CCR2 plays a critical role in dendritic cell maturation: possible role of CCL2 and NF-kappa B.

We postulated that CCR2-driven activation of the transcription factor NF-kappaB plays a critical role in dendritic cell (DC) maturation (e.g., migration, costimulation, and IL-12p70 production), necessary for the generation of protective immune responses against the intracellular pathogen Leishmania major. Supporting this notion, we found that CCR2, its ligand CCL2, and NF-kappaB were required for CCL19 production and adequate Langerhans cell (LC) migration both ex vivo and in vivo. Furthermore, a role for CCR2 in upregulating costimulatory molecules was indicated by the reduced expression of CD80, CD86, and CD40 in Ccr2(-/-) bone marrow-derived dendritic cells (BMDCs) compared with wild-type (WT) BMDCs. Four lines of evidence suggested that CCR2 plays a critical role in the induction of protective immunity against L. major by regulating IL-12p70 production and migration of DC populations such as LCs. First, compared with WT, Ccr2(-/-) lymph node cells, splenocytes, BMDCs, and LCs produced lower levels of IL-12p70 following stimulation with LPS/IFN-gamma or L. major. Second, a reduced number of LCs carried L. major from the skin to the draining lymph nodes in Ccr2(-/-) mice compared with WT mice. Third, early treatment with exogenous IL-12 reversed the susceptibility to L. major infection in Ccr2(-/-) mice. Finally, disruption of IL-12p70 in radioresistant cells, such as LCs, but not in BMDCs resulted in the inability to mount a fully protective immune response in bone marrow chimeric mice. Collectively, our data point to an important role for CCR2-driven activation of NF-kappaB in the regulation of DC/LC maturation processes that regulate protective immunity against intracellular pathogens.

Colchicine: A potential therapeutic tool against COVID-19. Experience of 5 patients.

COVID-19 is a newly emerged disease that has become a global public health challenge. Due to a lack of knowledge about the virus, a significant number of potential targets for using a particular drug have been proposed. Five cases with a clinical history of biopolymers in the gluteal region that developed iatrogenic allogenosis (IA) are presented here. The 5 cases were put under colchicine treatment for IA crisis and had non-specific symptoms (headache, cough without dyspnea, and arthralgias) with a positive SARS-CoV-2 test. Their close contacts had mild to severe symptoms and three of them died. In the SARS-CoV-2 infection different inflammatory pathways are altered where colchicine reduces cytokine levels as well as the activation of macrophages, neutrophils, and the inflammasome. The possible mechanisms that colchicine may use to prevent acute respiratory distress syndrome (ARDS) in patients with COVID-19 infection are also reviewed in this article.

T Helper 17 Response to Severe Acute Respiratory Syndrome Coronavirus 2: A Type of Immune Response with Possible Therapeutic Implications.

The initial immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) includes an interferon-dependent antiviral response. A late and uncontrolled inflammatory response characterized by high activity of proinflammatory cytokines and the recruitment of neutrophils and macrophages develops in predisposed individuals and is potentially harmful in some cases. Interleukin (IL)-17 is one of the many cytokines released during coronavirus disease 2019 (COVID-19). IL-17 is crucial in recruiting and activating neutrophils, cells that can migrate to the lung, and are heavily involved in the pathogenesis of COVID-19. During the infection T helper 17 (Th17) cells and IL-17-related pathways are associated with a worse outcome of the disease. All these have practical consequences considering that some drugs with therapeutic targets related to the Th17 response may have a beneficial effect on patients with SARS-CoV-2 infection. Herein, we present the arguments underlying our assumption that blocking the IL-23/IL-17 axis using targeted biological therapies as well as drugs that act indirectly on this pathway such as convalescent plasma therapy and colchicine may be good therapeutic options.

Colchicine: A potential therapeutic tool against COVID-19. Experience of 5 patients.

COVID-19 is a newly emerged disease that has become a global public health challenge. Due to a lack of knowledge about the virus, a significant number of potential targets for using a particular drug have been proposed. Five cases with a clinical history of biopolymers in the gluteal region that developed iatrogenic allogenosis (IA) are presented here. The 5 cases were put under colchicine treatment for IA crisis and had non-specific symptoms (headache, cough without dyspnea, and arthralgias) with a positive SARS-CoV-2 test. Their close contacts had mild to severe symptoms and three of them died. In the SARS-CoV-2 infection different inflammatory pathways are altered where colchicine reduces cytokine levels as well as the activation of macrophages, neutrophils, and the inflammasome. The possible mechanisms that colchicine may use to prevent acute respiratory distress syndrome (ARDS) in patients with COVID-19 infection are also reviewed in this article.

COVID-19 es una enfermedad de aparición reciente, que se ha convertido en un reto global de salud pública. Debido a la falta de conocimiento acerca del virus, se ha propuesto un número significativo de objetivos potenciales para utilizar un fármaco en particular. Presentamos 5 casos con historia clínica de biopolímeros en la región glútea, que desarrollaron alogenosis iatrogénica (AI). A los 5 casos se les administró tratamiento de colchicina debido a la crisis de AI, no teniendo síntomas específicos (cefalea, tos sin disnea y artralgias), con resultado positivo en el test de SARS-CoV-2. Sus contactos cercanos tenían síntomas de leves a graves, y 3 de ellos fallecieron. En la infección por SARS-CoV-2 se alteran diferentes rutas inflamatorias, en las que la colchicina reduce los niveles de citocinas y la activación de macrófagos, neutrófilos e inflamasoma. Revisamos también, en este artículo, los posibles mecanismos que puede utilizar colchicina para prevenir el síndrome de distrés respiratorio agudo (SDRA) en pacientes con COVID-19.

Non-Cirrhotic Portal Hypertension in a Patient With Colonic Carcinoma Treated With Oxaliplatin.

Oxaliplatin is a chemotherapeutic agent with direct toxic action on deoxyribonucleic acid (DNA), which is known to cause an arrest in its synthesis and inducing cell death. It is a crucial medication for colorectal carcinoma, and in combination with other medications has demonstrated to exhibit synergism, managing to increase patients' survival, especially when compared to monotherapy with 5-fluoracil. Neurotoxicity is its most well-known adverse effect. However, other less frequent secondary effects have been described in case reports, among them liver injury, which is usually secondary to liver sinusoid injury. Despite the wide frequency of the use of this drug, the relationship of oxaliplatin with the development of portal non-cirrhotic hypertension is largely unknown, which translates into a sub-diagnosis, representing an additional risk to patients who develop this complication. We present the case of an adult patient, who during treatment with the FOLFOX scheme for colorectal carcinoma, presents signs suggestive of portal hypertension, without other risk factors besides the administration of oxaliplatin.

Oxaliplatin-Induced Thrombotic Microangiopathy in a Patient with Stage IV Gallbladder Carcinoma: Primary Association or Multiple Hits?

Thrombotic microangiopathies (TMA) include a variety of vascular disorders characterized by the presence of microthrombi, coagulopathy by platelet activation and consumption, and systemic damage. The most frequent secondary causes are infections and some medications. However, the presence of chemotherapeutic agents is not so common, and the induction of TMA by oxaliplatin is poorly understood, with few published case reports. We present the case of a patient with a history of gallbladder carcinoma, in whom findings compatible with TMA were documented, and with a temporal and sole relation to oxaliplatin.

Experimental arthritis in CC chemokine receptor 2-null mice closely mimics severe human rheumatoid arthritis.

The prevailing paradigm is that in human rheumatoid arthritis (RA), the accumulation of monocytes and T cells in the joint, mediated in part by such CC chemokine receptors (CCRs) as CCR2 and CCR5, respectively, plays a central role in disease pathogenesis. To further validate this paradigm, we conducted proof-of-principle studies and tested the hypothesis that gene inactivation of Ccr2 or Ccr5 will ameliorate experimental RA. Contrary to our expectations, we found that in two well-established murine models of experimental RA, CCR2 expression in the hematopoietic cell compartment served as a negative regulator of autoantibody production as well as arthritic disease onset, severity, and resolution. In contrast, the RA phenotype in Ccr5-null mice was similar to that of WT mice. Remarkably, the collagen-induced arthritis phenotype of Ccr2-/- mice mimicked closely that of severe human RA, including production of rheumatoid factor, enhanced T cell production, and monocyte/macrophage accumulation in the joints. Our findings demonstrate an essential protective role of CCR2 expression in RA, indicate the existence of alternative receptors responsible for monocyte/macrophage accumulation to inflamed joints, and emphasize the need to clarify carefully the complex effects of the chemokine system in RA before they can be considered as therapeutic targets.

CCR5 deficiency is not protective in the early stages of atherogenesis in apoE knockout mice.

The accumulation of macrophages and T lymphocytes in vessel walls is a hallmark of atherogenesis. It has recently been demonstrated in mouse models of atherosclerosis that full disease potential is dependent on several regulators of leukocyte trafficking, including the chemokine monocyte chemotactic protein 1 (MCP-1) and the chemokine receptors CCR2 and CXCR2. A possible role for the chemokine receptor CCR5 in atherogenesis has been suggested by CCR5 expression on macrophages, T cells, coronary endothelial cells and aortic smooth muscle cells and by the presence of CCR5 ligands in atherosclerotic plaques. Moreover, individuals who are naturally deficient in CCR5 were reported to be at reduced risk for severe coronary artery disease (CAD) and early myocardial infarction (MI). To investigate whether CCR5 is pro-atherogenic in mice, we generated CCR5-deficient mice and crossed them with atherosclerosis-prone apoE-deficient mice. Although CCR5-deficient mice exhibit defects in induced macrophage trafficking, mean atherosclerotic lesion area did not differ significantly between apoE-deficient mice and apoE/CCR5-deficient mice after 16 weeks on a diet of normal chow. Ribonuclease protection assays (RPA) on RNA isolated from plaques from both apoE-deficient and apoE/CCR5-deficient animals showed strong signals for the macrophage marker F4/80 but no evidence for expression of prominent markers of T and B lymphocytes. These results indicate that the early stages of plaque formation in this model of lipid-mediated atherogenesis do not depend on CCR5.

Concordancia entre escalas Framingham ATP III, SCORE y ACC/AHA 2013. En una cohorte de pacientes en un hospital de cuarto nivel en el año 2015 / Concordance between the Framingham ATP III SCORE and ACC/AHA 2013 Scales. En a cohort of patients in a fourth level hospital in 2015

Resumen Introducción: identificar las personas sin enfermedad cardiovascular establecida con alto riesgo es el objetivo de la intervención primaria en prevención cardiovascular. En nuestro medio se han aplicado múltiples escalas de riesgo cardiovascular; sin embargo, en Colombia la única escala validada es la de Framingham. Objetivo: estimar la concordancia entre las escalas Framingham ATP III, SCORE y ACC/ AHA 2013 para la predicción de riesgo cardiovascular en pacientes entre 40 y 75 años en una institución de cuarto nivel durante el año 2015. Material y métodos: estudio de tipo observacional de corte transversal en pacientes de 40 -75 años que asistieron durante el año 2015 en el servicio de chequeo general de un hospital de cuarto nivel, de 4783 individuos se tomó una muestra aleatorizada simple de 861, se calculó el riesgo cardiovascular con las escalas de Framingham, SCORE y AHA/ACC2013. Se describieron las variables cualitativas mediante distribuciones de frecuencias, las variables cuantitativas con medidas de tendencia central, se realizó un análisis bivariado con el coeficiente de correlación Kappa de Cohen considerándose como buena correlación >60. Resultados: el cálculo del riesgo cardiovascular con cada una de las escalas encontró para alto riesgo AHA 2013 de 14.6%, Framingham 2.2% y SCORE con 1.1%. Para riesgo medio SCORE de 26.9%, AHA 2013 de 17.1% y Framingham de 14.4%, y riesgo bajo la estimación fue de Framingham de 83.3%, SCORE de 73% y AHA 2013 68.3%. El índice de concordancia de Kappa de Cohen para alto riesgo cardiovascular entre la escala Framingham modificada y SCORE se evidencia fuerza de concordancia moderada (Kappa: 0.47) al calcular este índice entre Framingham modificada y AHA 2013 la fuerza concordancia es débil (Kappa: 0.3497). Conclusión: con los hallazgos del estudio se concluye que el comportamiento en cuanto a la estimación de riesgo de las escalas de SCORE y AHA 2013 no es concordante, por lo tanto, sus estimaciones no son intercambiables, tendiendo a sobreestimar o subestimar el riesgo. (Acta Med Colomb 2018; 43: 192-199).

Abstract Introduction: identifying people without established cardiovascular disease at high risk is the goal of primary intervention in cardiovascular prevention. In our environment, multiple scales of cardiovascular risk have been applied; however, in Colombia the only scale validated is Framingham. Objective: to estimate the agreement between the Framingham ATP III, SCORE and ACC / AHA 2013 scales for the prediction of cardiovascular risk in patients between 40 and 75 years old in a fourth level institution during 2015. Material and methods: cross-sectional observational study in patients aged 40-75 years who attended in 2015 in the general check-up service of a fourth-level hospital. Of 4783 individuals a simple randomized sample of 861 was taken. Cardiovascular risk with the Framingham, SCORE and AHA / ACC2013 scales was calculated. Qualitative variables were described by frequency distributions, quantitative variables with measures of central tendency, and a bivariate analysis was performed with Cohen's Kappa correlation coefficient considering as a good correlation > 60. Results: the calculation of cardiovascular risk with each of the scales found for high risk AHA 2013 of 14.6%, Framingham 2.2% and SCORE with 1.1%. For average risk SCORE of 26.9%, AHA 2013 of 17.1% and Framingham of 14.4%, and risk under the estimate was of Framingham of 83.3%, SCORE of 73% and AHA 2013 68.3%. The Cohen's Kappa concordance index for high cardiovascular risk between the modified Framingham scale and SCORE evidence a moderate concordance strength (Kappa: 0.47); when calculating this index between modified Framingham and AHA 2013 concordance strength is weak (Kappa: 0.3497). Conclusion: with the findings of the study it is concluded that the behavior regarding the risk estimation of SCORE and AHA 2013 scales is not concordant; therefore, their estimates are not interchangeable, tending to overestimate or underestimate the risk. (Acta Med Colomb 2018; 43: 192-199).

CC chemokine receptor 2 expression in donor cells serves an essential role in graft-versus-host-disease.

The complete repertoire of cellular and molecular determinants that influence graft-vs-host disease (GVHD) is not known. Using a well-established murine model of GVHD (B6-->bm12 mice), we sought to elucidate the role of the donor non-T cell compartment and molecular determinants therein in the pathogenesis of GVHD. In this model the acute GVHD-inducing effects of purified B6 wild-type (wt) CD4(+) T cells was inhibited by wt non-T cells in a dose-dependent manner. Paradoxically, unlike the chronic GVHD phenotype observed in bm12 mice transplanted with B6wt unfractionated splenocytes, bm12 recipients of B6ccr2-null unfractionated splenocytes developed acute GVHD and died of IFN-gamma-mediated bone marrow aplasia. This switch from chronic to acute GVHD was associated with increased target organ infiltration of activated CD4(+) T cells as well as enhanced expression of Th1/Th2 cytokines, chemokines, and the antiapoptotic factor bfl1. In vitro, ccr2(-/-) CD4(+) T cells in unfractionated splenocytes underwent significantly less activation-induced cell death than B6wt CD4(+) T cells, providing another potential mechanistic basis along with enhanced expression of bfl1 for the increased numbers of activated T cells in target organs of B6ccr2(-/-) splenocyte-->bm12 mice. Collectively, these findings have important clinical implications, as they implicate the donor non-T cell compartment as a critical regulator of GVHD and suggest that ccr2 expression in this cellular compartment may be an important molecular determinant of activation-induced cell death and GVHD pathogenesis.

Tolerancia inmunologica: ¿por que convivimos con nuestros tejidos? / Inmunologic tolerance

En este artículo se resumen los aspectos generales de la tolerancia inmunológica con énfasis en la distinción entre tolerancia e ignorancia. Este último concepto está relacionado con la incapacidad del sistema inmunitario para reconocer todos los auto-antígenos o con la ausencia de linfocitos vírgenes recirculantes en los tejidos periféricos