The role of IL-23 in the immunopathogenesis of psoriasis

In just 10 years from its discovery in 2000, interleukin-23 has quickly moved from being recognized as a pro-inflammatory cytokine to a key player and potential therapeutic target in psoriasis

Gene–Environment Interaction Affects Risk of Atopic Eczema:Population and In Vitro Studies

BackgroundMultiple environmental and genetic factors play a role in the pathogenesis of atopic eczema (AE). We aimed to investigate gene–environment interactions (G × E) to improve understanding of the pathophysiology. MethodsWe analysed data from 16 European studies to test for interaction between the 24 most significant AE-associated loci identified from genome-wide association studies and 18 early-life environmental factors. We tested for replication using a further 10 studies and in vitro modeling to independently assess findings. ResultsThe discovery analysis (including 25,339 individuals) showed suggestive evidence for interaction (p &lt; 0.05) between seven environmental factors (antibiotic use, cat ownership, dog ownership, breastfeeding, elder sibling, smoking and washing practices) and at least one established variant for AE, 14 interactions in total. In the replication analysis (254,532 individuals) dog exposure × rs10214237 (on chromosome 5p13.2 near IL7R) was nominally significant (ORinteraction = 0.91 [0.83–0.99] p = 0.025), with a risk effect of the T allele observed only in those not exposed to dogs. A similar interaction with rs10214237 was observed for siblings in the discovery analysis (ORinteraction = 0.84 [0.75–0.94] p = 0.003), but replication analysis was under-powered (ORinteraction = 1.09 [0.82–1.46]). rs10214237 homozygous risk genotype is associated with lower IL-7R expression in human keratinocytes, and dog exposure modelled in vitro showed a differential response according to rs10214237 genotype. ConclusionInteraction analysis and functional assessment provide preliminary evidence that early-life dog exposure may modify the genetic effect of rs10214237 on AE via IL7R, supporting observational epidemiology showing a protective effect for dog ownership. The lack of evidence for other G × E studied here implies only weak effects are likely to occur.</p

Distritos industriales, territorio e innovación: un aprendizaje para las economías regionales argentinas

La introducción de innovaciones tecnológicas en los sectores productivos locales constituye uno de los temas centrales de desarrollo local y uno de los mayores desafíos para las economías latinoamericanas. En esta última temática, existe una vasta literatura que hace referencia a los distritos industriales italianos como modelos de desarrollo económico local, que se caracterizan por un conjunto de pequeñas y medianas empresas localizadas e interconectadas territorialmente, que a través de la interacción y movilización de los recursos endógenos del territorio crean condiciones favorables para el desarrollo y la innovación. En sustancia, la mayor capacidad de esta forma de organización para intensificar la transferencia de conocimiento e innovaciones en las empresas, hizo que la propia idea de medio innovador3 apareciera desde sus inicios, muy ligada a la conceptualización de distrito industrial. Por lo tanto, el interés se centra en conocer cómo funciona este medio innovador y los elementos que lo conforman, su dinámica y su desarrollo interno, para lo cual se describe y recrea un proceso de innovación desarrollado en el distrito metalmecánico geográficamente localizado en la Provincia de Módena (Italia). A través del análisis de un caso empírico4 se intentará mostrar de qué forma se desarrolla este proceso en el interno del distrito y cómo las empresas en las aglomeraciones territoriales deben combinar sus relaciones internas con otros actores, como instituciones locales que pueden servir como agentes intermediarios para el acceso a nuevas fuentes de conocimiento

Differential Influences of the Aryl Hydrocarbon Receptor on Th17 Mediated Responses in vitro and in vivo

The aryl hydrocarbon receptor (AhR) has been attributed with anti-inflammatory effects in the development of pathologicalimmune responses leading to experimental autoimmune encephalomyelitis (EAE) via the induction of regulatory T cells. Inagreement with previously published findings, we find that TCDD administration confers protection from EAE, however, thisimmuno-modulatory effect was not the consequence of de novo Treg generation, but the inhibition of Th17 celldifferentiation. Systemic application of FICZ at the time of immunization also reduced EAE pathology albeit to a lesserdegree than TCDD. In vitro Th17 differentiation in the presence of AhR agonists, including TCDD, promoted IL-17 and IL-22expression, but did not induce Treg differentiation. AhR affinity influenced the amounts of IL-17 and IL-22 protein that wassecreted by Th17 cells, but did not seem to affect susceptibility to EAE in vivo. Making use of conditional AhR-deficient mice,we show that the anti-inflammatory effect of TCDD depends on AhR activation in both T cells and dendritic cells, furtheremphasising the ability of TCDD to interfere with T effector cell differentiation in vivo. The dichotomy between the in vivoand in vitro effects of AhR reveals the complexity of the AhR pathway, which has the capacity of affecting different AhRexpressingcell types involved in mounting immune responses, thus participating in defining their outcome

Recurrent extreme bilateral gigantomastia caused by pseudoangiomatous stromal hyperplasia (PASH) syndrome: a case report

Pseudoangiomatous stromal hyperplasia (PASH) of the breast is a rare and benign medical condition in which the breast tissue is affected by an abnormal myofibroblastic proliferation, which mimics a low-grade sarcoma angiomatous proliferation. PASH usually presents itself either as a palpable mass or as an incidental diagnosis during breast specimens' histological examination. A few cases have been reported in the literature of a diffuse form of breast PASH syndrome in which the clinical presentation is a bilateral form of gigantomastia without palpable masses. In such cases, the optimal surgical management is still debated due to a significant risk of relapse after breast reduction. Mastectomy seems to be the endpoint of this condition in relapsing cases. Recent studies report a good outcome with a Tamoxifen regimen when surgery cannot be performed, supporting a hormonal component for the etiology of the condition. This study reports on an extremely rare case of bilateral, rapid, and severe PASH in a young patient, presenting as a truly disabling gigantomastia that forced the patient to use a wheelchair due to the excessive breast weights (25 kg the right breast and 21 kg the left). We describe her complicated medical history, her diagnosis, and our course of treatment

Mesenchymal stromal cells as rescue therapy in biologic-refractory psoriasis: insights from a case series

Cytokine-targeted biologics have revolutionized the management of moderate-to-severe psoriasis; however, all available therapies have failed a growing number of patients. Mesenchymal stromal cells (MSCs), with their immunomodulatory properties, offer a novel therapeutic option. Here, we report the cases of three adult female patients with long-standing, severe plaque psoriasis who were refractory to multiple biologic therapies, and were consequently treated with two intravenous infusions of allogeneic umbilical cord-derived MSCs (UC-MSCs; 1.96 – 3.00 × 106 cells/kg) 1 week (W) apart. Two patients received UC-MSCs as monotherapy; one received them alongside etanercept. Upon relapse, two patients resumed their last failed biologic at W9, while one switched to a new biologic at W24. UC-MSCs were well-tolerated and yielded variable clinical benefits. The best responder to MSCs experienced an 87% reduction in the Psoriasis Area and Severity Index (PASI 87) by W4. Two patients showed improved responses to previously failed biologics (absolute PASI of 0–2), sustained for over 2 years following reinitiation. Multi-parameter flow cytometry revealed increased frequencies of CD4+ and CD8+ skin-homing (CLA+CD103−) and skin-recirculating (CLA+CD103+) memory T cells, CD25HiCD127LoFoxP3+ regulatory T cells, and non-classical (CD14LoCD16+) monocytes, associated with clinical improvements. These findings suggest that UC-MSCs may potentially provide direct benefits for biologic-refractory psoriasis and restore responsiveness to previously ineffective biologics, possibly by resetting the immune response. Further investigation in larger cohorts is warranted.</p

Exploring the role of immune pathways in the risk and development of depression in adolescence : research protocol of the IDEA-FLAME study

Extensive research suggests a role for the innate immune system in the pathogenesis of depression, but most of the studies are conducted in adult populations, in high-income countries and mainly focus on the study of inflammatory proteins alone, which provides only a limited understanding of the immune pathways involved in the development of depression. The IDEA-FLAME study aims to identify immune phenotypes underlying increased risk of developing depression in adolescence in a middle-income country. To this end, we will perform deep-immunophenotyping of peripheral blood mononuclear cells and RNA genome-wide gene expression analyses in a longitudinal cohort of Brazilian adolescents stratified for depression risk. The project will involve the 3-year follow-up of an already recruited cohort of 150 Brazilian adolescents selected for risk/presence of depression on the basis of a composite risk score we developed using sociodemographic characteristics (50 adolescents with low-risk and 50 with high-risk of developing depression, and 50 adolescents with a current major depressive disorder). We will 1) test whether the risk group classification at baseline is associated with differences in immune cell frequency, phenotype and functional status, 2) test whether baseline immune markers (cytokines and immune cell markers) are associated with severity of depression at 3-year follow-up, and 3) identify changes in gene expression of immune pathways over the 3-year follow-up in adolescents with increased risk and presence of depression. Because of the exploratory nature of the study, the findings would need to be replicated in a separate and larger sample. Ultimately, this research will contribute to elucidating key immune therapeutic targets and inform the development of interventions to prevent onset of depression among adolescents

Activation of the aryl hydrocarbon receptor dampens the severity of inflammatory skin conditions

Environmental stimuli are known to contribute to psoriasis pathogenesis and that of other autoimmune diseases, but the mechanisms are largely unknown. Here we show that the aryl hydrocarbon receptor (AhR), a transcription factor that senses environmental stimuli, modulates pathology in psoriasis. AhR-activating ligands reduced inflammation in the lesional skin of psoriasis patients, whereas AhR antagonists increased inflammation. Similarly, AhR signaling via the endogenous ligand FICZ reduced the inflammatory response in the imiquimod-induced model of skin inflammation and AhR-deficient mice exhibited a substantial exacerbation of the disease, compared to AhR-sufficient controls. Nonhematopoietic cells, in particular keratinocytes, were responsible for this hyperinflammatory response, which involved upregulation of AP-1 family members of transcription factors. Thus, our data suggest a critical role for AhR in the regulation of inflammatory responses and open the possibility for novel therapeutic strategies in chronic inflammatory disorders.</p

Mesenchymal stromal cells as rescue therapy in biologic-refractory psoriasis: insights from a case series

Cytokine-targeted biologics have revolutionized the management of moderate-to-severe psoriasis; however, all available therapies have failed a growing number of patients. Mesenchymal stromal cells (MSCs), with their immunomodulatory properties, offer a novel therapeutic option. Here, we report the cases of three adult female patients with long-standing, severe plaque psoriasis who were refractory to multiple biologic therapies, and were consequently treated with two intravenous infusions of allogeneic umbilical cord-derived MSCs (UC-MSCs; 1.96 – 3.00 × 106 cells/kg) 1 week (W) apart. Two patients received UC-MSCs as monotherapy; one received them alongside etanercept. Upon relapse, two patients resumed their last failed biologic at W9, while one switched to a new biologic at W24. UC-MSCs were well-tolerated and yielded variable clinical benefits. The best responder to MSCs experienced an 87% reduction in the Psoriasis Area and Severity Index (PASI 87) by W4. Two patients showed improved responses to previously failed biologics (absolute PASI of 0–2), sustained for over 2 years following reinitiation. Multi-parameter flow cytometry revealed increased frequencies of CD4+ and CD8+ skin-homing (CLA+CD103−) and skin-recirculating (CLA+CD103+) memory T cells, CD25HiCD127LoFoxP3+ regulatory T cells, and non-classical (CD14LoCD16+) monocytes, associated with clinical improvements. These findings suggest that UC-MSCs may potentially provide direct benefits for biologic-refractory psoriasis and restore responsiveness to previously ineffective biologics, possibly by resetting the immune response. Further investigation in larger cohorts is warranted