NK cells at the crossroads in COVID-19: a question of timing / Células NK en la encrucijada en COVID-19: una cuestión de tiempo

The outbreak of the novel coronavirus SARS-CoV-2 and the attendant physiological symptoms associated with the COVID-19 disease have led to an explosion of interest studying different aspects of the immune response. As of yet, the particular roles of natural killer cells are not well understood in this disease. NK cells are critical first-response cytotoxic cells of the innate immune system. NK cells are traditionally considered important for their roles in innate immunity against tumors and viral infected cells, as well as their ability to produce cytokines, particularly interferon-γ, and participate in antibody dependent cell cytotoxicity (ADCC). Here, we describe the role of NK cells in peripheral blood and in the lungs with respect to the pathology caused by SARS-CoV-2 and discuss the implications of proposed different types of therapies on NK cells. Evidence is accumulating that NK cells play an important role in initial surveillance as part of innate immunity. With the progression of the disease and rising inflammation, these cells, when in circulation, appear to become exhausted and ineffective. In the COVID lung, however, a complex interplay between inflammatory cells, chemokines, cytokines and aberrantly activated migratory NK cells occurs, potentiating local inflammation and the critical situation in the lungs.

El brote del nuevo coronavirus SARS-CoV-2 y los síntomas fisiológicos concomitantes asociados con la enfermedad COVID-19 han provocado una explosión de interés en la investigación de diferentes aspectos de la respuesta inmune. Hasta el momento, no se comprenden bien las funciones particulares de las células asesinas naturales (NK, por sus siglas en inglés: natural killer) en esta enfermedad. Las células NK son importantes células citotóxicas de primera línea que forman parte del sistema inmune innato. Las células NK se consideran tradicionalmente importantes por su papel en la inmunidad innata contra tumores y contra células infectadas por virus, así como por su capacidad para producir citoquinas y participar en la citotoxicidad celular dependiente de anticuerpos (ADCC, por sus siglas en inglés: antibody-dependent cell-mediated cytotoxicity). Aquí, se describe el papel de las células NK en sangre periférica y en pulmones con respecto a la nueva patología causada por SARS-CoV-2 y discute las implicaciones de los diferentes tipos de terapias propuestos con respecto a células NK. Al momento, diversos tipos de evidencia comienzan a revelar que las células NK podrían desempeñar un papel crucial en la vigilancia inicial contra el SARS-CoV-2. Con la progresión de la enfermedad y el aumento de la inflamación, estas células cuando están en circulación, parecen agotarse ("exhausted") y volverse ineficaces. En los pulmones de pacientes con COVID-19, sin embargo, se produce una interacción compleja entre células inflamatorias, quimioquinas, citoquinas y células NK migratorias activadas de manera aberrante, lo que potencia la inflamación local, contribuyendo a una situación más crítica a la función pulmonar.

Innate immunity and effector and regulatory mechanisms involved in allergic contact dermatitis

Abstract: Skin's innate immunity is the initial activator of immune response mechanisms, influencing the development of adaptive immunity. Some contact allergens are detected by Toll-like receptors (TLRs) and inflammasome NLR3. Keratinocytes participate in innate immunity and, in addition to functioning as an anatomical barrier, secrete cytokines, such as TNF, IL-1β, and IL-18, contributing to the development of Allergic Contact Dermatitis. Dendritic cells recognize and process antigenic peptides into T cells. Neutrophils cause pro-inflammatory reactions, mast cells induce migration/maturation of skin DCs, the natural killer cells have natural cytotoxic capacity, the γδ T cells favor contact with hapten during the sensitization phase, and the innate lymphoid cells act in the early stages by secreting cytokines, as well as act in inflammation and tissue homeostasis. The antigen-specific inflammation is mediated by T cells, and each subtype of T cells (Th1/Tc1, Th2/Tc2, and Th17/Tc17) activates resident skin cells, thus contributing to inflammation. Skin's regulatory T cells have a strong ability to inhibit the proliferation of hapten-specific T cells, acting at the end of the Allergic Contact Dermatitis response and in the control of systemic immune responses. In this review, we report how cutaneous innate immunity is the first line of defense and focus its role in the activation of the adaptive immune response, with effector response induction and its regulation.

Manipulación de la inmunosenescencia / Immunosenescence manipulation

En la actualidad existe un aumento del envejecimiento poblacional en Cuba y a nivel mundial, consecuencia del éxito de las políticas de salud pública y del desarrollo socioeconómico. Con el incremento progresivo de la edad se evidencian cambios en el sistema inmunológico que contribuyen a una susceptibilidad incrementada a las enfermedades infecciosas, condiciones patológicas relacionadas con la inflamación, enfermedades autoinmunes, el cáncer y se manifiesta una respuesta reducida ante la vacunación. La manipulación de la inmunosenescencia a través de diferentes terapéuticas se espera que contribuya al rejuvenecimiento del sistema inmune y por consiguiente a la restauración de la inmunidad en individuos inmunocomprometidos, al control del cáncer y al incremento de la eficacia de la vacunación en ancianos(AU)

There is an increase of population aging in Cuba and globally, as a result of the success of public health policies and socio-economic development. With the progressive increase in age, there are changes in the immune system that contribute to an increased susceptibility to infectious diseases, pathological conditions related to inflammation, autoimmune diseases, cancer and a reduced response to vaccination. The manipulation of immunosenescence through different therapies has been studied. It is expected to possibly contribute to the 'rejuvenation' of the immune system and consequently, to the restoration of immunity in immunocompromised individuals, the improvement of the effectiveness of vaccination in the elderly and the control of cancer(AU)

Innate immunity and HPV: friends or foes

Most human papillomavirus infections are readily cleared by the host immune response. However, in some individuals, human papillomavirus can establish a persistent infection. The persistence of high-risk human papillomavirus infection is the major risk factor for cervical cancer development. These viruses have developed mechanisms to evade the host immune system, which is an important step in persistence and, ultimately, in tumor development. Several cell types, receptors, transcription factors and inflammatory mediators involved in the antiviral immune response are viral targets and contribute to tumorigenesis. These targets include antigen-presenting cells, macrophages, natural killer cells, Toll-like receptors, nuclear factor kappa B and several cytokines and chemokines, such as interleukins, interferon and tumor necrosis factor. In the present review, we address both the main innate immune response mechanisms involved in HPV infection clearance and the viral strategies that promote viral persistence and may contribute to cancer development. Finally, we discuss the possibility of exploiting this knowledge to develop effective therapeutic strategies.

Haplotypes in CCR5-CCR2 , CCL3 and CCL5 are associated with natural resistance to HIV-1 infection in a Colombian cohort / Los haplotipos en CCR5-CCR2 , CCL3 y CCL5 se asocian con resistencia natural a la infección por el HIV-1 en una cohorte colombiana

RESUMEN Introduction: Variants in genes encoding for HIV-1 co-receptors and their natural ligands have been individually associated to natural resistance to HIV-1 infection. However, the simultaneous presence of these variants has been poorly studied. Objective: To evaluate the association of single and multilocus haplotypes in genes coding for the viral co-receptors CCR5 and CCR2, and their ligands CCL3 and CCL5, with resistance or susceptibility to HIV-1 infection. Materials and methods: Nine variants in CCR5-CCR2, two SNPs in CCL3 and two in CCL5 were genotyped by PCR-RFLP in 35 seropositive (cases) and 49 HIV-1-exposed seronegative Colombian individuals (controls). Haplotypes were inferred using the Arlequin software, and their frequency in individual or combined loci was compared between cases and controls by the chi-square test. A p' value <0.05 after Bonferroni correction was considered significant. Results: Homozygosis of the human haplogroup (HH) E was absent in controls and frequent in cases, showing a tendency to susceptibility. The haplotypes C-C and T-T in CCL3 were associated with susceptibility (p'=0.016) and resistance (p'<0.0001) to HIV-1 infection, respectively. Finally, in multilocus analysis, the haplotype combinations formed by HHC in CCR5-CCR2, T-T in CCL3 and G-C in CCL5 were associated with resistance (p'=0.006). Conclusion: Our results suggest that specific combinations of variants in genes from the same signaling pathway can define an HIV-1 resistant phenotype. Despite our small sample size, our statistically significant associations suggest strong effects; however, these results should be further validated in larger cohorts.

ABSTRACT Introducción. Algunas variantes en genes que codifican los correceptores del HIV-1 y sus ligandos se han asociado individualmente a la resistencia natural frente a dicha infección. Sin embargo, su presencia simultánea ha sido poco estudiada. Objetivo. Evaluar la asociación de haplotipos individuales y multilocus en genes que codifican los correceptores virales CCR5 y CCR2 y sus ligandos CCL3 y CCL5 con la resistencia o la propensión a la infección por el HIV-1. Materiales y métodos. Nueve variantes en CCR5-CCR2, dos en CCL3 y dos en CCL5 fueron genotipificadas mediante reacción en cadena de la polimerasa de polimorfismos de longitud de fragmentos de restricción (Restriction Fragment Length Polymorphism-PCR-RFLP) en 35 individuos seropositivos (casos) y 49 seronegativos expuestos (controles) de Colombia. Los haplotipos se infirieron utilizando el programa Arlequín, y su frecuencia individual o combinada se comparó en los casos y los controles mediante la prueba de ji al cuadrado. Se consideró significativo un valor de p'<0,05 después de la corrección de Bonferroni. Resultados. La homocigosis del haplogrupo humano (HH) E estaba ausente en los controles y era frecuente en los casos, es decir, con tendencia hacia la propensión. Los haplotipos C-C y T-T en CCL3 se asociaron con la propensión (p'=0,016) y la resistencia (p'<0,0001), respectivamente. Por último, en el análisis multilocus, el haplotipo combinado formado por HHC en CCR5-CCR2, T-T en CCL3 y G-C en CCL5 se asoció con la resistencia (p'=0,006). Conclusión. Los resultados de este estudio sugieren que ciertas combinaciones específicas de variantes en los genes de una misma vía de señalización pueden definir un fenotipo resistente al HIV-1. Aunque el tamaño de la muestra era pequeño, las asociaciones estadísticamente significativas sugieren un efecto considerable; sin embargo, estos resultados deben validarse en cohortes de mayor tamaño.

Células dendríticas, macrófagos, natural killer e linfócitos t CD8+ desempenham papel fundamental no controle do HSV-1 no gânglio trigêmeo produzindo IL-1 beta, iNOS e granzima B

O Herpes simples tipo 1 (HSV-1) é um vírus neurotrópico que causa sintomas brandos mas também, em alguns casos, cegueira e encefalite. Estudos anteriores demonstraram que a resposta imune contra o HSV-1 ocorre principalmente no gânglio trigêmeo (GT) e que os receptores do tipo Toll 2 e 9 (TLR2/9) são importantes na mediação desta resposta. Adicionalmente, foi evidenciado que a enzima iNOS (óxido nítrico sintase) e a interleucina 1 beta (IL-1β) têm papel essencial na defesa contra a infecção por HSV-1. Assim, o presente trabalho teve como objetivo identificar as principais células responsáveis pela produção de iNOS e IL-1β, bem como, avaliar outras importantes células e moléculas que podem ou não dependerem dos receptores TLR2/9 para mediar a resposta imune contra o HSV-1. Para tanto, camundongos C57BL/6 (selvagens, WT) e TLR2/9-/- foram infectados por via intranasal com 1 x 106 p.f.u. de HSV-1. Para análise das populações de células, suspensões celulares do GT e baço de animais WT e TLR2/9-/-, infectados e não infectados, foram obtidas e analisadas por citometria de fluxo. A porcentagem de células produtoras de iNOS, IL-1β, granzima B e perforina também foi determinada por citometria de fluxo. Os mRNAs das quimiocinas MCP-1 (proteína quimiotática de monócitos 1) e IP-10 (proteína 10 induzida por interferon gama (IFN-γ)) foram quantificados no pulmão e na traqueia por PCR em tempo real. A quimiocina MCP-1 também foi quantificada em nível de proteína, contudo, por Cytometric Bead Array (CBA) no GT, baço, linfonodo e pulmão.

As expressões dos transcritos de IL-1β, dos IFNs do tipo I, das interleucinas 5 e 10 (IL-5 e IL-10) e da granzima B foram quantificados por real time PCR. Os resultados indicam que as células dendríticas (DCs) e os monócitos/macrófagos (Mo/Mɸ) são as principais células produtoras de IL-β e iNOS, respectivamente, e que, junto com os IFNs do tipo I, são essenciais para a resposta imune contra o HSV-1. Além disso, demonstramos que a granzima B produzida por linfócitos T CD8+ e células NK e, as quimiocinas MCP-1 e IP-10 são também importantes para esta resposta imune. Do mesmo modo, nossos dados indicam que os níveis substanciais de MCP-1, IP-10 e granzima B ou são TLR-independentes ou regulados por estes receptores no GT de camundongos TLR2/9-/- infectados. Assim, nossos dados fornecem forte evidência de que as respostas mediadas por DCs, Mo/Mɸ, NK e linfócitos T CD8+ através da produção de IL-1β, iNOS e granzima B, respectivamente, em conjunto com a precoce produção dos IFNs do tipo I no início da infecção, são cruciais para a defesa do hospedeiro contra o HSV-1.

Inflammasomes and dermatology

Abstract: Inflammasomes are intracellular multiprotein complexes that comprise part of the innate immune response. Since their definition, inflammasome disorders have been linked to an increasing number of diseases. Autoinflammatory diseases refer to disorders in which local factors lead to the activation of innate immune cells, causing tissue damage when in the absence of autoantigens and autoantibodies. Skin symptoms include the main features of monogenic inflammasomopathies, such as Cryopyrin-Associated Periodic Syndromes (CAPS), Familial Mediterranean Fever (FMF), Schnitzler Syndrome, Hyper-IgD Syndrome (HIDS), PAPA Syndrome, and Deficiency of IL-1 Receptor Antagonist (DIRA). Concepts from other pathologies have also been reviewed in recent years, such as psoriasis, after the recognition of a combined contribution of innate and adaptive immunity in its pathogenesis. Inflammasomes are also involved in the response to various infections, malignancies, such as melanoma, autoimmune diseases, including vitiligo and lupus erythematosus, atopic and contact dermatitis, acne, hidradenitis suppurativa, among others. Inhibition of the inflammasome pathway may be a target for future therapies, as already occurs in the handling of CAPS, through the introduction of IL-1 inhibitors. This study presents a literature review focusing on the participation of inflammasomes in skin diseases.

Efeito da infecção por HPV nas vias de sinalização por toll like receptors / Effects of HPV infection on TLR signaling pathway

As oncoproteínas E6 e E7 do Papilomavírus Humano (HPV) estão envolvidas na desregulação do sistema imune inato, provocando alterações na expressão dos receptores do tipo Toll (TLR). Considerando-se a função da via de sinalização iniciada por TLR, haveria uma vantagem para o vírus capaz de manipular a resposta desta via de modo que possa persistir nas células sem ser detectado pelo sistema imune ou ainda modulando essa resposta e criando um ambiente mais propício à manutenção da infecção. No entanto, muitos dos mecanismos que levam à eliminação da infecção ou persistência do HPV ainda são pouco conhecidos. O objetivo principal desse trabalho é investigar o papel das vias de TLR no processo de carcinogênese mediado por HPV. Inicialmente, foi analisada a expressão de genes da via de TLR em linhagens de tumores cervicais e em células expressando as oncoproteínas virais. Foram identificados vários genes diferencialmente expressos entre linhagens de células tumorais e queratinócitos normais, incluindo moléculas adaptadoras da via de TLR e genes associados à via da MAP quinase, ativação de NFkappaB e resposta imune antiviral. Cerca de 90% destes genes foram regulados negativamente. Entre eles, destacamos HMGB1, que apesar de possuir menos RNAm nas células tumorais possui um nível proteico muito maior, além de ter-se mostrado de grande importância para a viabilidade e proliferação das células tumorais, conforme demonstrado através de experimentos de supressão gênica. Em conjunto, os nossos dados indicam que E6 e E7 de HPVs de alto risco inibem proteínas da via de sinalização de TLR

Previous studies have shown that E6 and E7 HPV oncoproteins are involved in innate immune system dysregulation, causing alterations on Toll-like receptors (TLR) expression. Considering TLR pathway function, it would be advantageous for a virus to manipulate the response of this pathway so it can persist in cells without being detected by the immune system or to modulate this response to create a better environment for persistence of infection. However, many of the mechanisms leading to HPV infection clearance or persistence are still unknown and matter of active investigation. We analyzed in cervical cancer cell lines expression of genes from TLR pathway; several were differentially expressed between tumor cells lines and normal keratinocytes, including TLR adaptors molecules and genes associated with MAP kinase pathway, NFkappaB activation and antiviral immune response. About 90% of these genes were down regulated. Among them, we selected HMGB1 for further characterization due to its interference with tumor cell viability and proliferation. Altogether, our data indicate that high risk HPV E6 and E7 can inhibit TLR signaling pathway

O sistema imune inato na patogênese da malária

Por muitas décadas de estudo sobre a patogênese da malária, tem-se estabelecido que as manifestações clínicas são frequentemente uma consequência da inflamação sistêmica provocada pelo parasito. Os imunocomplexos (ICs) são encontrados na circulação de pacientes com inflamação, seja ela estéril ou causada por infecções. O presente trabalho demonstra que pacientes com malária apresentam elevados níveis de anticorpos circulantes anti-DNA, bem como ICs contendo DNA do parasito. A ativação de monócitos por ICs resultou na formação de specks de inflamassomas contendo NLRP3, NLRP12 ou AIM2, ativação de caspase 1 e liberação de IL-1βativa. As células monocucleares do sangue periférico estimuladas com ICs produzem grandes quantidades de IL-1βe TNFαe, no entanto, baixos níveis de IL-10.

A principalfonte de citocinas pró-inflamatórias em pacientes de fase aguda da malária é a subpopulação de monócitos CD14+, que expressa o receptor FcγRIIIA (CD16). Os monócitos de pacientes em fase de convalescência apresentam um fenótipo anti-inflamatório e, quando estimulados com ICs, produzem elevados níveis de IL-10 e baixos níveis de TNFαe IL-1β. Portanto, dependendo do status de ativação do monócito, os ICs podem estimular ou modular a produção de citocinas pró-inflamatórias, atuando como um importante imunoregulador durante a malária. Os monócitos (MOs), macrófagos e células dendríticas (DCs) são populações de células heterogêneas que têm papel crucial na reparação de tecidos, detecção de presença de microrganismos invasivos, iniciando respostas imunitárias protetoras. Estudos recentes definiram novos marcadores que permitem a distinção entre monócitos inflamatórios de células dendríticas derivadas de monócitos (MO-DCs), no entanto, a contribuição destas células para neuroinflamaçãodurante a MCE não foi avaliada

Neste trabalho, observamos que a infecção por Plasmodium berghei ANKA (PbA) promove a diferenciação de monócitos inflamatórios esplênicos e DCs convencionais por células dendríticas derivadas de monócitos (MO-DCs), que são CD11c+CD11b+F4/80+DC-SIGN+Ly6C+. Estas células respondem a IFNγ sendo a principal fonte de CXCL9 e CXCL10. Além disso, células MO-DCs expressando CXCL9/10 emergem no cérebro via CCR5 dependente, coincidindo com o influxo de células T CD8+e o desenvolvimento da síndrome neuropatológica letal. Assim, nossos dados fornecem evidências de que as MO-DCs induzidas pela infecção com PbA desempenham um papel central nas respostas imunes, mediando o desenvolvimento de MCE. De acordo com nossos resultados, após a diferenciação, MO-DCs, que expressam CXCL9 e CXCL10, tem um papel importante na ativação de células T CD4+e T CD8+no baço e também migram para o SNC dependente de CCR5, onde atraem e ativam células T CD8+, levando ao desenvolvimento de MCE

Avaliação dos estudantes de enfermagem sobre a aprendizagem com a simulação clínica / Evaluación de los estudiantes de enfermería sobre el aprendizaje con la simulación clínica / Evaluation of nursing students about learning with clinical simulation

RESUMO Objetivo: descrever as contribuições da simulação clínica para aprendizagem de atributos cognitivos e procedimentais, por meio do debriefing, na perspectiva dos estudantes de enfermagem. Método: estudo descritivo exploratório. Participaram 20 estudantes de Graduação em Enfermagem de uma universidade do interior paulista. Na coleta de dados, realizada na etapa do debriefing, foi registrada a percepção do aluno sobre a simulação, aspectos positivos e o que poderia ser feito de forma diferente. Os relatos foram agrupados em categorias temáticas centrais, segundo referencial de análise de conteúdo de Bardin (2011), analisadas por meio de estatística descritiva. Resultados: identificada valorização da aprendizagem ativa, crítica e reflexiva (47,5%) em decorrência da aproximação à realidade assistencial (20,3%), manifestação dos sentimentos vivenciados durante a simulação (16,9%) e composição do cenário (15,3%). Conclusão: a simulação clínica seguida do debriefing favorece a compreensão da relação entre ação e resultados alcançados na aprendizagem. .

RESUMEN Objetivo: describir las contribuciones de simulación clínica para aprender atributos cognitivos y de procedimiento, a través de debriefing, desde la perspectiva de los estudiantes de enfermería. Método: estudio exploratorio descriptivo. 20 estudiantes participaron en el Pregrado en Enfermería de una universidad de São Paulo. Durante la recolección de datos, que se aplicó durante el debriefing, fue grabado en la percepción de los estudiantes de la simulación, los aspectos positivos y lo que podría hacerse de otra manera. Los informes de los estudiantes se agrupan de acuerdo a los temas centrales, según el referencial de análisis de contenido de Bardin (2011) y analizados mediante estadística descriptiva. Resultados: identificado la mejora de aprendizaje activo, crítico y reflexivo (47,5%) debido a la aproximación a la realidad en la atención de enfermería (20,3%), un resultado de la composición del escenario (16,9%), lo que favorece el desarrollo de sentimientos experimentados durante la simulación (15,3%). Conclusión: la simulación clínica seguida de debriefing favorece la comprensión de la relación entre la acción y los resultados obtenidos en el aprendizaje. .

ABSTRACT Objective: to describe the contributions of clinical simulation for learning cognitive and procedural attributes through debriefi ng, from the perspective of nursing students. Method: descriptive exploratory study. Twenty nursing undergraduate students from a university in the interior of the state of São Paulo participated in this study. Data collection was performed at the debriefi ng stage. Student’s perceptions about the simulation, positive aspects and what they could have done differently were registered. The students’ statements were grouped according to the central themes and the framework of Bardin’s content analysis (2011) and were analyzed using descriptive statistics. Results: enhancement of active, critical and refl ective learning (47.5%) was identifi ed due to the closeness to reality in nursing care (20.3%), manifestation of feelings experienced during the simulation (15.3%) and composition of the scenario (15.3%). Conclusion: the clinical simulation followed by debriefi ng promotes the understanding of the link between action and achievements in learning. .

Modulation of cell proliferation, survival and gene expression by RAGE and TLR signaling in cells of the innate and adaptive immune response: role of p38 MAPK and NF-KB

Objective: The aim of this study was to evaluate a possible synergism between AGE-RAGE and TLR4 signaling and the role of p38 MAPK and NF-kB signaling pathways on the modulation of the expression of inflammatory cytokines and proliferation of cells from the innate and adaptive immune response. Material and Methods: T lymphocyte (JM) and monocyte (U937) cell lines were stimulated with LPS and AGE-BSA independently and associated, both in the presence and absence of p38 MAPK and NF-kB inhibitors. Proliferation was assessed by direct counting and viability was assessed by a biochemical assay of mitochondrial function. Cytokine gene expression for RAGe, CCL3, CCR5, IL-6 and TNF-α was studied by RT-PCR and RT-qPCR. Results: RAGE mRNA expression was detected in both cell lines. LPS and AGE-BSA did not influence cell proliferation and viability of either cell line up to 72 hours. LPS and LPS associated with AGE induced expression of IL-6 and TNF-α in monocytes and T cells, respectively. Conclusions: There is no synergistic effect between RAGE and TLR signaling on the expression of IL-6, TNF-α , RAGE, CCR5 and CCL3 by monocytes and lymphocytes. Activation of RAGE associated or not with TLR signaling also had no effect on cell proliferation and survival of these cell types. .

Immune responses to Leptospira infection: roles as biomarkers for disease severity

Various leptospiral components have been identified and shown to be involved in tissue destruction. In addition, immune responses to leptospires have been implicated in target organ damages in severe leptospirosis cases. Several inflammatory mediators were shown to be higher in susceptible animals than in resistant hosts. Moreover, cytokines/chemokines and serum proteins induced following Leptospira infection were suggested to be biomarkers for disease severity in human leptospirosis. This review focuses on the role of immune responses in the severity of leptospirosis. Studies in both animal models and humans are discussed.

Role of Innate Immunity in the Pathogenesis of Type 1 and Type 2 Diabetes

The importance of innate immunity in host defense is becoming clear after discovery of innate immune receptors such as Toll-like receptor or Nod-like receptor. Innate immune system plays an important role in diverse pathological situations such as autoimmune diseases. Role of innate immunity in the pathogenesis of metabolic disorders such as type 2 diabetes, metabolic syndrome or atherosclerosis that has not been previously considered as inflammatory disorders, is also being appreciated. Here, the role of innate immunity in the development of type 1 diabetes, a classical organ-specific autoimmune disease, and type 2 diabetes will be discussed, focusing on the role of specific innate immune receptors involved in these disease processes.

Immune Response and the Tumor Microenvironment: How They Communicate to Regulate Gastric Cancer

Gastric cancer is the second most common cause of cancer-related death in the world. A growing body of evidence indicates that inflammation is closely associated with the initiation, progression, and metastasis of many tumors, including those of gastric cancer. In addition, approximately 60% of the world's population is colonized by Helicobacter pylori, which accounts for more than 50% of gastric cancers. While the role of inflammation in intestinal and colonic cancers is relatively well defined, its role in stomach neoplasia is still unclear because of the limited access of pathogens to the acidic environment and the technical difficulties isolating and characterizing immune cells in the stomach, especially in animal models. In this review, we will provide recent updates addressing how inflammation is involved in gastric malignancies, and what immune characteristics regulate the pathogenesis of stomach cancer. Also, we will discuss potential therapeutics that target the immune system for the efficient treatment of gastric cancer.

Involvement and interactions of different immune cells and their cytokines in human visceral leishmaniasis

Visceral leishmaniasis (VL) or kala-azar, a disseminated infection of the lymphoreticular system of the body, is marked by severe defect in immune system of the host. Successful cure of VL depends on the immune status of the host in combination with the effects of the antileishmanial drugs. The rationale approach towards eradication of this disease would be to potentiate the immune functioning of the host in addition to parasite killing. This review deals with different aspects of adaptive and innate immune responses and explores their role in protection or pathogenesis of VL. IL-10 has emerged as the principal cytokine responsible for disease pathogenesis, although evidences regarding its source during active VL remain inconclusive. On the other hand, IFNγ, under the influence of IL-12, is mostly correlated with healing of the disease. Chemokines are important in mounting cell-mediated immune response as they can prevent parasite invasion in association with cytokines. Different types of T cells like CD4, CD8 and NK T cells also contribute to the immunology of this disease. In spite of conflicting reports, the role of regulatory T cells in VL pathogenesis is important. Recently discovered Th17 subset and its different members have been reported to perform diverse functions in the course of VL and leishmaniasis as a whole. Innate immune responses, depending on the cell types, are essential in early parasite detection and subsequent development of an efficient NK cell response. Immunotherapy targeting IL-10 could be looked upon as an interesting option for the treatment of VL.

Pathophysiology of bacterial infection of the central nervous system and its putative role in the pathogenesis of behavioral changes

Invasion of the central nervous system (CNS) by microorganisms is a severe and frequently fatal event during the course of many infectious diseases. It may lead to deafness, blindness, cerebral palsy, hydrocephalus, cognitive impairment or permanent neurological dysfunction in survivors. Pathogens can cross the blood-brain barrier by transcellular migration, paracellular migration and in infected macrophages. Pathogens may breach the blood-brain barrier and be recognized by antigen-presenting cells through the binding of Toll-like receptors. This induces the activation of nuclear factor kappa B or mitogen-activated protein kinase pathways and subsequently induces leukocyte infiltration and proliferation and the expression of numerous proteins involved in inflammation and the immune response. Many brain cells can produce cytokines, chemokines and other pro-inflammatory molecules in response to bacteria stimuli; as a consequence, polymorphonuclear cells are attracted and activated, and release large amounts of superoxide anion and nitric oxide, leading to peroxynitrite formation and oxidative stress. This cascade leads to lipid peroxidation, mitochondrial damage and blood-brain barrier breakdown, contributing to cellular injury during neuronal infection. Current evidence suggests that bacterial CNS infections can play a role in the etiopathogenesis of behavioral disorders by increasing pro-inflammatory cytokines and bacterial virulence factors. The aim of this review is to summarize the current knowledge of the relevant pathophysiologic steps in CNS infections.

Production of cytokine and chemokines by human mononuclear cells and whole blood cells after infection with Trypanosoma cruzi / Produção de citocinas e quimiocinas por células mononucleares e células do sangue total humano após infecção com Trypanosoma cruzi

INTRODUCTION: The innate immune response is the first mechanism of protection against Trypanosoma cruzi, and the interaction of inflammatory cells with parasite molecules may activate this response and modulate the adaptive immune system. This study aimed to analyze the levels of cytokines and chemokines synthesized by the whole blood cells (WBC) and peripheral blood mononuclear cells (PBMC) of individuals seronegative for Chagas disease after interaction with live T. cruzi trypomastigotes. METHODS: IL-12, IL-10, TNF-α, TGF-β, CCL-5, CCL-2, CCL-3, and CXCL-9 were measured by ELISA. Nitrite was determined by the Griess method. RESULTS: IL-10 was produced at high levels by WBC compared with PBMC, even after incubation with live trypomastigotes. Production of TNF-α by both PBMC and WBC was significantly higher after stimulation with trypomastigotes. Only PBMC produced significantly higher levels of IL-12 after parasite stimulation. Stimulation of cultures with trypomastigotes induced an increase of CXCL-9 levels produced by WBC. Nitrite levels produced by PBMC increased after the addition of parasites to the culture. CONCLUSIONS: Surface molecules of T. cruzi may induce the production of cytokines and chemokines by cells of the innate immune system through the activation of specific receptors not evaluated in this experiment. The ability to induce IL-12 and TNF-α contributes to shift the adaptive response towards a Th1 profile.

INTRODUÇÃO: A resposta imune inata é o primeiro mecanismo de proteção contra o Trypanosoma cruzi e a interação de células inflamatórias com moléculas do parasita pode ativar esta resposta e modular a resposta adaptativa. O objetivo deste trabalho foi analisar os níveis de citocinas e quimiocinas sintetizados por células do sangue total (WBC) e células mononucleares do sangue periférico (PBMC) de voluntários soronegativos para doença de Chagas depois da interação com Trypanosoma cruzi. MÉTODOS: IL-12, IL-10, TNF-α, TGF-β, CCL5, CCL2, CCL3, CXC-9 foram avaliados por ELISA. Níveis de nitrito foram determinados pelo método de Griess. RESULTADOS: Foram produzidos altos níveis de IL-10 por WBC quando comparado aos sintetizados por PBMC, inclusive após incubação com tripomastigotas. A produção de TNF-α foi significativamente maior nas culturas de PBMC e WBC após estímulo com o parasita. O aumento significativo dos níveis de IL-12 foi observado apenas em PBMC depois do estímulo com tripomastigotas. A adição de tripomastigotas nas culturas induziu aumento dos níveis de CXCL9 produzidos por WBC. Os níveis de nitrito produzidos pelos PBMCs de todos os voluntários após a adição de parasito nas culturas aumentaram. CONCLUSÕES: Moléculas de superfície do parasito podem induzir a produção de citocinas e quimiocinas pelas células da resposta imune inata através da ativação dos receptores específicos não avaliados neste experimento. A habilidade de induzir IL-12 e TNF-α contribui para direcionar uma resposta imune adaptativa de perfil Th1.

Recognition of enteroinvasive Escherichia coli and Shigella flexneri by dendritic cells: distinct dendritic cell activation states

The innate and adaptive immune responses of dendritic cells (DCs) to enteroinvasive Escherichia coli (EIEC) infection were compared with DC responses to Shigella flexneri infection. EIEC triggered DCs to produce interleukin (IL)-10, IL-12 and tumour necrosis factor (TNF)-α, whereas S. flexneri induced only the production of TNF-α. Unlike S. flexneri, EIEC strongly increased the expression of toll like receptor (TLR)-4 and TLR-5 in DCs and diminished the expression of co-stimulatory molecules that may cooperate to inhibit CD4+ T-lymphocyte proliferation. The inflammation elicited by EIEC seems to be related to innate immunity both because of the aforementioned results and because only EIEC were able to stimulate DC transmigration across polarised Caco-2 cell monolayers, a mechanism likely to be associated with the secretion of CC chemokine ligands (CCL)20 and TNF-α. Understanding intestinal DC biology is critical to unravelling the infection strategies of EIEC and may aid in the design of treatments for infectious diseases.

Micoses superficiais e os elementos da resposta imune / Superficial mycosis and the immune response elements

As micoses superficiais são prevalentes em todo o mundo, geralmente ocasionadas por dermatófitos e restritas à camada córnea. A resposta imunológica do hospedeiro às infecções dos fungos dermatófitos depende basicamente das defesas do hospedeiro a metabólitos do fungo, da virulência da cepa ou da espécie infectante e da localização anatômica da infecção. Serão revistos alguns dos fatores da defesa imunológica do hospedeiro que influenciam na eficácia da resposta imune. Em especial, a participação dos receptores de padrão de reconhecimento (PRRs), tais como os receptores toll-like ou os da família lectina (DC-SIGN e dectin-2), que participam da resposta imune inata, conferindo-lhe especificidade e definindo o padrão da resposta imune como um todo. O predomínio celular ou humoral da resposta imune definirá o quadro clínico e o prognóstico da infecção, levando à cura ou cronicidade.

Superficial mycoses are prevalent worldwide. They are often caused by dermatophytes and restricted to the stratum corneum. The host's immune response against infections caused by dermatophytes basically depends on the host's defense against metabolites of the fungi, virulence of the infecting strain or species and anatomical site of the infection. We will review some of the factors of the host's immune defense that influence the efficacy of the immune response. We will particularly review the role of pattern recognition receptors (PRRs), such as toll-like receptors or lectin receptors (DCSIGN and Dectin 2), which participate in the innate immune response, bringing specificity to the immune response and setting its pattern. The predominance of a cellular or humoral immune response determines the clinical manifestations and the prognosis of the infection, leading to healing or chronicity.