-17 transcripts were observed. The increased expression of transcripts for CTLA-4, PD-1 and arginase-1, provided evidence of immune regulatory mechanisms within the granulomatous lesions. Also, our results indicate iron as a key element for the granuloma to function, where a high number of transcripts related to fungal siderophores for iron uptake was observed, a mechanism of fungal virulence not previously described in granulomas. Furthermore, transcriptomics and proteomics analyzes indicated a low fungal activity within the granuloma, as demonstrated by the decreased expression of genes and proteins related to energy metabolism and cell cycle.

HLA-G*14 bp indel variant in autism spectrum disorder in a population from southern Brazil.

Altered immune response during pregnancy has been associated with ASD susceptibility. HLA-G is expressed by the trophoblast at the maternal/fetal interface and induces allogenic tolerance toward the fetus. A 14-bp insertion in the HLA-G 3'UTR (rs371194629) was associated with reduced levels of HLA-G. We aimed to assess the influence of the HLA-G*14 bp indel variant in ASD susceptibility and symptomatology in a Brazilian admixed sample. The insertion genotype (14 bp+/14 bp+) was firstly associated with hetero aggression, but statistical significance was lost after correction (p = 0.035, pcorrected = 0.35). No association between the HLA-G variant and susceptibility to ASD or differential clinical manifestations were observed.

The immunosuppressive activity of myeloid-derived suppressor cells in murine Paracoccidioidomycosis relies on Indoleamine 2,3-dioxygenase activity and Dectin-1 and TLRs signaling.

Paracoccidioidomycosis (PCM) is a systemic mycosis with a high incidence in Latin America. Prior studies have demonstrated the significance of the enzyme Indoleamine 2,3-dioxygenase (IDO-1) in the immune regulation of PCM as well as the vital role of myeloid-derived suppressor cells (MDSCs) in moderating PCM severity. Additionally, Dectin-1 and Toll-Like Receptors (TLRs) signaling in cancer, infection, and autoimmune diseases have been shown to impact MDSC-IDO-1+ activity. To expand our understanding of MDSCs and the role of IDO-1 and pattern recognition receptors (PRRs) signaling in PCM, we generated MDSCs in vitro and administered an IDO-1 inhibitor before challenging the cells with Paracoccidioides brasiliensis yeasts. By co-culturing MDSCs with lymphocytes, we assessed T-cell proliferation to examine the influence of IDO-1 on MDSC activity. Moreover, we utilized specific antibodies and MDSCs from Dectin-1, TLR4, and TLR2 knockout mice to evaluate the effect of these PRRs on IDO-1 production by MDSCs. We confirmed the importance of these in vitro findings by assessing MDSC-IDO-1+ in the lungs of mice following the fungal infection. Taken together, our data show that IDO-1 expression by MDSCs is crucial for the control of T-cell proliferation, and the production of this enzyme is partially dependent on Dectin-1, TLR2, and TLR4 signaling during murine PCM.

Exploring potential impacts of pregnancy-related maternal immune activation and extracellular vesicles on immune alterations observed in autism spectrum disorder.

Autism Spectrum Disorder (ASD) is a set of neurodevelopmental disorders usually observed in early life, with impacts on behavioral and social skills. Incidence of ASD has been dramatically increasing worldwide, possibly due to increase in awareness/diagnosis as well as to genetic and environmental triggers. Currently, it is estimated that ∼1% of the world population presents ASD symptoms. In addition to its genetic background, environmental and immune-related factors also influence the ASD etiology. In this context, maternal immune activation (MIA) has recently been suggested as a component potentially involved in ASD development. In addition, extracellular vesicles (EVs) are abundant at the maternal-fetal interface and are actively involved in the immunoregulation required for a healthy pregnancy. Considering that alterations in concentration and content of EVs have also been associated with ASD, this article raises a debate about the potential roles of EVs in the processes surrounding MIA. This represents the major differential of the present review compared to other ASD studies. To support the suggested correlations and hypotheses, findings regarding the roles of EVs during pregnancy and potential influences on ASD are discussed, along with a review and update concerning the participation of infections, cytokine unbalances, overweight and obesity, maternal anti-fetal brain antibodies, maternal fever, gestational diabetes, preeclampsia, labor type and microbiota unbalances in MIA and ASD.

Association between NKG2/KLR gene variants and epilepsy in Autism Spectrum Disorder.

Autism Spectrum Disorder (ASD) is a set of neurodevelopmental disorders mainly characterized by repetitive, restrictive and stereotypical behaviors, and impaired communication skills. Several lines of evidence indicate that alterations of the immune system account for ASD development, including the presence of brain-reactive antibodies, abnormal T cell activation, altered cytokine levels in brain, cerebrospinal fluid and peripheral blood circulation, increased levels of circulating monocytes, and dysregulation in Natural Killer (NK) cells activity. Regarding NK cells, a lower cytotoxic activity, a higher level of activation and an increased number of these cells in individuals with ASD have been described. In 2019, a study showed that NK cells derived from patients with ASD show a characteristic pattern of NKG2C overexpression, highlighting the importance of the NK cell pathway in ASD. In fact, the study of genes related to NK cell activity has proven to be an excellent research target, both in terms of susceptibility as well as a marker for the different clinical manifestations observed in ASD individuals. Here, we evaluated the influence of KLRC2 gene deletion as well as KLRK1 rs1049174 and rs2255336 variants in a cohort of 185 children diagnosed with ASD and their respective biological parents in southern Brazil. Of note, this is the first study concerning genetic variants of the KLRC2 and KLRK1 genes in an ASD sample. The KLRC2 gene deletion (p = 0.001; pc = 0.009), KLRK1 rs1049174 (p = 0.005; pc = 0.045) and KLRK1 rs2255336 (p = 0.001; pc = 0.009) were associated with epilepsy in ASD patients. The results indicate that KLRC2 deletion, KLRK1 rs2255336, and KLRK1 rs1049174 could be involved in epilepsy manifestation in ASD patients, possibly impacting the NK dysregulation already described in ASD and epileptic patients.

Myeloid-derived suppressor cells are associated with impaired Th1 and Th17 responses and severe pulmonary paracoccidioidomycosis which is reversed by anti-Gr1 therapy.

Previous studies on paracoccidioidomycosis (PCM), the most prevalent systemic mycosis in Latin America, revealed that host immunity is tightly regulated by several suppressive mechanisms mediated by tolerogenic plasmacytoid dendritic cells, the enzyme 2,3 indoleamine dioxygenase (IDO-1), and regulatory T-cells (Tregs). IDO-1 orchestrates local and systemic immunosuppressive effects through the recruitment and activation of myeloid-derived suppressor cells (MDSCs), a heterogeneous population of myeloid cells possessing a potent ability to suppress T-cell responses. However, the involvement of MDSCs in PCM remains uninvestigated. The presence, phenotype, and immunosuppressive activity of MDSCs were evaluated at 96 h, 2 weeks, and 8 weeks of pulmonary infection in C57BL/6 mice. Disease severity and immune responses were assessed in MDSC-depleted and nondepleted mice using an anti-Gr1 antibody. Both monocytic-like MDSCs (M-MDSCs) and polymorphonuclear-like MDSCs (PMN-MDSCs) massively infiltrated the lungs during Paracoccidioides brasiliensis infection. Partial reduction of MDSC frequency led to a robust Th1/Th17 lymphocyte response, resulting in regressive disease with a reduced fungal burden on target organs, diminishing lung pathology, and reducing mortality ratio compared with control IgG2b-treated mice. The suppressive activity of MDSCs on CD4 and CD8 T-lymphocytes and Th1/Th17 cells was also demonstrated in vitro using coculture experiments. Conversely, adoptive transfer of MDSCs to recipient P. brasiliensis-infected mice resulted in a more severe disease. Taken together, our data showed that the increased influx of MDSCs into the lungs was linked to more severe disease and impaired Th1 and Th17 protective responses. However, protective immunity was rescued by anti-Gr1 treatment, resulting in a less severe disease and controlled tissue pathology. In conclusion, MDSCs have emerged as potential target cells for the adjuvant therapy of PCM.

The Anti-Biofilm Efficacy of Caffeic Acid Phenethyl Ester (CAPE) In Vitro and a Murine Model of Oral Candidiasis.

Candida albicans is the main fungal species associated with the development of oral candidiasis. Currently, therapeutic options for these infections are limited by the adverse effects of antifungal drugs and by the emergence of drug resistant strains. Thus, the development of new antifungal agents is needed for the prevention and treatment of oral Candida infections. Caffeic acid phenethyl ester (CAPE) is a natural compound from propolis polyphenolic groups that exhibits many pharmacological properties. In this study, we investigated whether CAPE can have antifungal and immunomodulatory effects on oral candidiasis. Preliminary tests to assess the antifungal activity of CAPE were performed using the Minimum Inhibitory Concentration (MIC) assay that demonstrated inhibition in a range from 16 to 32 µg/mL, confirming its antifungal activity on several C. albicans strains isolated from the oral cavity. Subsequently, we analyzed Candida spp biofilms formed in vitro, in which CAPE treatment at 5 x MIC caused a reduction of 68.5% in the total biomass and ~2.60 Log in the viable cell count (CFU/mL) in relation to the untreated biofilm (p<0.0001). Next, RNA was extracted from untreated and CAPE-treated biofilms and analyzed by real-time qPCR. A series of genes analyzed (ALS1, ECE1, EPA1, HWP1, YWP1, BCR1, BGR1, CPH1, EFG1, NDT80, ROB1, TEC1, UME6, SAP2, SAP5, PBL2, and LIP9) were downregulated by CAPE compared to the untreated control group (p<0.0001). In in vivo studies using Galleria mellonella, the treatment with CAPE prolonged survival of larvae infected by C. albicans by 44.5% (p < 0.05) and accompanied by a 2.07-fold increase in the number of hemocytes. Flow cytometry revealed the most prominent increases were in types P2 and P3 hemocytes, granular cells, which phagocytize pathogens. In addition, CAPE treatment decreased the fungal load in the hemolymph and stimulated the expression of antifungal peptide genes such as galiomicin and gallerimycin. The antifungal and immunomodulatory activities observed in G. mellonella were extended to a murine model of oral candidiasis, in which CAPE decreased the levels of C. albicans colonization (~2 log CFU/mL) in relation to the untreated control group. In addition, CAPE treatment significantly reduced pseudomembranous lesions, invasion of hyphae on epithelium surfaces, tissue damage and inflammatory infiltrate (p < 0.05). CAPE was also able to increase the expression of ß-defensin 3 compared to the infected and untreated group by 3.91-fold (p < 0.0001). Taken together, these results show that CAPE has both antifungal and immunomodulatory effects, making it a promising natural antifungal agent for the treatment and prevention of candidiasis and shows impact to oral candidiasis.

Control and prevention of infectious diseases from a One Health perspective.

The ongoing COVID-19 pandemic has caught the attention of the global community and rekindled the debate about our ability to prevent and manage outbreaks, epidemics, and pandemics. Many alternatives are suggested to address these urgent issues. Some of them are quite interesting, but with little practical application in the short or medium term. To realistically control infectious diseases, human, animal, and environmental factors need to be considered together, based on the One Health perspective. In this article, we highlight the most effective initiatives for the control and prevention of infectious diseases: vaccination; environmental sanitation; vector control; social programs that encourage a reduction in the population growth; control of urbanization; safe sex stimulation; testing; treatment of sexually and vertically transmitted infections; promotion of personal hygiene practices; food safety and proper nutrition; reduction of the human contact with wildlife and livestock; reduction of social inequalities; infectious disease surveillance; and biodiversity preservation. Subsequently, this article highlights the impacts of human genetics on susceptibility to infections and disease progression, using the SARS-CoV-2 infection as a study model. Finally, actions focused on mitigation of outbreaks and epidemics and the importance of conservation of ecosystems and translational ecology as public health strategies are also discussed.

Increased systemic IL-6 levels point to inflammation as a determinant of renal cell carcinoma development

Introduction: Renal cell carcinoma (RCC) is one of the most prevalent kidney tumors. Inflammation is believed to be a key factor in its progression and spread since inflammatory markers are generally associated with poor prognosis in RCC patients. Cytokines are cell communication molecules involved in both healthy and pathological processes, including tumor growth and progression. Recent findings suggest that cytokine level measurements could be used for cancer monitoring and prognosis. Methods: This study characterized and compared the levels of different cytokines associated with the classical Th1, Th2, and Th17 immune responses in plasma samples from RCC patients (n = 25) and healthy controls (n = 29). Cytokine levels (IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ, and IL-17A) were evaluated by flow cytometry using a BD Cytometric Bead Array (CBA) kit. Results: No statistical differences in systemic IL-2, IL-4, IL-10, IL-17A, TNF, and INF-γ levels were observed between RCC patients and controls (p > 0.05). However, higher systemic IL-6 levels were observed in RCC patients (p = 0.0034). Conclusions: This study highlights the importance of assessing the impact of IL-6 on RCC pathogenesis and its potential role as a biomarker of disease progression. (AU)

Beyond HIV infection: Neglected and varied impacts of CCR5 and CCR5Δ32 on viral diseases.

The interactions between chemokine receptors and their ligands may affect susceptibility to infectious diseases as well as their clinical manifestations. These interactions mediate both the traffic of inflammatory cells and virus-associated immune responses. In the context of viral infections, the human C-C chemokine receptor type 5 (CCR5) receives great attention from the scientific community due to its role as an HIV-1 co-receptor. The genetic variant CCR5Δ32 (32 base-pair deletion in CCR5 gene) impairs CCR5 expression on the cell surface and is associated with protection against HIV infection in homozygous individuals. Also, the genetic variant CCR5Δ32 modifies the CCR5-mediated inflammatory responses in various conditions, such as inflammatory and infectious diseases. CCR5 antagonists mimic, at least in part, the natural effects of the CCR5Δ32 in humans, which explains the growing interest in the potential benefits of using CCR5 modulators for the treatment of different diseases. Nevertheless, beyond HIV infection, understanding the effects of the CCR5Δ32 variant in multiple viral infections is essential to shed light on the potential effects of the CCR5 modulators from a broader perspective. In this context, this review discusses the involvement of CCR5 and the effects of the CCR5Δ32 in human infections caused by the following pathogens: West Nile virus, Influenza virus, Human papillomavirus, Hepatitis B virus, Hepatitis C virus, Poliovirus, Dengue virus, Human cytomegalovirus, Crimean-Congo hemorrhagic fever virus, Enterovirus, Japanese encephalitis virus, and Hantavirus. Subsequently, this review addresses the impacts of CCR5 gene editing and CCR5 modulation on health and viral diseases. Also, this article connects recent findings regarding extracellular vesicles (e.g., exosomes), viruses, and CCR5. Neglected and emerging topics in "CCR5 research" are briefly described, with focus on Rocio virus, Zika virus, Epstein-Barr virus, and Rhinovirus. Finally, the potential influence of CCR5 on the immune responses to coronaviruses is discussed.

Increased IL-8 levels in HIV-infected individuals who initiated ART with CD4+ T cell counts <350 cells/mm3 - A potential hallmark of chronic inflammation.

The identification of inflammatory markers in HIV+ individuals on ART is fundamental since chronic ART-controlled HIV infection is linked to an increased inflammatory state. In this context, we assessed plasma levels of pro-inflammatory cytokines (IL-1ß, IL-8, and IL-12p70) of HIV+ individuals who initiated ART after immunosuppression (CD4+ T cell counts <350 cells/mm3). HIV+ individuals were stratified according to two extreme phenotypes: Slow Progressors (SPs; individuals with at least 8 years of infection before ART initiation) and Rapid Progressors (RPs; individuals who needed to initiate ART within 1-4 years after infection). A control group was composed of HIV-uninfected individuals. We found increased IL-8 levels (median: 5.13 pg/mL; SPs and RPs together) in HIV-infected individuals on ART as compared to controls (median: 3.2 pg/mL; p = 0.04), although no association with the progression profile (slow or rapid progressors) or CD4+ T cell counts at sampling was observed. This result indicates that IL-8 is a general marker of chronic inflammation in HIV+ individuals on ART, independently of CD4+ T cell counts at the beginning of the treatment or of the potential progression profile of the patient. In this sense, IL-8 may be considered a possible target for novel therapies focused on reducing inflammation in chronic HIV infection.

CCR5 and CCR5Δ32 in bacterial and parasitic infections: Thinking chemokine receptors outside the HIV box.

The CCR5 molecule was reported in 1996 as the main HIV-1 co-receptor. In that same year, the CCR5Δ32 genetic variant was described as a strong protective factor against HIV-1 infection. These findings led to extensive research regarding the CCR5, culminating in critical scientific advances, such as the development of CCR5 inhibitors for the treatment of HIV infection. Recently, the research landscape surrounding CCR5 has begun to change. Different research groups have realized that, since CCR5 has such important effects in the chemokine system, it could also affect other different physiological systems. Therefore, the effect of reduced CCR5 expression due to the presence of the CCR5Δ32 variant began to be further studied. Several studies have investigated the role of CCR5 and the impacts of CCR5Δ32 on autoimmune and inflammatory diseases, various types of cancer, and viral diseases. However, the role of CCR5 in diseases caused by bacteria and parasites is still poorly understood. Therefore, the aim of this article is to review the role of CCR5 and the effects of CCR5Δ32 on bacterial (brucellosis, osteomyelitis, pneumonia, tuberculosis and infection by Chlamydia trachomatis) and parasitic infections (toxoplasmosis, leishmaniasis, Chagas disease and schistosomiasis). Basic information about each of these infections was also addressed. The neglected role of CCR5 in fungal disease and emerging studies regarding the action of CCR5 on regulatory T cells are briefly covered in this review. Considering the "renaissance of CCR5 research," this article is useful for updating researchers who develop studies involving CCR5 and CCR5Δ32 in different infectious diseases.

Extracellular vesicles in host-pathogen interactions and immune regulation - exosomes as emerging actors in the immunological theater of pregnancy.

This review correlates and summarizes the role of the maternal-fetal interface in the immune tolerance of the fetus and the processes that lead to infection avoidance, emphasizing the participation of exosomes and other extracellular vesicles in both situations. Exosomes are released into the extracellular medium by several cell types and are excellent carriers of biomolecules. Host-derived exosomes and the transport of pathogen-derived molecules by exosomes impact infections in different ways. The interactions of exosomes with the maternal immune system are pivotal to a favorable gestational outcome. In this review, we highlight the potential role of exosomes in the establishment of an adequate milieu that enables embryo implantation and discuss the participation of exosomes released at the maternal-fetal interface during the establishment of an immune-privileged compartment for fetal development. The placenta is a component where important strategies are used to minimize the risk of infection. To present a contrast, we also discuss possible mechanisms used by pathogens to cross the maternal-fetal interface. We review the processes, mechanisms, and potential consequences of dysregulation in all of the abovementioned phenomena. Basic information about exosomes and their roles in viral immune evasion is also presented. The interactions between extracellular vesicles and bacteria, fungi, parasites and proteinaceous infectious agents are addressed. The discovery of the placental microbiota and the implications of this new microbiota are also discussed, and current proposals that explain fetal/placental colonization by both pathogenic and commensal microbes are addressed. The comprehension of such interactions will help us to understand the immune dynamics of human pregnancy and the mechanisms of immune evasion used by different pathogens.

Emerging infectious disease prevention: Where should we invest our resources and efforts?

Strategies focused on the prevention of emerging infectious disease outbreaks are currently in the spotlight of discussions among researchers committed to infectious disease control. In this mini-review, we provided a brief update on this discussion and characterized the three main targets for investments in emerging infectious disease prevention: animals, human sentinels for spillover events, and the general human population. Furthermore, the pros and cons of each target are highlighted. Despite the particularities of the proposed targets, each of them can fill different gaps in the surveillance of infectious diseases. When all three targets are focused on together, they create a powerful strategy of emerging infectious disease prevention.

Influence of NKG2C gene deletion and CCR5Δ32 in Pre-eclampsia-Approaching the effect of innate immune gene variants in pregnancy.

Pre-eclampsia (PE) is a hypertensive disorder that affects an important number of pregnant women worldwide. The exact causes of PE remain poorly understood. However, inflammation and deregulation of innate immune cells, such as natural killer (NK) cells, contribute to PE pathogenesis. Besides, the mother's genetic background also impacts on PE susceptibility. Thus, genetic variants that potentially modify the behaviour of inflammatory cells may help us to understand the causes of PE. Variants of genes encoding NKG2C (expressed in NK cells) and C-C chemokine receptor type 5 (CCR5) (expressed mainly in leucocytes) are important targets in the study of gestational disorders. In this context, we evaluated the impact of both NKGC2 gene deletion and CCR5Δ32 gene variant on PE susceptibility in a population sample from central-southeast Brazil composed by 369 women (156 with PE and 213 healthy pregnant women). No statistically significant association between the NKG2C gene deletion and susceptibility to PE was observed. However, taking into consideration the important role of NK cells in pregnancy, the influence of NKG2C gene deletion on PE pathogenesis should not be ruled out and deserves further studies in populations with different genetic/ethnic backgrounds. In addition, our results regarding CCR5Δ32 corroborate previous data from our group approaching a distinct cohort and reinforce CCR5Δ32 as a protective factor against PE development (p < 0.05).

IL-17 blood levels increase in healthy pregnancy but not in spontaneous abortion.

Cytokines are essential to maintain and coordinate the correct activity of immune cells during human pregnancy. IL-17 is a pro-inflammatory cytokine that induces the expression of many inflammatory mediators. The aim of this study was to compare the levels of Th1, Th2 and Th17 cytokines of women ongoing normal pregnancy with those found in women who suffered spontaneous abortion. IL-2, IL-4, IL-6, IL-10, IL-17, TNF-α, and IFN-γ peripheral blood levels were measured in women who suffered spontaneous abortion (n = 13, blood collected up to 24 h after abortion), and were compared with healthy successful pregnancies (n = 16). Cytokine levels were measured using a cytometric bead array (CBA analysis). Similar cytokine levels were observed between spontaneous abortion and healthy pregnant women excepted to IL-17, which levels were increased in the healthy pregnant women (p = 0.0232). Our results show high IL-17 levels in the peripheral blood of women at late stages of healthy pregnancy, although low IL-17 levels were detected in the peripheral blood of women just after spontaneous abortion. In line with recent studies, this finding highlights IL-17 as a regulatory cytokine essential to the maintenance of a successful pregnancy.

Genetic Variants in Preeclampsia: Lessons From Studies in Latin-American Populations.

Placental vascularization is a tightly regulated physiological process in which the maternal immune system plays a fundamental role. Vascularization of the maternal-placental interface involves a wide range of mechanisms primarily orchestrated by the fetal extravillous trophoblast and maternal immune cells. In a healthy pregnancy, an immune cross-talk between the mother and fetal cells results in the secretion of immunomodulatory mediators, apoptosis of specific cells, cellular differentiation/proliferation, angiogenesis, and vasculogenesis, altogether favoring a suitable microenvironment for the developing embryo. In the context of vasculopathy underlying common pregnancy disorders, it is believed that inefficient invasion of extravillous trophoblast cells in the endometrium leads to a poor placental blood supply, which, in turn, leads to decreased secretion of angiogenic factors, hypoxia, and inflammation commonly associated with preterm delivery, intrauterine growth restriction, and preeclampsia. In this review, we will focus on studies published by Latin American research groups, providing an extensive review of the role of genetic variants from candidate genes involved in a broad spectrum of biological processes underlying the pathophysiology of preeclampsia. In addition, we will discuss how these studies contribute to fill gaps in the current understanding of preeclampsia. Finally, we discuss some trending topics from important fields associated with pregnancy vascular disorders (e.g., epigenetics, transplantation biology, and non-coding RNAs) and underscore their possible implications in the pathophysiology of preeclampsia. As a result, these efforts are expected to give an overview of the extent of scientific research produced in Latin America and encourage multicentric collaborations by highlighted regional research groups involved in preeclampsia investigation.

Immunogenetic studies of the hepatitis C virus infection in an era of pan-genotype antiviral therapies - Effective treatment is coming.

What are the factors that influence human hepatitis C virus (HCV) infection, hepatitis status establishment, and disease progression? Firstly, one has to consider the genetic background of the host and HCV genotypes. The immunogenetic host profile will reflect how each infected individual deals with infection. Secondly, there are environmental factors that drive susceptibility or resistance to certain viral strains. These will dictate (I) the susceptibility to infection; (II) whether or not an infected person will promote viral clearance; (III) the immune response and the response profile to therapy; and (IV) whether and how long it would take to the development of HCV-associated diseases, as well as their severity. Looking at this scenario, this review addresses clinical aspects of HCV infection, following by an update of molecular and cellular features of the immune response against the virus. The evasion mechanisms used by HCV are presented, considering the potential role of exosomes in infection. Genetic factors influencing HCV infection and pathogenesis are the main topics of the article. Shortly, HLAs, MBLs, TLRs, ILs, and IFNLs genes have relevant roles in the susceptibility to HCV infection. In addition, ILs, IFNLs, as well as TLRs genes are important modulators of HCV-associated diseases. The viral aspects that influence HCV infection are presented, followed by a discussion about evolutionary aspects of host and HCV interaction. HCV and HIV infections are close related. Thus, we also present a discussion about HIV/HCV co-infection, focusing on cellular and molecular aspects of this interaction. Pharmacogenetics and treatment of HCV infection are the last topics of this review. The understanding of how the host genetics interacts with viral and environmental factors is crucial for the development of new strategies to prevent HCV infection, even in an era of potential development of pan-genotypic antivirals.