The Role of AIRE in the Immunity Against Candida Albicans in a Model of Human Macrophages.

Autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a primary immunodeficiency caused by mutations in the autoimmune regulator gene (AIRE). Patients with AIRE mutations are susceptible to Candida albicans infection and present with autoimmune disorders. We previously demonstrated that cytoplasmic AIRE regulates the Syk-dependent Dectin-1 pathway. In this study, we further evaluated direct contact with fungal elements, synapse formation, and the response of macrophage-like THP-1 cells to C. albicans hyphae to determine the role of AIRE upon Dectin receptors function and signaling. We examined the fungal synapse (FS) formation in wild-type and AIRE-knockdown THP-1 cells differentiated to macrophages, as well as monocyte-derived macrophages from APECED patients. We evaluated Dectin-2 receptor signaling, phagocytosis, and cytokine secretion upon hyphal stimulation. AIRE co-localized with Dectin-2 and Syk at the FS upon hyphal stimulation of macrophage-like THP-1 cells. AIRE-knockdown macrophage-like THP-1 cells exhibited less Dectin-1 and Dectin-2 receptors accumulation, decreased signaling pathway activity at the FS, lower C. albicans phagocytosis, and less lysosome formation. Furthermore, IL-1ß, IL-6, or TNF-α secretion by AIRE-knockdown macrophage-like THP-1 cells and AIRE-deficient patient macrophages was decreased compared to control cells. Our results suggest that AIRE modulates the FS formation and hyphal recognition and help to orchestrate an effective immune response against C. albicans.

Hypercalcitoninemia is not pathognomonic of medullary thyroid carcinoma.

Hypercalcitoninemia has frequently been reported as a marker for medullary thyroid carcinoma. Currently, calcitonin measurements are mostly useful in the evaluation of tumor size and progression, and as an index of biochemical improvement of medullary thyroid carcinomas. Although measurement of calcitonin is a highly sensitive method for the detection of medullary thyroid carcinoma, it presents a low specificity for this tumor. Several physiologic and pathologic conditions other than medullary thyroid carcinoma have been associated with increased levels of calcitonin. Several cases of thyroid nodules associated with increased values of calcitonin are not medullary thyroid carcinomas, but rather are related to other conditions, such as hypercalcemias, hypergastrinemias, neuroendocrine tumors, renal insufficiency, papillary and follicular thyroid carcinomas, and goiter. Furthermore, prolonged treatment with omeprazole (>2-4 months), beta-blockers, glucocorticoids and potential secretagogues, have been associated with hypercalcitoninemia. An association between calcitonin levels and chronic auto-immune thyroiditis remains controversial. Patients with calcitonin levels >100 pg/mL have a high risk for medullary thyroid carcinoma (approximately 90%-100%), whereas patients with values from 10 to 100 pg/mL (normal values: <8.5 pg/mL for men, <5.0 pg/mL for women; immunochemiluminometric assay) have a <25% risk for medullary thyroid carcinoma.In multiple endocrine neoplasia type 2 (MEN2), RET mutation analysis is the gold-standard for the recommendation of total preventive thyroidectomy to relatives at risk of harboring a germline RET mutation (50%). False-positive calcitonin results within MEN2 families have led to incorrect indications of preventive total thyroidectomy to RET mutation negative relatives. In this review, we focus on the differential diagnosis of hypercalcitoninemia, underlining its importance for the avoidance of misdiagnosis of medullary thyroid carcinoma and consequent incorrect recommendation for thyroid surgery.

Hypercalcitoninemia is not pathognomonic of medullary thyroid carcinoma: [revision]

Hypercalcitoninemia has frequently been reported as a marker for medullary thyroid carcinoma. Currently, calcitonin measurements are mostly useful in the evaluation of tumor size and progression, and as an index of biochemical improvement of medullary thyroid carcinomas. Although measurement of calcitonin is a highly sensitive method for the detection of medullary thyroid carcinoma, it presents a low specificity for this tumor. Several physiologic and pathologic conditions other than medullary thyroid carcinoma have been associated with increased levels of calcitonin. Several cases of thyroid nodules associated with increased values of calcitonin are not medullary thyroid carcinomas, but rather are related to other conditions, such as hypercalcemias, hypergastrinemias, neuroendocrine tumors, renal insufficiency, papillary and follicular thyroid carcinomas, and goiter. Furthermore, prolonged treatment with omeprazole (> 2-4 months), beta-blockers, glucocorticoids and potential secretagogues, have been associated with hypercalcitoninemia. An association between calcitonin levels and chronic auto-immune thyroiditis remains controversial. Patients with calcitonin levels >100 pg/mL have a high risk for medullary thyroid carcinoma (~90%-100%), whereas patients with values from 10 to 100 pg/mL (normal values: <8.5 pg/mL for men, < 5.0 pg/mL for women; immunochemiluminometric assay) have a <25% risk for medullary thyroid carcinoma. In multiple endocrine neoplasia type 2 (MEN2), RET mutation analysis is the gold-standard for the recommendation of total preventivethyroidectomy to relatives at risk of harboring a germline RET mutation (50%). False-positive calcitonin results within MEN2 families have led to incorrect indications of preventive total thyroidectomy to RET mutation negative relatives. In this review, we focus on the differential diagnosis of hypercalcitoninemia, underlining its importance for the avoidance of misdiagnosis...

Contaminación del aire exterior y enfermedades alérgicas de la vía aérea / Outdoor air pollution and airway allergic diseases

La prevalencia de enfermedades alérgicas de la vía aérea, como el asma y la rinitis, ha aumentado en las últimas décadas en la mayoría de los países industrializados. La manifestación de enfermedad alérgica depende de una interacción entre factores genéticos y ambientales. Se ha postulado que los factores ambientales pueden jugar un papel muy importante en el desarrollo de enfermedades alérgicas de la vía aérea, ya que es improbable que solamente los factores genéticos expliquen este aumento en un período de tiempo tan breve. Estos factores ambientales son exposición a los alimentos, a alérgenos inhalantes, humo de tabaco, contaminación del aire externo, estrés, hábitos alimenticios, infecciones en la infancia. Muchos estudios experimentales y epidemiológicos proporcionan evidencia de que la exposición a contaminantes del aire pueden exacerbar los síntomas del asma y rinitis y probablemente contribuye al aumento de estas enfermedades en todo el mundo. En la mayoría de las áreas urbanas, la contaminación del aire externo es principalmente resultado de la combustión incompleta de combustibles fósiles de vehículos motorizados, industrias y centrales eléctricas. Los contaminantes más ligados a efectos en enfermedades alérgicas de la vía aérea son el dióxido de nitrógeno, ozono y partículas. No hay evidencia de que ellos puedan inducir reacciones inflamatorias agudas en la vía aérea e incrementar las reacciones de fase inmediata y tardía a alérgenos comunes. El propósito de este análisis es describir la evidencia epidemiológica y posibles mecanismos por los cuales la contaminación del aire externo puede aumentar el riesgo de enfermedades alérgicas de la vía aérea.

The prevalence of airway allergic diseases, as asthma and rhinitis, has increased in most industrialized countries over the last decades. The expression of allergic disease depends on an interaction between genetic and environmental factors. It has been postulated that environmental factors may play an important role in the development of airway allergic diseases, as it is unlikely that genetic factors alone would account for this increase in such a short period of time. These environmental factors are exposure to food, to inhalant allergens, to tobacco smoke, to outdoor air pollution, stress, eating habits, infections in early childhood. Many experimental and epidemiological studies provide evidence that exposure to air pollutants can exacerbate asthma symptoms and rhinitis and, probably, contributes for the increase of these diseases worldwide. In most urban areas, outdoor air pollution is mainly a result of incomplete combustion of fossil fuels by motor vehicles, industries, and power plants. The pollutants most linked to effects on allergic airway diseases are nitrogen dioxide, ozone, and particles. There’s evidence that they can induce acute inflammatory responses in the airway and enhance immediate- and late-phase responses to common allergens. The aim of this review is to describe epidemiological evidence and possible mechanisms by which outdoor air pollution mayincrease the risk of allergic airway diseases.