Skin expression of IL-23 drives the development of psoriasis and psoriatic arthritis in mice

Psoriasis (PS) is a chronic skin inflammation. Up to 30% of the patients with PS develop psoriatic arthritis (PsA), a condition characterized by inflammatory arthritis that affects joints or entheses. Although there is mounting evidence for a critical role of interleukin-23 (IL-23) signaling in the pathogenesis of both PS and PsA, it remains unclear whether IL-23-induced skin inflammation drives joint disease. Here, we show that mice expressing increased levels of IL-23 in the skin (K23 mice) develop a PS-like disease that is characterized by acanthosis, parakeratosis, hyperkeratosis, and inflammatory infiltrates in the dermis. Skin disease preceded development of PsA, including enthesitis, dactylitis, and bone destruction. The development of enthesitis and dactylitis was not due to high circulating levels of IL-23, as transgenic animals and controls had similar levels of this cytokine in circulation. IL-22, a downstream cytokine of IL-23, was highly increased in the serum of K23 mice. Although IL-22 deficiency did not affect skin disease development, IL-22 deficiency aggravated the PsA-like disease in K23 mice. Our results demonstrate a central role for skin expressed IL-23 in the initiation of PS and on pathogenic processes leading to PsA.Fil: Chen, Lili. Icahn School of Medicine at Mount Sinai; Estados UnidosFil: Deshpande, Madhura. Icahn School of Medicine at Mount Sinai; Estados UnidosFil: Grisotto, Marcos. Icahn School of Medicine at Mount Sinai; Estados UnidosFil: Smaldini, Paola Lorena. Icahn School of Medicine at Mount Sinai; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Estudios Inmunológicos y Fisiopatológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Estudios Inmunológicos y Fisiopatológicos; ArgentinaFil: Garcia, Roberto. Hospital for Special Surgery; Estados UnidosFil: He, Zhengxiang. Icahn School of Medicine at Mount Sinai; Estados UnidosFil: Gulko, Percio. Icahn School of Medicine at Mount Sinai; Estados UnidosFil: Lira, Sergio A.. Icahn School of Medicine at Mount Sinai; Estados UnidosFil: Furtado, Glaucia C.. Icahn School of Medicine at Mount Sinai; Estados Unido

Blood-derived dermal langerin+ dendritic cells survey the skin in the steady state

Langerin is a C-type lectin receptor that recognizes glycosylated patterns on pathogens. Langerin is used to identify human and mouse epidermal Langerhans cells (LCs), as well as migratory LCs in the dermis and the skin draining lymph nodes (DLNs). Using a mouse model that allows conditional ablation of langerin+ cells in vivo, together with congenic bone marrow chimeras and parabiotic mice as tools to differentiate LC- and blood-derived dendritic cells (DCs), we have revisited the origin of langerin+ DCs in the skin DLNs. Our results show that in contrast to the current view, langerin+CD8− DCs in the skin DLNs do not derive exclusively from migratory LCs, but also include blood-borne langerin+ DCs that transit through the dermis before reaching the DLN. The recruitment of circulating langerin+ DCs to the skin is dependent on endothelial selectins and CCR2, whereas their recruitment to the skin DLNs requires CCR7 and is independent of CD62L. We also show that circulating langerin+ DCs patrol the dermis in the steady state and migrate to the skin DLNs charged with skin antigens. We propose that this is an important and previously unappreciated element of immunosurveillance that needs to be taken into account in the design of novel vaccine strategies

LEVANTAMENTO EPIDEMIOLÓGICO DA MALÁRIA NO ESTADO DO MARANHÃO, BRASIL NOS ANOS DE 2007 A 2012

A malária é um problema global e signifcativo para a saúde pública, atingindo entre 300 e 500 milhões de pessoas e ocasionando aproximadamente dois milhões de óbitos anualmente. A malária é endêmica no Brasil, especifcamente na região da Amazônia Legal, com média de 500 mil casos ao ano.  Das 156 espécies de plasmódio, somente cinco estão associadas à etiologia em humanos: Plasmodium vivax, P. falciparum, P. malariae, P. ovale e P. knowlesi. O presente estudo teve por objetivo  realizar um  levantamento epidemiológico dos casos de malária no Estado do Maranhão entre os anos de 2007 e 2012, através da análise de dados de  indivíduos  infectados disponível no Sistema de Vigilância Epidemiológica - SIVEP/MALÁRIA. Foram avaliados os seguintes parâmetros: número total de casos por ano, índice parasitário anual (IPA), origem da contaminação (casos autóctones ou importados), distribuição dos indivíduos acometidos por idade e sexo além da espécie de parasito causador. De 2007 a 2012 houve uma redução progressiva do número casos notifcados de malária no Estado do Maranhão, com consequente redução do IPA, exceto no ano de 2009. Verifcou-se a prevalência de casos de malária em indivíduos do sexo masculino, em idade adulta (de 20 a 39 anos), sendo a maioria dos casos por transmissão autóctone. No Maranhão, bem como na Amazônia Legal, a grande maioria de casos de malária foi causada por Plasmodium vivax.Descritores: Malária. Plasmodium sp. SIVEP. Maranhão.AbstractEpidemiological survey of malaria cases  in the state of Maranhão, Brazil from 2007 to 2012. Malaria is a global problem with great  impact  in public health, affecting between 300 and 500 million people and causing nearly  two million deaths annually. Malaria is endemic in Brazil, specifcally in the Amazon region, with the average of 500.000 cases per year. Over 156  species of Plasmodium are known, but only fve are associated with disease  in humans: Plasmodium vivax, P. falciparum, P. malariae, P. ovale and P. knowlesi. The aim of this study was to perform an epidemiological survey of malaria cases in the state of Maranhão, during the years of 2007 to 2012, by analyzing the data of infected individuals available at  the Epidemiological Surveillance System- SIVEP/MALARIA. The following parameters were analyzed: total number of cases per year, the annual parasite incidence (API), source of contamination (indigenous or imported cases) and distribution of affected individuals by age, sex and species of infecting parasite. From 2007 to 2012 there was a progressive reduction of notifed malaria cases in Maranhão, as well as the API, except in the year of 2009. The cases of malaria were prevalent in males, aged mostly from 20 to 39 year old, and were due to indigenous contamination. In Maranhão, as well as in the Amazon region, the vast majority of the malaria infections were caused by Plasmodium vivax.Descriptors: Malaria. Plasmodium sp. SIVEP. Maranhao

AVALIAÇÃO DE MARCADORES DE ATIVAÇÃO E REGULAÇÃO EM LEUCÓCITOS DE PACIENTES INFECTADOS POR Plasmodium vivax

A malária é uma doença infecciosa aguda causada por protozoários do gênero Plasmodium e é transmitida ao homem pela picada da fêmea do mosquito Anopheles. Dentre as cinco espécies de Plasmodium que infectam seres humanos o P. falciparum e P. vivax são as mais prevalentes na região Amazônica. Dentre os mecanismos imunológicos associados a essa doença, muitos fatores ainda não são totalmente compreendidos, como relação entre ativação de células do sistema imunes e a função das células regulatórias no controle da parasitemia. Este trabalho analisou marcadores de ativação, regulação e moléculas coestimulatórias de células do sistema imune durante a infecção pelo Plasmodium vivax em pacientes infectados residentes na cidade de Cruzeiro do Sul (AC). O sangue periférico dos pacientes infectados foi coletado para realização de imunofenotipagem por citometria de fluxo. Indivíduos sadios nunca infectados com malária serviram como controle. Resultados: A infecção pelo Plasmodium vivax induziu o aumento de CD69 por células T CD4+, CD8+ e linfócitos B e de HLA-DR por linfócitos T CD4+. A expressão aumentada das moléculas coestimulatórias OX40 e ICOS mas não GITR também foi observada em células T CD4+ e CD8+ dos indivíduos acometidos pelo Plasmodium vivax em comparação com controles sadios. Por outro lado, um percentual significantemente maior de células T reguladoras foi observado no grupo de pacientes. Em conjunto, esses dados sugerem que a infecção pelo P. vivax promove aumento de marcadores de ativação e moléculas coestimulatórias em indivíduos infectados bem como condiciona um aumento no compartimento de células T reguladoras.Descritores: Plasmodium vivax. Células reguladoras. Co-estimulação.AbstractMalaria is an acute infectious disease caused by a protozoa of the genus Plasmodium being transmitted by the bite of the female Anopheles´ mosquito. Considering the five species of Plasmodium that infect humans, P. falciparum and P. vivax are the most prevalent in the Amazon region. Among the immunological mechanisms associated with this disease, many factors are still not fully understood, as the relationship between the immune system cell activation and function of regulatory T cells in the control of parasitaemia. This study examined activation markers, regulation and co-stimulatory molecules of the immune system cells during infection by Plasmodium vivax-infected patients living in the city of Cruzeiro do Sul (AC). The peripheral blood cells of infected patients ware collected to perform Immunophenotyping by flow cytometry. Healthy individuals never infected with malaria served as controls. Results: Infection with Plasmodium vivax induced increase of CD69 on CD4+, CD8+ T and B cells and HLA-DR on CD4 + T cells. The increased expression of co-stimulatory molecules OX40 and ICOS but not GITR was also observed in CD4+ and CD8+ T cells of individuals affected by Plasmodium vivax, compared to healthy controls. On the other hand, a significantly greater percentage of T regulatory cells was observed in the group of patients. Altogether, these data suggest that the P. vivax infection promotes an increase in activation markers and co-stimulatory molecules in infected individuals as well as an increase in the regulatory T cell compartment.Descriptors: Plasmodium vivax. Regulatory T cells. Co-stimulation

Differential rates of replacement of human dermal dendritic cells and macrophages during hematopoietic stem cell transplantation

Animal models of hematopoietic stem cell transplantation have been used to analyze the turnover of bone marrow–derived cells and to demonstrate the critical role of recipient antigen-presenting cells (APC) in graft versus host disease (GVHD). In humans, the phenotype and lineage relationships of myeloid-derived tissue APC remain incompletely understood. It has also been proposed that the risk of acute GVHD, which extends over many months, is related to the protracted survival of certain recipient APC. Human dermis contains three principal subsets of CD45+HLA-DR+ cells: CD1a+CD14− DC, CD1a−CD14+ DC, and CD1a−CD14+FXIIIa+ macrophages. In vitro, each subset has characteristic properties. After transplantation, both CD1a+ and CD14+ DC are rapidly depleted and replaced by donor cells, but recipient macrophages can be found in GVHD lesions and may persist for many months. Macrophages isolated from normal dermis secrete proinflammatory cytokines. Although they stimulate little proliferation of naive or memory CD4+ T cells, macrophages induce cytokine expression in memory CD4+ T cells and activation and proliferation of CD8+ T cells. These observations suggest that dermal macrophages and DC are from distinct lineages and that persistent recipient macrophages, although unlikely to initiate alloreactivity, may contribute to GVHD by sustaining the responses of previously activated T cells

Association of Malaria Infection During Pregnancy With Head Circumference of Newborns in the Brazilian Amazon.

Importance: Malaria during pregnancy is associated with adverse events for the fetus and newborn, but the association of malaria during pregnancy with the head circumference of the newborn is unclear. Objective: To investigate the association of malaria during pregnancy with fetal head growth. Design, Setting, and Participants: Two cohort studies were conducted at the general maternity hospital of Cruzeiro do Sul (Acre, Brazil) in the Amazonian region. One cohort study prospectively enrolled noninfected and malaria-infected pregnant women who were followed up until delivery, between January 2013 and April 2015. The other cohort study was assembled retrospectively using clinical and malaria data from all deliveries that occurred between January 2012 and December 2013. Data analyses were conducted from January to August 2017 and revised in November 2018. Clinical data from pregnant women and anthropometric measures of their newborns were evaluated. A total of 600 pregnant women were enrolled through volunteer sampling (prospective cohort study), and 4697 pregnant women were selected by population-based sampling (retrospective cohort study). After application of exclusion criteria, data from 251 (prospective cohort study) and 232 (retrospective cohort study) malaria-infected and 158 (prospective cohort study) and 3650 (retrospective cohort study) noninfected women were evaluated. Exposure: Malaria during pregnancy. Main Outcomes and Measures: The primary end point was the incidence of altered head circumference in newborns delivered from malaria-infected mothers compared with that from noninfected mothers. Secondary end points included measures of placental pathology relative to newborn head circumference. Results: In total, 4291 maternal-child pairs were analyzed. Among 409 newborns in the prospective cohort study, the mothers of 251 newborns had malaria during pregnancy, infected with Plasmodium vivax, Plasmodium falciparum, or both. Among 3882 newborns in the retrospective cohort study, 232 were born from mothers that had malaria during pregnancy. The prevalence of newborns with a small head (19 [30.7%] in the prospective cohort study and 30 [36.6%] in the retrospective cohort study) and the prevalence of microcephaly among newborns (5 [8.1%] in the prospective cohort study and 6 [7.3%] in the retrospective cohort study) were higher among newborns from women infected with P falciparum during pregnancy. Multivariate logistic regression analyses revealed that P falciparum infection during pregnancy represented a significant risk factor for the occurrence of small head circumference in newborns (prospective cohort study: odds ratio, 3.15; 95% CI, 1.52-6.53; P = .002; retrospective cohort study: odds ratio, 1.91; 95% CI, 1.21-3.04; P = .006). Placental pathologic findings corroborated this association, with more syncytial nuclear aggregates and inflammatory infiltrates occurring in placentas of newborns born with decreased head circumference. Conclusions and Relevance: This study indicates that falciparum malaria during pregnancy is associated with decreased head circumference in newborns, which is in turn associated with evidence of placental malaria

The human herpesvirus 8 chemokine receptor vGPCR triggers autonomous proliferation of endothelial cells

We have used a novel conditional transgenic system to study the mechanisms of angioproliferation induced by viral G protein–coupled receptor (vGPCR), the constitutively active chemokine receptor encoded by human herpesvirus 8 (HHV8, also known as Kaposi sarcoma herpesvirus). Using this system, we were able to control temporal expression of vGPCR and to monitor its expression in situ via the use of the surrogate marker LacZ. Upon treatment with doxycycline (DOX), cells expressing vGPCR and LacZ (vGPCR/LacZ(+) cells) progressively accumulated in areas where angioproliferation was observed. Sorted vGPCR/LacZ(+) cells from angiogenic lesions expressed markers characteristic of endothelial progenitor cells, produced angiogenic factors, and proliferated in vitro. Prolonged treatment of transgenic mice with DOX led to development of tumors in the skin of ears, tail, nose, and paws. vGPCR/LacZ(+) cells were frequent in early lesions but scarce within these tumors. Finally, transfer of vGPCR/LacZ(+) cells into Rag1(–/–) mice treated with DOX led to angioproliferation and, with time, to development of tumors containing both vGPCR/LacZ(+) and vGPCR/LacZ(–) cells. Taken together, these results indicate that vGPCR triggers angioproliferation directly and suggest a novel role for this molecule in the pathogenesis of Kaposi sarcoma