The rare DRB1*04:08-DQ8 haplotype is the main HLA class II genetic driver and discriminative factor of Early-onset Type 1 diabetes in the Portuguese population.

Introduction: Early-onset Type 1 diabetes (EOT1D) is considered a disease subtype with distinctive immunological and clinical features. While both Human Leukocyte Antigen (HLA) and non-HLA variants contribute to age at T1D diagnosis, detailed analyses of EOT1D-specific genetic determinants are still lacking. This study scrutinized the involvement of the HLA class II locus in EOT1D genetic control.

Targeting circulating labile heme as a defense strategy against malaria.

Severe presentations of malaria emerge as parasites invade and lyse red blood cells (RBC), producing extracellular hemoglobin (HB), from which labile heme is released. Here, we tested whether scavenging of extracellular HB and/or labile heme, by haptoglobin (HP) and/or hemopexin (HPX), respectively, counter the pathogenesis of severe presentations of malaria. We found that circulating labile heme is an independent risk factor for cerebral and non-cerebral presentations of severe malaria in children.

Corrigendum: Brain endothelial cells exposure to malaria parasites links type I interferon signalling to antigen presentation, immunoproteasome activation, endothelium disruption, and cellular metabolism.

[This corrects the article DOI: 10.3389/fimmu.2023.

Endothelial type I interferon response and brain diseases: identifying STING as a therapeutic target.

The endothelium layer lining the inner surface of blood vessels serves relevant physiological functions in all body systems, including the exchanges between blood and extravascular space. However, endothelial cells also participate in innate and adaptive immune response that contribute to the pathophysiology of inflammatory disorders. Type I Interferon (IFN) signaling is an inflammatory response triggered by a variety of pathogens, but it can also be induced by misplaced DNA in the cytosol caused by cell stress or gene mutations.

Brain endothelial cells exposure to malaria parasites links type I interferon signalling to antigen presentation, immunoproteasome activation, endothelium disruption, and cellular metabolism.

Introduction: Cerebral malaria (CM) lethality is attributable to induction of brain edema induction but the cellular mechanisms involving brain microvascular endothelium in CM pathogenesis are unexplored.

Results: Activation of the STING-INFb-CXCL10 axis in brain endothelial cells (BECs) is a prominent component of the innate immune response in CM development in mouse models. Using a T cell-reporter system, we show that Type 1 IFN signaling in BECs exposed to -infected erythrocytes (-IE), functionally enhances MHC Class-I antigen presentation through gamma-interferon independent immunoproteasome activation and impacted the proteome functionally related to vesicle trafficking, protein processing/folding and antigen presentation.

In vitro model of brain endothelial cell barrier reveals alterations induced by Plasmodium blood stage factors.

Cerebral malaria (CM) is a severe neurological condition caused by Plasmodium falciparum. Disruption of the brain-blood barrier (BBB) is a key pathological event leading to brain edema and vascular leakage in both humans and in the mouse model of CM. Interactions of brain endothelial cells with infected red blood cells (iRBCs) and with circulating inflammatory mediators and immune cells contribute to BBB dysfunction in CM.

Clinical Features Related to Severity and Mortality among COVID-19 Patients in a Pre-Vaccine Period in Luanda, Angola.

Background: Infection due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with clinical features of diverse severity. Few studies investigated the severity and mortality predictors of coronavirus disease 2019 (COVID-19) in Africa. Herein, we investigated the clinical features of severity and mortality among COVID-19 patients in Luanda, Angola.

Brain endothelial STING1 activation by -sequestered heme promotes cerebral malaria via type I IFN response.

Cerebral malaria (CM) is a life-threatening form of infection caused by brain inflammation. Brain endothelium dysfunction is a hallmark of CM pathology, which is also associated with the activation of the type I interferon (IFN) inflammatory pathway. The molecular triggers and sensors eliciting brain type I IFN cellular responses during CM remain largely unknown.

Prediabetes blunts DPP4 genetic control of postprandial glycaemia and insulin secretion.

Aims/hypothesis: Imbalances in glucose metabolism are hallmarks of clinically silent prediabetes (defined as impaired fasting glucose and/or impaired glucose tolerance) representing dysmetabolism trajectories leading to type 2 diabetes. CD26/dipeptidyl peptidase 4 (DPP4) is a clinically proven molecular target of diabetes-controlling drugs but the DPP4 gene control of dysglycaemia is not proven.

Methods: We dissected the genetic control of post-OGTT and insulin release responses by the DPP4 gene in a Portuguese population-based cohort of mainly European ancestry that comprised individuals with normoglycaemia and prediabetes, and in mouse experimental models of Dpp4 deficiency and hyperenergetic diet.

Individual variation in susceptibility or exposure to SARS-CoV-2 lowers the herd immunity threshold.

Individual variation in susceptibility and exposure is subject to selection by natural infection, accelerating the acquisition of immunity, and reducing herd immunity thresholds and epidemic final sizes. This is a manifestation of a wider population phenomenon known as "frailty variation". Despite theoretical understanding, public health policies continue to be guided by mathematical models that leave out considerable variation and as a result inflate projected disease burdens and overestimate the impact of interventions.

Longitudinal Analysis of Antibody Responses to the mRNA BNT162b2 Vaccine in Patients Undergoing Maintenance Hemodialysis: A 6-Month Follow-Up.

Patients on hemodialysis (HD) are at higher risk for COVID-19, overall are poor responders to vaccines, and were prioritized in the Portuguese vaccination campaign. This work aimed at evaluating in HD patients the immunogenicity of BTN162b2 after the two doses induction phase, the persistence of specific antibodies along time, and factors predicting these outcomes. We performed a prospective, 6-month long longitudinal cohort analysis of 156 HD patients scheduled to receive BTN162b2.

Signatures in SARS-CoV-2 spike protein conferring escape to neutralizing antibodies.

Understanding SARS-CoV-2 evolution and host immunity is critical to control COVID-19 pandemics. At the core is an arms-race between SARS-CoV-2 antibody and angiotensin-converting enzyme 2 (ACE2) recognition, a function of the viral protein spike. Mutations in spike impacting antibody and/or ACE2 binding are appearing worldwide, imposing the need to monitor SARS-CoV2 evolution and dynamics in the population.

Insights into Macrophage/Monocyte-Endothelial Cell Crosstalk in the Liver: A Role for Trem-2.

Liver disease accounts for millions of deaths worldwide annually being a major cause of global morbidity. Hepatotoxic insults elicit a multilayered response involving tissue damage, inflammation, scar formation, and tissue regeneration. Liver cell populations act coordinately to maintain tissue homeostasis and providing a barrier to external aggressors.

Loss of postprandial insulin clearance control by Insulin-degrading enzyme drives dysmetabolism traits.

Systemic insulin availability is determined by a balance between beta-cell secretion capacity and insulin clearance (IC). Insulin-degrading enzyme (IDE) is involved in the intracellular mechanisms underlying IC. The liver is a major player in IC control yet the role of hepatic IDE in glucose and lipid homeostasis remains unexplored.

Trem-2 Promotes Emergence of Restorative Macrophages and Endothelial Cells During Recovery From Hepatic Tissue Damage.

Macrophages are pivotal in mounting liver inflammatory and tissue repair responses upon hepatic injury, showing remarkable functional plasticity. The molecular mechanisms determining macrophage transition from inflammatory to restorative phenotypes in the damaged liver remain unclear. Using mouse models of acute (APAP) and chronic (CCl4) drug-induced hepatotoxic injury we show that the immune receptor Trem-2 controls phenotypic shifts of liver macrophages and impacts endothelial cell differentiation during tissue recovery.

Metabolic Footprint, towards Understanding Type 2 Diabetes beyond Glycemia.

Type 2 diabetes (T2D) heterogeneity is a major determinant of complications risk and treatment response. Using cluster analysis, we aimed to stratify glycemia within metabolic multidimensionality and extract pathophysiological insights out of metabolic profiling. We performed a cluster analysis to stratify 974 subjects (PREVADIAB2 cohort) with normoglycemia, prediabetes, or non-treated diabetes.

Individual variation in susceptibility or exposure to SARS-CoV-2 lowers the herd immunity threshold.

Individual variation in susceptibility and exposure is subject to selection by natural infection, accelerating the acquisition of immunity, and reducing herd immunity thresholds and epidemic final sizes. This is a manifestation of a wider population phenomenon known as "frailty variation". Despite theoretical understanding, public health policies continue to be guided by mathematical models that leave out considerable variation and as a result inflate projected disease burdens and overestimate the impact of interventions.

Inflammasome activation and IL-1 signaling during placental malaria induce poor pregnancy outcomes.

Placental malaria (PM) is associated with severe inflammation leading to abortion, preterm delivery, and intrauterine growth restriction. Innate immunity responses play critical roles, but the mechanisms underlying placental immunopathology are still unclear. Here, we investigated the role of inflammasome activation in PM by scrutinizing human placenta samples from an endemic area and ablating inflammasome components in a PM mouse model.

Intravital imaging of host-parasite interactions in organs of the thoracic and abdominopelvic cavities.

Infections with protozoan and helminthic parasites affect multiple organs in the mammalian host. Imaging pathogens in their natural environment takes a more holistic view on biomedical aspects of parasitic infections. Here, we focus on selected organs of the thoracic and abdominopelvic cavities most commonly affected by parasites.

Genetics of Malaria Inflammatory Responses: A Pathogenesis Perspective.

Despite significant progress in combating malaria in recent years the burden of severe disease and death due to infections remains a global public health concern. Only a fraction of infected people develops severe clinical syndromes motivating a longstanding search for genetic determinants of malaria severity. Strong genetic effects have been repeatedly ascribed to mutations and allelic variants of proteins expressed in red blood cells but the role of inflammatory response genes in disease pathogenesis has been difficult to discern.

Maternal-Fetal Conflict During Infection: Lessons From a Mouse Model of Placental Malaria.

Infections that reach the placenta via maternal blood can target the fetal-placental barrier and are associated with reduced birth weight, increased stillbirth, miscarriage and perinatal mortality. Malaria during pregnancy can lead to infection of the placental tissue and to adverse effects on the unborn child even if the parasite is successfully cleared, indicating that placental sufficiency is significantly compromised. Human samples and animal models of placental malaria have been used to unravel mechanisms contributing to this insufficiency and have implicated molecular pathways related to inflammation, innate immunity and nutrient transport.