Leptin: a central modulator of imune responses.

A leptina é um mediador tanto de respostas neuroendócrinas como imunes, e tem sido associada a diversas autoimunidades. O nosso objetivo foi estudar a importância da leptina na modulação da resposta imunológica no transplante experimental, com ênfase em seu papel na plasticidade de linfócitos T e de células dendríticas (DC). Observamos que os animais deficientes em leptina têm uma sobrevida aumentada do enxerto de pele e uma menor frequência de células Th1 e maior T reguladoras (Treg), Th2 e Th17. Ademais, células T CD4+ naive diferenciam-se mais eficientemente em células Treg e Th17 tanto com DC como sem DC, na ausência de leptina. Nossos dados indicam que BMDC, imaturas e maduras, é comprometida na ausência de leptina, induzindo menor proliferação de linfócitos CD4+ e maior geração/expansão de células Treg, Th17 e Th2. Assim, a ausência de leptina resultou num predomínio de células Treg um padrão Th2 que, em conjunto com o perfil tolerogênico das DC, poderiam ser um dos mecanismos responsáveis pelo aumento da sobrevida do enxerto alogenêico de pele.Leptin is a mediator of both neuroendocrine and immune responses, and has been associated with several autoimmune diseases. Our objective was to study the importance of leptin in modulating the immune response in experimental transplantation, with emphasis on its role in the plasticity of T lymphocytes and dendritic cells (DC). We observed that animals leptin deficient had an increased skin graft survival and lower frequency of Th1 and increased regulatory (Treg), Th2 and Th17 T cells. Furthermore, naive CD4+ T cells differentiate more efficiently in Treg and Th17 cells, with DC and without DC, in the absence of leptin. Our data indicate that BMDC, mature and immature, is compromised in the absence of leptin, leading to less proliferation of CD4+ and increased generation / expansion of Treg cells, Th2 and Th17. Thus, the lack of leptin resulted in a predominance of Th2 and Treg T cells, which together with the profile of tolerogenic DC could be one of the mechanisms responsible for increased survival of allograft skin

Study of the immunologic molecular profile in operational tolerance kidney transplanted individuals

A indução de tolerância ao aloenxerto, no contexto do transplante clínico, é um dos maiores desafios da imunologia. Existem pacientes transplantados que mesmo após a retirada de imunossupressores mantêm a função estável do aloenxerto. Este estado é chamado de tolerância operacional. Nosso objetivo foi analisar se os indivíduos em tolerância operacional tem um perfil imunológico molecular diferencial em relação aos outros grupos clínicos, visando identificar potenciais mecanismos envolvidos na manutenção desse estado de não agressão ao órgão transplantado. Analisamos 10 doadores renais saudáveis (Sau) e 32 indivíduos transplantados renais, sendo 4 tolerantes operacionais (TO), 11 com rejeição crônica (RC), 12 com função renal estável e imunossupressão convencional (Est) e 5 com função renal estável e baixa imunossupressão (BI). Analisamos a expressão gênica, em células mononucleares do sangue, de um painel de moléculas predominantemente imunorreguladoras ou próinflamatórias (REGULA/INFLAMA), por PCR em tempo real, em duas amostras, com intervalos de 4-6 meses. Quantificamos as células T CD4+CD25+Foxp3+, por citometria de fluxo, e estudamos a ativação de duas vias de sinalização, IL-6/STAT3 e IL-4/STAT6, por PhosFlow, nos diferentes grupos de estudo. Nós observamos algumas diferenças significativas entre os indivíduos TO e os outros grupos de estudo, (p<0,05). A expressão dos genes de TGF- e TGF-R foi maior no grupo de indivíduos TO em comparação aos grupos Est e BI, analisando-se 2 tempos distintos. A expressão de GATA-3 foi maior no grupo TO comparado a todos os outros grupos de estudo. A expressão gênica de Foxp3 foi maior no grupo TO comparado aos grupos RC e BI, apenas quando analisamos as 2 amostras. Neste painel REGULA/INFLAMA, o grupo TO teve um predomínio de modificações do tipo REGULA, em ambos os tempos estudados, e maior estabilidade na expressão gênica entre as 2 amostras. Em relação as células T CD4+CD25+Foxp3+, os grupos RC e Est tiveram menores números absolutos e porcentagens em comparação aos outros grupos. O grupo TO teve uma quantidade dessas células semelhantes aos grupos Sau e BI. No estudo das vias de sinalização observamos que a fosforilação de STAT6, na região de monócitos, foi menor em indivíduos TO quando comparada a todos os outros grupos estudados. O painel de moléculas REGULA/INFLAMA, utilizado neste estudo, permitiu determinar um perfil imunológico molecular com características predominantemente imunorreguladoras no grupo TO. O perfil de fosforilação da via de sinalização IL-4/STAT6 nos indivíduos TO, na região de monócitos, nos permite interpretar que essas vias sejam mobilizadas de forma diferente, podendo participar deste estado de não agressão ao enxerto. A redução de células T CD4+CD25+Foxp3+ nos indivíduos com imunossupressão convencional (grupos RC e Est) nos permite interpretar que a imunossupressão afeta essa população celular, potencialmente imunorreguladora. O maior número de células T CD4+CD25+Foxp3+, nos indivíduos TO e BI nos permite sugerir que essas células tenham um papel importante no estado de tolerância operacional. Também o fator de transcrição GATA-3 parece desempenhar um importante papel na indução/manutenção do estado de TO, sugerindo que um desvio Th2 seja relevante para a manutenção deste estado. Os nossos resultados nos permitem interpretar que o estado de tolerância operacional tem uma repercussão sistêmica e que essas moléculas parecem ser relevantes e talvez dominantes neste estado de homeostase no contexto do transplante renal humano.standard immunosuppression, lead us to suggest that these cells may be affected by immunosuppression. Moreover, the higher numbers of CD4+CD25+Foxp3+ T cells observed in TO and BI individuals suggest that these cells may have an important role in the induction/maintenance of these two homeostatic states of minimal, or of no aggression to the graft. Furthermore, the higher mRNA expression of GATA-3, in the TO group, suggests that a Th2 deviation may also be relevant to the maintenance of operational tolerance. Our results allowed us to interpret that the state of operational tolerance has systemic repercussion, and that the molecules studied in our work may be relevant to the process of homeostasis in the context of human kidney transplantation

Dendritic cells: immune response in infectious diseases and autoimmunity

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Exploring the Role of Soluble Factors Associated with Immune Regulatory Properties of Mesenchymal Stem Cells

Mesenchymal stem cells (MSCs) are characterized as multipotent stromal cells with the capacity for both self-renewal and differentiation into mesodermal cell lineages. MSCs also have a fibroblast-like phenotype and can be isolated from several tissues. In recent years, researchers have found that MSCs secrete several soluble factors that exert immunosuppressive effects by modulating both innate (macrophages, dendritic and NK cells) and adaptive (B cells and CD4+ and CD8+ T cells) immune responses. This review summarizes the principal trophic factors that are related to immune regulation and secreted by MSCs under both autoimmune and inflammatory conditions. The understanding of mechanisms that regulate immunity in MSCs field is important for their future use as a novel cellular-based immunotherapy with clinical applications in several diseases.State of Sao Paulo Foundation for Research Support (FAPESP) [08/55447-1, 09/51649-1, 10/12295-7, 10/16213-5, 07/07139-3]State of Sao Paulo Foundation for Research Support (FAPESP)Brazilian Council of Scientific and Technologic Development (CNPq/DECIT/MS) [470533/2007-2]Brazilian Council of Scientific and Technologic Development (CNPq/DECIT/MS)Complex Fluids INCTComplex Fluids INC

Exploring the Role of Soluble Factors Associated with Immune Regulatory Properties of Mesenchymal Stem Cells

Mesenchymal stem cells (MSCs) are characterized as multipotent stromal cells with the capacity for both self-renewal and differentiation into mesodermal cell lineages. MSCs also have a fibroblast-like phenotype and can be isolated from several tissues. In recent years, researchers have found that MSCs secrete several soluble factors that exert immunosuppressive effects by modulating both innate (macrophages, dendritic and NK cells) and adaptive (B cells and CD4+ and CD8+ T cells) immune responses. This review summarizes the principal trophic factors that are related to immune regulation and secreted by MSCs under both autoimmune and inflammatory conditions. The understanding of mechanisms that regulate immunity in MSCs field is important for their future use as a novel cellular-based immunotherapy with clinical applications in several diseases.State of Sao Paulo Foundation for Research Support (FAPESP) [08/55447-1, 09/51649-1, 10/12295-7, 10/16213-5, 07/07139-3]State of Sao Paulo Foundation for Research Support (FAPESP)Brazilian Council of Scientific and Technologic Development (CNPq/DECIT/MS) [470533/2007-2]Brazilian Council of Scientific and Technologic Development (CNPq/DECIT/MS)Complex Fluids INCTComplex Fluids INC

Mitochondria as central hub of the immune system

Nearly 130 years after the first insights into the existence of mitochondria, new rolesassociated with these organelles continue to emerge. As essential hubs that dictate cell fate, mitochondria integrate cell physiology, signaling pathways and metabolism. Thus, recent research has focused on understanding how these multifaceted functions can be used to improve inflammatory responses and prevent cellular dysfunction. Here, we describe the role of mitochondria on the development and function of immune cells, highlighting metabolic aspects and pointing out some metabolic- independent features of mitochondria that sustain cell function26CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQCOORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPnão temnão tem2014/10910-7; 2015/15626-8; 2015/26682-6; 2016/18031-8; 2017/05264-

The macrophage switch in obesity development

Immune cell infiltration in (white) adipose tissue during obesity is associated with the development of insulin resistance. In adipose tissue, the main population of leukocytes are macrophages. Macrophages can be classified into two major populations: M1, classically activated macrophages, and M2, alternatively activated macrophages, although recent studies have identified a broad range of macrophage subsets. During obesity, adipose tissue M1 macrophage numbers increase and correlate with adipose tissue inflammation and insulin resistance. Upon activation, pro-inflammatory M1 macrophages induce aerobic glycolysis. By contrast, in lean humans and mice, the number of M2 macrophages predominates. M2 macrophages secrete anti-inflammatory cytokines and utilize oxidative metabolism to maintain adipose tissue homeostasis. Here we review the immunologic and metabolic functions of adipose tissue macrophages and their different facets in obesity and the metabolic syndrome

NEOTROPICAL ALIEN MAMMALS: a data set of occurrence and abundance of alien mammals in the Neotropics

Biological invasion is one of the main threats to native biodiversity. For a species to become invasive, it must be voluntarily or involuntarily introduced by humans into a nonnative habitat. Mammals were among first taxa to be introduced worldwide for game, meat, and labor, yet the number of species introduced in the Neotropics remains unknown. In this data set, we make available occurrence and abundance data on mammal species that (1) transposed a geographical barrier and (2) were voluntarily or involuntarily introduced by humans into the Neotropics. Our data set is composed of 73,738 historical and current georeferenced records on alien mammal species of which around 96% correspond to occurrence data on 77 species belonging to eight orders and 26 families. Data cover 26 continental countries in the Neotropics, ranging from Mexico and its frontier regions (southern Florida and coastal-central Florida in the southeast United States) to Argentina, Paraguay, Chile, and Uruguay, and the 13 countries of Caribbean islands. Our data set also includes neotropical species (e.g., Callithrix sp., Myocastor coypus, Nasua nasua) considered alien in particular areas of Neotropics. The most numerous species in terms of records are from Bos sp. (n = 37,782), Sus scrofa (n = 6,730), and Canis familiaris (n = 10,084); 17 species were represented by only one record (e.g., Syncerus caffer, Cervus timorensis, Cervus unicolor, Canis latrans). Primates have the highest number of species in the data set (n = 20 species), partly because of uncertainties regarding taxonomic identification of the genera Callithrix, which includes the species Callithrix aurita, Callithrix flaviceps, Callithrix geoffroyi, Callithrix jacchus, Callithrix kuhlii, Callithrix penicillata, and their hybrids. This unique data set will be a valuable source of information on invasion risk assessments, biodiversity redistribution and conservation-related research. There are no copyright restrictions. Please cite this data paper when using the data in publications. We also request that researchers and teachers inform us on how they are using the data

NEOTROPICAL XENARTHRANS: a data set of occurrence of xenarthran species in the Neotropics

Xenarthrans—anteaters, sloths, and armadillos—have essential functions for ecosystem maintenance, such as insect control and nutrient cycling, playing key roles as ecosystem engineers. Because of habitat loss and fragmentation, hunting pressure, and conflicts with domestic dogs, these species have been threatened locally, regionally, or even across their full distribution ranges. The Neotropics harbor 21 species of armadillos, 10 anteaters, and 6 sloths. Our data set includes the families Chlamyphoridae (13), Dasypodidae (7), Myrmecophagidae (3), Bradypodidae (4), and Megalonychidae (2). We have no occurrence data on Dasypus pilosus (Dasypodidae). Regarding Cyclopedidae, until recently, only one species was recognized, but new genetic studies have revealed that the group is represented by seven species. In this data paper, we compiled a total of 42,528 records of 31 species, represented by occurrence and quantitative data, totaling 24,847 unique georeferenced records. The geographic range is from the southern United States, Mexico, and Caribbean countries at the northern portion of the Neotropics, to the austral distribution in Argentina, Paraguay, Chile, and Uruguay. Regarding anteaters, Myrmecophaga tridactyla has the most records (n = 5,941), and Cyclopes sp. have the fewest (n = 240). The armadillo species with the most data is Dasypus novemcinctus (n = 11,588), and the fewest data are recorded for Calyptophractus retusus (n = 33). With regard to sloth species, Bradypus variegatus has the most records (n = 962), and Bradypus pygmaeus has the fewest (n = 12). Our main objective with Neotropical Xenarthrans is to make occurrence and quantitative data available to facilitate more ecological research, particularly if we integrate the xenarthran data with other data sets of Neotropical Series that will become available very soon (i.e., Neotropical Carnivores, Neotropical Invasive Mammals, and Neotropical Hunters and Dogs). Therefore, studies on trophic cascades, hunting pressure, habitat loss, fragmentation effects, species invasion, and climate change effects will be possible with the Neotropical Xenarthrans data set. Please cite this data paper when using its data in publications. We also request that researchers and teachers inform us of how they are using these data