Enfermedad celiaca

Celiac disease is an autoimmune disorder. Unleashed by the attack of immune cells. Against the cells of the intestinal mucosa. Is Immune activation produces inflammation Chronic (constant) that ends up atrophying.(destroying) the villi of the cells. intestinal, which are necessary to absorb correctly the food. This makes We can absorb well the nutrients found in theThe food and we weaken.La enfermedad celiaca es un desorden autoinmune provocado por el ataque de células inmunológicas contra las células de la mucosa intestinal. Esta activación inmunológica produce una inflamación crónica (constante) que termina atrofiando (destruyendo) las vellosidades de las células intestinales, las cuales son necesarias para absorber correctamente los alimentos. Esto provoca que no podamos absorber bien los nutrientes que están en la comida y nos debilitamos.&nbsp

Perturbation-Based Modeling Unveils the Autophagic Modulation of Chemosensitivity and Immunogenicity in Breast Cancer Cells

In the absence of new therapeutic strategies, chemotherapeutic drugs are the most widely used strategy against metastatic breast cancer, in spite of eliciting multiple adverse effects and having low responses with an average 5-year patient survival rate. Among the new therapeutic targets that are currently in clinical trials, here, we addressed the association between the regulation of the metabolic process of autophagy and the exposure of damage-associated molecular patterns associated (DAMPs) to immunogenic cell death (ICD), which has not been previously studied. After validating an mCHR-GFP tandem LC3 sensor capacity to report dynamic changes of the autophagic metabolic flux in response to external stimuli and demonstrating that both basal autophagy levels and response to diverse autophagy regulators fluctuate among different cell lines, we explored the interaction between autophagy modulators and chemotherapeutic agents in regards of cytotoxicity and ICD using three different breast cancer cell lines. Since these interactions are very complex and variable throughout different cell lines, we designed a perturbation-based model in which we propose specific modes of action of chemotherapeutic agents on the autophagic flux and the corresponding strategies of modulation to enhance the response to chemotherapy. Our results point towards a promising therapeutic potential of the metabolic regulation of autophagy to overcome chemotherapy resistance by eliciting ICD.Universidad de Costa Rica/[803-B6-600]/UCR/Costa RicaUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Centro de Investigación en Enfermedades Tropicales (CIET)UCR::Vicerrectoría de Docencia::Salud::Facultad de Microbiologí

Gastric cancer in the era of immune checkpoint blockade

Gastric cancer (GC) is one of the most important malignancies worldwide because of its high incidence and mortality. The very low survival rates are mainly related to late diagnosis and limited treatment options. GC is the final clinical outcome of a stepwise process that starts with a chronic and sustained inflammatory reaction mounted in response to Helicobacter pylori infection. The bacterium modulates innate and adaptive immunity presumably as part of the strategies to survive, which favors the creation of an immunosuppressive microenvironment that ultimately facilitates GC progression. T-cell exhaustion, which is characterized by elevated expression of immune checkpoint (IC) proteins, is one of the most salient manifestations of immunosuppressive microenvironments. It has been consistently demonstrated that the tumor-immune microenvironment(TIME)‐exhausted phenotype can be reverted by blocking ICs with monoclonal antibodies. Although these therapies are associated with long-lasting response rates, only a subset of patients derive clinical benefit, which varies according to tumor site. The search for biomarkers to predict the response to IC inhibition is a matter of intense investigation as this may contribute to maximize disease control, reduce side effects, and minimize cost. The approval of pembrolizumab for its use in GC has rocketed immuno-oncology research in this cancer type. In this review, we summarize the current knowledge centered around the immune contexture and recent findings in connection with IC inhibition in GC.UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias Básicas::Centro de Investigación en Estructuras Microscópicas (CIEMIC)UCR::Vicerrectoría de Docencia::Salud::Facultad de MicrobiologíaUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto de Investigaciones en Salud (INISA)UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Centro de Investigación en Enfermedades Tropicales (CIET)UCR::Vicerrectoría de Docencia::Salud::Facultad de Medicina::Escuela de Medicin

Identificación de moléculas inmunorreguladoras inducidas por la bacteria Helicobacter pylori en modelos in vitro e in vivo

El cáncer gástrico (CG) es el cuarto tipo de cáncer más mortal a nivel mundial, principalmente por su detección tardía y la falta de terapias eficaces. La inmunoterapia ha mostrado ser muy prometedora en el tratamiento del cáncer al revitalizar la respuesta anti-tumoral que está inhibida en tumores por el establecimiento de microambientes inmunosupresores. Sin embargo, un porcentaje importante de pacientes no responde, lo cual evidencia que todavía queda mucho por comprender respecto al microambiente inmunológico en cada tipo de cáncer y cómo este se conforma durante el proceso carcinogénico. El fin último es que la comprensión del microambiente inmunológico se traduzca en estrategias aplicables a la práctica clínica para que más pacientes se beneficien de estas novedosas terapias. Siendo la inflamación crónica desencadenada ante la infección por Helicobacter pylori uno de los factores determinantes en la génesis del CG, es importante dilucidar el impacto que tiene esta infección en la expresión de moléculas inmunorreguladoras que contribuyen a la generación de un microambiente inmunosupresor y que, eventualmente, podrían ser blancos terapéuticos de la inmunoterapia. En el presente trabajo se analizó la expresión génica de ocho moléculas inmunorreguladoras en líneas celulares de CG expuestas a diferentes cepas de H. pylori. Se observó que la bacteria induce la expresión de estas moléculas, principalmente PD-L1, PVR, ICOSL, TNFRSF14 y TNFRSF9, lo cual es dependiente de la Isla de Patogenicidad Cag. Además, en un modelo murino, se evidenció que la infección de la mucosa gástrica por H. pylori provoca un aumento en el número de células inmunológicas infiltrantes positivas para PD-L1 y para su receptor PD-1. También, se analizó la expresión génica de las moléculas inmunorreguladoras PVR/TIGIT, ICOSL/ICOS, TNFRSF14/BTLA y TNFRSF9 en tejido tumoral de pacientes con CG y se determinó que la expresión de estas es mayor que la expresión génica de PD-L1/PD-1, el eje inmunorregulador que actualmente cuenta con inhibidores aprobados para uso clínico en varios tipos de cáncer, incluyendo CG. En conclusión, los resultados de este estudio sugieren que varias moléculas inmunorreguladoras que contribuyen a la generación de microambientes inmunosupresores en cáncer son inducidas en la mucosa gástrica ante la infección por H. pylori. La principal implicación de esto es que la infección estaría favoreciendo el establecimiento de un microambiente inmunosupresor muy tempranamente, lo cual facilitaría el avance en la secuencia de lesiones pre-malignas que culmina en CG. Asimismo, los resultados obtenidos apuntan a que otras moléculas inmunorreguladoras, diferentes de PD-L1/PD-1, podrían contribuir en mayor medida a la inmunosupresión del microambiente (pre)tumoral gástrico y, eventualmente, estas podrían valorarse como nuevos blancos terapéuticos de la inmunoterapia para CG.Gastric cancer (GC) is the fourth most deadly type of cancer worldwide, mainly due to its late detection and the lack of effective therapies. Immunotherapy has displayed great promise in cancer treatment by revitalizing antitumor responses that are mostly inhibited in tumors through the development of immunosuppressive microenvironments. However, a significant percentage of patients do not respond, which shows that much remains to be understood regarding the immune microenvironment in each type of cancer and how it is shaped during the carcinogenic process. The overall purpose is that the understanding of the immune microenvironment translates into strategies applicable to clinical practice so that more patients benefit from these novel therapies. Since chronic inflammation triggered by Helicobacter pylori infection is one of the defining factors in GC genesis, it is important to elucidate the impact of this infection on the expression of immunoregulatory molecules that contribute to immunosuppressive microenvironments and, therefore, may eventually become therapeutic targets for immunotherapy. In this study, gene expression of eight immunoregulatory molecules was analyzed in GC cell lines exposed to different strains of H. pylori. It was observed that the bacterium induces the expression of these molecules, mainly PD-L1, PVR, ICOSL, TNFRSF14 and TNFRSF9, which was dependent on the Cag Pathogenicity Island. In addition, in a mouse model, H. pylori infection of the gastric mucosa prompted an increase in the number of PD-L1 positive infiltrating immune cells as well PD-1 positive infiltrating immune cells. Also, the gene expression of immunoregulatory molecules PVR/TIGIT, ICOSL/ICOS, TNFRSF14/BTLA, and TNFRSF9 was analyzed in tumor tissue of patients with GC and it was determined that the expression of these molecules is greater than the expression of PD-L1/ PD-1, the immunoregulatory axis that currently has inhibitors approved for clinical use in various types of cancer, including GC. In conclusion, the results of this study suggest that several immunoregulatory molecules that contribute to the generation of immunosuppressive microenvironments in cancer are induced in gastric mucosa upon H. pylori infection. The main implication of this is that the infection would be favoring the very early establishment of an immunosuppressive microenvironment, which would facilitate progress in the sequence of pre-malignant lesions that culminates in GC. Likewise, the results suggest that other immunoregulatory molecules than PD-L1/PD-1 could contribute to a greater extent to the immunosuppression of the gastric (pre)tumor microenvironment and, eventually, these could be considered as new therapeutic targets for GC immunotherapy.UCR::Vicerrectoría de Investigación::Sistema de Estudios de Posgrado::Salud::Maestría Académica en Microbiologí

Neutropenia: a short review on its etiology and clinical approach

La neutropenia se define como un recuento absoluto de neutrófilos (RAN) menor a 1 500 células/μl. Puesto que los neutrófilos proveen protección contra una variedad amplia de hongos y bacterias, la frecuencia y la severidad de las infecciones por estos microorganismos son mayores en pacientes neutropénicos; cuanto más bajo sea el RAN y más larga la duración de la neutropenia, hay más riesgo. Sin embargo, la severidad de la neutropenia también depende de otros factores que pueden influenciar la susceptibilidad a infección, como la rapidez de la aparición de la neutropenia, la reserva mieloide en médula ósea, el conteo de monocitos y linfocitos absolutos circulantes, el estado funcional de los fagocitos, la concentración de inmunoglobulinas en suero, la integridad de la piel y las membranas mucosas, la irrigación vascular a los tejidos y el estado nutricional del paciente. Todos estos factores dependerán de la enfermedad subyacente que provoque la neutropenia, la cual puede ser desde un desorden en la producción de neutrófilos, como la neutropenia congénita severa, la neutropenia cíclica, la neutropenia en pacientes con cáncer o producto de inmunodeficiencias o enfermedades metabólicas, hasta un desorden en la distribución o utilización de neutrófilos, como lo son la neutropenia autoinmune, la neutraopenia inducida por medicamentos, la neutropenia producto de enfermedades infecciosas o autoinmunes, o incluso de causa idiopática. Cada una de estas posibles causas representa un riesgo mayor o menor de que el paciente desarrolle un cuadro infeccioso severo; por consiguiente, la identificación de la enfermedad subyacente en cualquier paciente neutropénico es de suma importancia. Para esto, es necesario un abordaje clínico que incluya historia familiar y personal, examinación física y pruebas de laboratorio, así como el análisis de la reserva de progenitores en médula ósea.Neutropenia is defined as the reduction in the absolute number of neutrophils in the blood circulation below 1 500/μl. Since neutrophils provide protection against a wide variety of bacterial and fungal pathogens, the frequency and severity of infections caused by these organisms is increased in patients with neutropenia; the lowest and longer the neutropenia, the greater the risk of infection. Nevertheless, neutropenia severity also depends on some other factors that can influence this risk, such as the myeloid reserve in the bone marrow, the absolute count of circulating monocytes and lymphocytes, the phagocytes functionality, the immunoglobulins concentration, the integrity of skin and mucous membranes, the vascular supply to tissues, and the nutritional status of the patient. All of these factors will rely on the subjacent disorder or disease that is causing the neutropenia: it can be a disorder that affects the neutrophil production in the bone marrow, such as severe congenital neutropenia, cyclic neutropenia, cancer, an immunodeficiency, or metabolic diseases; on the other hand, it can be a disorder in the distribution or utilization of neutrophils in peripheral blood, for example autoimmune neutropenia, drug-induced neutropenia, idiopathic neutropenia, or in patients with other autoimmune diseases. Each one of these conditions represents a higher or lower risk for the development of severe infectious diseases; therefore, the determination of the underlying cause of a low absolute number of neutrophils in the blood circulation requires an exhaustive clinical approach that includes familiar and personal history, physical examination, general and specific lab test, as well as the examination of the bone marrow progenitors.UCR::Vicerrectoría de Docencia::Salud::Facultad de Microbiologí

Helicobacter pylori infection induces gastric precancerous lesions and persistent expression of Angpt2, Vegf-A and Tnf-A in a mouse model

Helicobacter pylori colonizes the gastric mucosa and induces chronic inflammation. Using a mouse model of H. pylori-induced gastritis, we evaluated the mRNA and protein expression levels of proinflammatory and proangiogenic factors, as well as the histopathological changes in gastric mucosa in response to infection. Five- to six-week-old female C57BL/6N mice were challenged with H. pylori SS1 strain. Animals were euthanized after 5-, 10-, 20-, 30-, 40- and 50- weeks post infection. mRNA and protein expression of Angpt1, Angpt2, VegfA, Tnfa, bacterial colonization, inflammatory response and gastric lesions were evaluated. A robust bacterial colonization was observed in 30 to 50 weeksinfected mice, which was accompanied by immune cell infiltration in the gastric mucosa. Compared to non-infected animals, H. pylori-colonized animals showed an upregulation in the expression of Tnf-A, Angpt2 and VegfA at the mRNA and protein levels. In contrast, Angpt1 mRNA and protein expression was downregulated in H. pylori-colonized mice. Our data show that H. pylori infection induces the expression of Angpt2, Tnf-A and Vegf-A in murine gastric epithelium. This may contribute to the pathogenesis of H. pylori-associated gastritis, however the significance of this should be further addressedMinisterio de Ciencia y Tecnología, Gobierno de Costa Rica//CONICIT/Costa RicaUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto de Investigaciones en Salud (INISA)UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Laboratorio de Ensayos Biológicos (LEBI)UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias Básicas::Centro de Investigación en Estructuras Microscópicas (CIEMIC

Helicobacter pylori infection induces abnormal expression of pro‑angiogenic gene ANGPT2 and miR‑203a in AGS gastric cell line

Helicobacter pylori colonizes the stomach and induces an inflammatory response that can develop into gastric pathologies including cancer. The infection can alter the gastric vasculature by the deregulation of angiogenic factors and microRNAs. In this study, we investigate the expression level of pro-angiogenic genes (ANGPT2, ANGPT1, receptor TEK), and microRNAs (miR-135a, miR-200a, miR-203a) predicted to regulate those genes, using H. pylori co-cultures with gastric cancer cell lines. In vitro infections of different gastric cancer cell lines with H. pylori strains were performed, and the expression of ANGPT1, ANGPT2, and TEK genes, and miR-135a, miR-200a, and miR-203a, was quantified after 24 h of infection (h.p.i.). We performed a time course experiment of H. pylori 26695 infections in AGS cells at 6 different time points (3, 6, 12, 28, 24, and 36 h.p.i.). The angiogenic response induced by supernatants of non-infected and infected cells at 24 h.p.i. was evaluated in vivo, using the chicken chorioallantoic membrane (CAM) assay. In response to infection, ANGPT2 mRNA was upregulated at 24 h.p.i, and miR-203a was downregulated in AGS cells co-cultured with different H. pylori strains. The time course of H. pylori 26695 infection in AGS cells showed a gradual decrease of miR-203a expression concomitant with an increase of ANGPT2 mRNA and protein expression. Expression of ANGPT1 and TEK mRNA or protein could not be detected in any of the infected or non-infected cells. CAM assays showed that the supernatants of AGS-infected cells with 26695 strain induced a significantly higher angiogenic and inflammatory response. Our results suggest that H. pylori could contribute to the process of carcinogenesis by downregulating miR-203a, which further promotes angiogenesis in gastric mucosa by increasing ANGPT2 expression. Further investigation is needed to elucidate the underlying molecular mechanisms.UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto de Investigaciones en Salud (INISA)UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias Básicas::Centro de Investigación en Estructuras Microscópicas (CIEMIC)UCR::Vicerrectoría de Docencia::Salud::Facultad de Medicina::Escuela de MedicinaUCR::Vicerrectoría de Docencia::Salud::Facultad de MicrobiologíaUCR::Vicerrectoría de Docencia::Salud::Facultad de Medicina::Escuela de Nutrició

Difference in mortality rates in hospitalized COVID-19 patients identified by cytokine profile clustering using a machine learning approach. An outcome prediction alternative

COVID-19 is a disease caused by the novel Coronavirus SARS-CoV-2 causing an acute respiratory disease that can eventually lead to severe acute respiratory syndrome (SARS). An exacerbated inflammatory response is characteristic of SARS-CoV2 infection, which leads to a cytokine release syndrome also known as cytokine storm associated with the severity of the disease. Considering the importance of this event in the immunopathology of COVID-19, this study analyses cytokine levels of hospitalized patients to identify cytokine profiles associated with severity and mortality. Using a machine learning approach, 3 clusters of COVID-19 hospitalized patients were created based on their cytokine profile. Significant differences in the mortality rate were found among the clusters, associated to different CXCL10/IL-38 ratio. The balance of a CXCL10 induced inflammation with an appropriate immune regulation mediated by the anti-inflammatory cytokine IL-38 appears to generate the adequate immune context to overrule SARS-CoV2 infection without creating a harmful inflammatory reaction. This study supports the concept that analyzing a single cytokine is insufficient to determine the outcome of a complex disease such as COVID-19, and different strategies incorporating bioinformatic analyses considering a broader immune profile represent a more robust alternative to predict the outcome of hospitalized patients with SARS-CoV2 infection.Universidad de Costa Rica/[807-C1-357]/UCR/Costa RicaUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Centro de Investigación en Hematología y Trastornos Afines (CIHATA)UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Centro de Investigación en Enfermedades Tropicales (CIET)UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Centro de Investigación en Cirugía y Cáncer (CICICA