Cystatin from the helminth Ascaris lumbricoides upregulates mevalonate and cholesterol biosynthesis pathways and immunomodulatory genes in human monocyte-derived dendritic cells.

Background: Ascaris lumbricoides cystatin (Al-CPI) prevents the development of allergic airway inflammation and dextran-induced colitis in mice models. It has been suggested that helminth-derived cystatins inhibit cathepsins in dendritic cells (DC), but their immunomodulatory mechanisms are unclear. We aimed to analyze the transcriptional profile of human monocyte-derived DC (moDC) upon stimulation with Al-CPI to elucidate target genes and pathways of parasite immunomodulation. Methods: moDC were generated from peripheral blood monocytes from six healthy human donors of Denmark, stimulated with 1 µM of Al-CPI, and cultured for 5 hours at 37°C. RNA was sequenced using TrueSeq RNA libraries and the NextSeq 550 v2.5 (75 cycles) sequencing kit (Illumina, Inc). After QC, reads were aligned to the human GRCh38 genome using Spliced Transcripts Alignment to a Reference (STAR) software. Differential expression was calculated by DESEq2 and expressed in fold changes (FC). Cell surface markers and cytokine production by moDC were evaluated by flow cytometry. Results: Compared to unstimulated cells, Al-CPI stimulated moDC showed differential expression of 444 transcripts (|FC| ≥1.3). The top significant differences were in Kruppel-like factor 10 (KLF10, FC 3.3, PBH = 3 x 10-136), palladin (FC 2, PBH = 3 x 10-41), and the low-density lipoprotein receptor (LDLR, FC 2.6, PBH = 5 x 10-41). Upregulated genes were enriched in regulation of cholesterol biosynthesis by sterol regulatory element-binding proteins (SREBP) signaling pathways and immune pathways. Several genes in the cholesterol biosynthetic pathway showed significantly increased expression upon Al-CPI stimulation, even in the presence of lipopolysaccharide (LPS). Regarding the pathway of negative regulation of immune response, we found a significant decrease in the cell surface expression of CD86, HLA-DR, and PD-L1 upon stimulation with 1 µM Al-CPI. Conclusion: Al-CPI modifies the transcriptome of moDC, increasing several transcripts encoding enzymes involved in cholesterol biosynthesis and SREBP signaling. Moreover, Al-CPI target several transcripts in the TNF-alpha signaling pathway influencing cytokine release by moDC. In addition, mRNA levels of genes encoding KLF10 and other members of the TGF beta and the IL-10 families were also modified by Al-CPI stimulation. The regulation of the mevalonate pathway and cholesterol biosynthesis suggests new mechanisms involved in DC responses to helminth immunomodulatory molecules.

The Relationship of Parasite Allergens to Allergic Diseases.

PURPOSE OF REVIEW: Helminth infections modify the natural history of allergic diseases, by either decreasing or increasing their symptoms. Several helminth components are involved in the increasing of the allergic response and symptoms, overcoming the concomitant immunosuppression of helminthiases. However, the role of individual IgE-binding molecules in this process remains to be defined. RECENT FINDINGS: We updated the list of helminth allergens and IgE-binding molecules, their effects on asthma presentation, and their impact on allergy diagnosis. Data from genetic and epigenetic studies of ascariasis are analyzed. A new species-specific A. lumbricoides allergen has been discovered, with potential use in molecular diagnosis. Most helminth IgE-binding components are not officially classified as allergens in the WHO/IUIS database, although there is evidence of their influence increasing allergic manifestations. Further immunological characterization of these components is needed to better understand their mechanisms of action and evaluate the ways in which they can influence the diagnosis of allergy.

Serious neurological adverse events following immunization against SARS-CoV-2: a narrative review of the literature.

Amid the coronavirus disease 2019 (COVID-19) pandemic, massive immunization campaigns became the most promising public health measure. During clinical trials, certain neurological adverse effects following immunization (AEFIs) were observed; however, acceptable safety profiles lead to emergency authorization for the distribution and use of the vaccines. To contribute to pharmacovigilance and lessen the potential negative impact that vaccine hesitancy would have on immunization programs, we conducted a review of the scientific literature concerning the epidemiological data, clinical presentation, and potential mechanisms of these neurological AEFIs. There is some epidemiological evidence linking COVID-19 vaccines to cerebral venous sinus thrombosis, arterial ischemic stroke, convulsive disorder, Guillain-Barré syndrome, facial nerve palsy, and other neurological conditions. Cerebral venous sinus thrombosis has been associated with a thrombotic thrombocytopenia induced by the vaccine, similar to that induced by heparin, which suggests similar pathogenic mechanisms (likely involving antibodies against platelet factor 4, a chemokine released from activated platelets). Arterial ischemic stroke is another thrombotic condition observed among some COVID-19 vaccine recipients. Vaccine-induced convulsive disorder might be the result of structural abnormalities potentially caused by the vaccine or autoimmune mechanisms. Guillain-Barré syndrome and facial nerve palsy may also be linked to the immunization event, possibly due to immune mechanisms such as uncontrolled cytokine release, autoantibody production, or bystander effect. However, these events are mostly uncommon and the evidence for the association with the vaccine is not conclusive. Furthermore, the potential pathophysiological mechanisms remain largely unknown. Nevertheless, neurological AEFIs can be serious, life-threatening or even fatal. In sum, COVID-19 vaccines are generally safe and the risk of neurological AEFIs does not outweigh the benefits of immunization. However, early diagnosis and treatment of neurological AEFIs are of utmost importance, and both health professionals and the public should be aware of these conditions.

A review of undesired effects involving the nervous system following the administration of COVID-19 vaccines Among the range of complications that can occur after a vaccine, some of them can affect the nervous system and its vasculature. This narrative review aims to evaluate some serious neurological conditions following COVID-19 vaccination. We searched biomedical journal databases where physicians around the globe reported different complications after the administration of different COVID-19 vaccines. Besides reports of cases in individual patients or small groups, we reviewed studies that included bigger groups of patients (e.g. vaccinated versus non-vaccinated) and compared the occurrence of these events between them. We found that after the administration of a certain type of vaccine (e.g. ChAdOx1-S/Oxford, AstraZeneca vaccine), serious neurological complications were rare, with abnormal clot formation involving cerebral blood vessels being one of the most important among them. Nonetheless, other conditions have been observed after the administration of the vaccines; however, it is not certain yet if the vaccines are the actual cause of these complications. There are some hypotheses that could explain why these adverse reactions take place after a vaccine. For instance, an abnormal immune response to the vaccine leads to the production of antibodies (i.e. proteins made by the immune system in response to the presence of a foreign substance). These antibodies trigger a response that could eventually result in clot formation. Besides, the immune response can also produce other adverse effects, including convulsive disorder, Guillain­Barré syndrome, and facial nerve palsy. Scientific evidence suggests that vaccines are safe overall. While mild complications, such as pain at the site of injection or bruising might occur, more serious events remain rare. Furthermore, the complications derived from COVID-19 are far more likely in non-vaccinated individuals than the complications associated with the vaccine. Thus, vaccination continues to be the safest and most effective strategy to control the ongoing pandemic. However, both health professionals and the public should be aware of the possibility of serious neurological adverse reactions occurring after vaccination to allow early diagnosis and treatment.

Kawasaki disease in Colombia: A systematic review and contrast with multisystem inflammatory syndrome in children associated with COVID-19

Introduction: Kawasaki disease (KD) is an acute vasculitis with multisystem involvement. Recently, the increasing incidence of a condition that closely resembles KD in many cases, named multisystem inflammatory syndrome in children (MIS-C), has set off alarms amid the current worldwide coronavirus disease-19 (COVID-19) pandemic. Hence, the aim is to conduct a systematic review of the literature about KD in Colombia and contrast it with COVID-19-related MIS-C. Materials and methods: A search was carried out in both international and Latin American electronic databases for publications concerning patients with KD in the Colombian population. Records were then screened by titles and/or abstracts, assessed for eligibility, and reviewed. Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines were followed. The search included studies reporting MIS-C associated with COVID-19, and compared these patients with our findings of KD in Colombia. Results: Out of 36 publications retrieved, 17 were included, representing 120 individuals. Male to female ratio was 1.6, and most patients (90.4%) were aged 5 years or less. Among the main features of KD, fever was the most frequent (96.2% of the patients), while cervical lymphadenopathy was present in only 40.6%. Intravenous immunoglobulin was administered in 91.4% cases and 6.2% were resistant. Cardiac involvement was found in around 30%, and 20% had coronary artery lesions. Comparison between MIS-C associated with COVID-19 and KD in Colombia indicates that patients affected by MIS-C were older (72.2% of MIS-C patients > 5 years), had higher rates of cardiac involvement, and required critical care more often. Conclusions: Our findings of KD in Colombia are consistent with the available descriptions of KD in the scientific literature. Given the increasing rate of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in Colombia and Latin America, our study raises awareness about MIS-C in pediatric patients with COVID-19 and its relationship with KD.

Introducción: La enfermedad de Kawasaki (EK) es una vasculitis aguda con compromiso multisistémico. Recientemente, la incidencia creciente de una condición que se asemeja en forma considerable a la EK en muchos casos, denominada síndrome inflamatorio multisistémico (SIMS) en niños, ha encendido las alarmas en medio de la actual pandemia mundial de la enfermedad COVID-19. Por consiguiente, nos propusimos realizar una revisión sistemática de la literatura acerca de la EK en Colombia y contrastarla con el SIMS relacionado con COVID-19 en niños. Materiales y métodos: Buscamos publicaciones respecto a pacientes con EK en población colombiana, en bases de datos electrónicas tanto internacionales como latinoamericanas. Los registros hallados fueron tamizados por títulos o resúmenes, evaluados para elegibilidad y revisados. Se siguieron las guías Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). Posteriormente, buscamos estudios que reportaran SIMS temporalmente asociado con COVID-19 en niños y comparamos estos pacientes con nuestros hallazgos de EK en Colombia. Resultados: De 36 publicaciones encontradas se incluyeron 17, las cuales representaron 120 individuos. La razón hombre a mujer fue de 1,6 y la mayoría de los pacientes (90,4%) tenía 5 anos o menos. Entre las principales características de EK, la fiebre fue la más frecuente (96,2%), mientras que la linfadenopatía cervical estuvo presente solo en el 40,6%. La inmunoglobulina intravenosa se administró en el 91,4% de los casos y 6,2% presentaron resistencia. Se encontró compromiso cardiaco en alrededor del 30% de los pacientes, en tanto que el 20% tuvo lesiones de arterias coronarias. La comparación entre las características clínicas de la EK y el SIMS asociado a COVID-19 mostró que los individuos afectados por el SIMS eran mayores (72,2% con SIMS tenían más de cinco anos), tuvieron mayores índices de compromiso cardiaco y requirieron cuidado crítico con mayor frecuencia. Conclusiones: Nuestros hallazgos de EK en Colombia son consistentes con las descripciones disponibles de esta enfermedad en la literatura científica. Debido al aumento de infección por SARS-CoV-2 en Colombia y Latinoamérica, nuestro estudio busca crear conciencia sobre el SIMS en pacientes pediátricos con COVID-19 y su relación con la EK.

Helminths and Bacterial Microbiota: The Interactions of Two of Humans' "Old Friends".

Humans have coexisted with helminths and bacteria for the entire existence of our species. Nowadays, helminth infections affect more than 1.9 billion people worldwide, especially in underdeveloped regions that lack optimal sanitary conditions. In addition, commensal microorganisms inhabit several compartments of humans, including the gastrointestinal tract, constituting what we know as the microbiota. Helminths and bacterial microbiota can interact in various ways. In this review, the interactions between helminths and commensal bacteria are analyzed in both animal models and humans. In developing countries, the gut microbiota exhibits high diversity, which could be linked to the high burden of helminthiasis in these areas. In fact, several studies show that helminth infections are associated with an increased gut microbiota diversity and changes in its composition. Interestingly, these changes can modify the risk for some diseases, such as asthma, colitis, viral infections, and metabolic conditions. Besides, the microbiota is necessary for the establishment of some helminth infections and can also influence the evolution of these diseases. Specific bacterial taxa can contribute to the resistance or susceptibility to certain helminths. The mechanisms underlying helminth-microbiota interactions are not completely understood. More research is necessary to address this and other unmet needs, especially considering that available studies are heterogeneous and sometimes yield conflicting results.

Genetic and Molecular Aspects of Drug-Induced QT Interval Prolongation.

Long QT syndromes can be either acquired or congenital. Drugs are one of the many etiologies that may induce acquired long QT syndrome. In fact, many drugs frequently used in the clinical setting are a known risk factor for a prolonged QT interval, thus increasing the chances of developing torsade de pointes. The molecular mechanisms involved in the prolongation of the QT interval are common to most medications. However, there is considerable inter-individual variability in drug response, thus making the application of personalized medicine a relevant aspect in long QT syndrome, in order to evaluate the risk of every individual from a pharmacogenetic standpoint.

Perinatal and Early-Life Nutrition, Epigenetics, and Allergy.

Epidemiological studies have shown a dramatic increase in the incidence and the prevalence of allergic diseases over the last several decades. Environmental triggers including risk factors (e.g., pollution), the loss of rural living conditions (e.g., farming conditions), and nutritional status (e.g., maternal, breastfeeding) are considered major contributors to this increase. The influences of these environmental factors are thought to be mediated by epigenetic mechanisms which are heritable, reversible, and biologically relevant biochemical modifications of the chromatin carrying the genetic information without changing the nucleotide sequence of the genome. An important feature characterizing epigenetically-mediated processes is the existence of a time frame where the induced effects are the strongest and therefore most crucial. This period between conception, pregnancy, and the first years of life (e.g., first 1000 days) is considered the optimal time for environmental factors, such as nutrition, to exert their beneficial epigenetic effects. In the current review, we discussed the impact of the exposure to bacteria, viruses, parasites, fungal components, microbiome metabolites, and specific nutritional components (e.g., polyunsaturated fatty acids (PUFA), vitamins, plant- and animal-derived microRNAs, breast milk) on the epigenetic patterns related to allergic manifestations. We gave insight into the epigenetic signature of bioactive milk components and the effects of specific nutrition on neonatal T cell development. Several lines of evidence suggest that atypical metabolic reprogramming induced by extrinsic factors such as allergens, viruses, pollutants, diet, or microbiome might drive cellular metabolic dysfunctions and defective immune responses in allergic disease. Therefore, we described the current knowledge on the relationship between immunometabolism and allergy mediated by epigenetic mechanisms. The knowledge as presented will give insight into epigenetic changes and the potential of maternal and post-natal nutrition on the development of allergic disease.

Whole-Exome Sequencing in Patients Affected by Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Reveals New Variants Potentially Contributing to the Phenotype.

BACKGROUND: Adverse drug reactions (ADRs) are frequent occurring events that can essentially be defined as harmful or unpleasant symptoms secondary to the use of a medicinal product. ADRs involve a wide spectrum of clinical manifestations ranging from minor itching and rash to life-threatening reactions. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare ADRs. SJS-TEN may be considered a polygenic pathology due to additive/epistatic effects caused by sequence variants in numerous genes. Next-generation sequencing (NGS) represents a potentially interesting exploration tool in such scenario as it facilitates the simultaneous analysis of large genomic regions and genes at affordable cost. METHODS: The present study has involved using whole-exome sequencing (WES) for the first time on SJS-TEN patients. It involved robust and innovative multistep bioinformatics analysis focusing on 313 candidate genes potentially participating in the disease's aetiology, specific drugs' metabolism and gene regulation. RESULTS: We identified combinations of frequently occurring and rare variants that may contribute to the disease's pathogenesis. Depending on the specific drug being taken, different variants (and alleles) in NAT2, CYP2D8, CYP2B6, ABCC2, UGT2B7 and TCF3 were identified as coherent candidates representing potential future markers for SJS-TEN. CONCLUSION: The present study proposed and has described (for the first time) a large-scale genomic analysis of patients affected by SJS-TEN. The genes and variants identified represent relevant candidates potentially participating in the disease's pathogenesis. Corroborating that proposed by others, we found that complex combinations of frequently occurring and rare variants participating in particular drug metabolism molecular cascades could be associated with the phenotype. TCF3 TF may be considered a coherent candidate for SJS-TEN that should be analysed in new cohorts of patients having ADRs.