Mycotic aortic aneurysm in a debilitated patient with compromised immunity; beware of Candida! / Aneurisma micótico da aorta em paciente debilitado com imunidade comprometida - um alerta para Cândida

Abstract Candida is a rare cause of infected aortic aneurysms. We report the case of a diabetic patient with end stage kidney disease who underwent repair of a leaking abdominal aortic aneurysm. He was on long-term antibiotic treatment for malignant otitis externa. Candida albicans was isolated from the culture of the excised aneurysm wall. An infected aortic aneurysm due to Candida has not been previously reported in a patient with malignant otitis externa. This case report aims to highlight that Candida should be suspected as a cause of infected aortic aneurysms in patients with debilitation and chronic immunosuppression. Management of such cases can be extremely challenging, especially in resource-poor settings, and we will be touching upon the advantages and disadvantages of various treatment options.

Resumo A cândida é uma causa rara de aneurismas da aorta infecciosos. Relatamos o caso de um paciente diabético com doença renal terminal, que foi submetido a reparo de aneurisma da aorta abdominal com vazamento. Ele estava em tratamento de longo prazo com antibióticos para otite externa maligna. A Candida albicans foi isolada da cultura da parede do aneurisma que sofreu a excisão. Não há relatos prévios de aneurisma da aorta infeccioso causado por cândida em pacientes com otite externa maligna. Este relato de caso visa reforçar que a cândida deve ser uma das suspeitas de causa de aneurisma da aorta infeccioso em pacientes debilitados e com imunossupressão crônica. O manejo desses casos pode ser extremamente desafiador, principalmente em contextos em que os recursos são escassos, e mencionaremos as vantagens e desvantagens das diversas opções de tratamento.

Efectividad de inducción de tolerancia inmune en niños con hemofilia A y aloanticuerpos neutralizantes / Immunotolerance induction effectivity in hemophilia A children and neutralizing alloantibodies

Resumen: Introducción: El desarrollo de aloanticuerpos neutralizantes anti-factor VIII en hemofilia A es la complicación más seria relacionada al tratamiento. La inducción de tolerancia inmune (ITI) o inmunotolerancia es el único tratamiento que erradica inhibidores, permitiendo utilizar nuevamente factor VIII para el tratamiento o profilaxis de eventos hemorrágicos. Objetivo: reportar la experiencia en niños sometidos a inmunotolerancia en la red pública del país. Pacientes y Método: Análisis retrospectivo y descriptivo de 13 niños con Hemofilia A severa e inhibidores persistentes de alto título, que recibieron ITI y seguimiento completo. Se utilizó concentrado de FVIII plasmático en dosis de 70-180 UI/Kg/diarias, definiendo éxito como la negativización del inhibidor y recu peración de la vida media del FVIII. Resultados expresados en media (rango). Resultados: En 13 pacientes se identificó el inhibidor, a una edad de 17,6 meses (2-48), tras 35,2 días (9-112) de exposición a FVIII. Once pacientes (84,6%) recuperaron la vida media del FVIII, tras 49,6 meses (26-70) de tratamiento. En los pacientes que respondieron, el título del inhibidor se negativizó en 7,3 meses (1-20). Conclusiones: En niños con hemofilia A e inhibidores persistentes de alto título, la ITI tiene un elevado éxito. Dado que el tiempo de respuesta es variable, la inmunotolerancia debe ser personalizada.

Abstract: Introduction: The development of anti-factor VIII neutralizing antibodies in hemophilia A is the most severe com plication related to treatment. Immune tolerance induction (ITI) is the only known treatment for eradicating inhibitors. A successful ITI allows using factor VIII (FVIII) again for the treatment or prophylaxis of hemorrhagic events. Objective: To report the experience of pediatric patients who underwent ITI in the country's public health care network. Patients and Method: Retrospective and descriptive analysis of 13 pediatric patients with severe Hemophilia A and high-titer inhibitors persis tence who underwent ITI and complete follow-up. Plasma-derived FVIII concentrate was used at 70 180 IU/kg/day doses. The success of the treatment is defined by achieving a negative titer and a half life recovery of the FVIII. The results were expressed in median (range). Results: In 13 patients, the inhibitor was identified at an average age of 17.6 months, after 35.2 days of exposure to the FVIII. 11 patients (84.6%) recovered the half-life of FVIII after 49.6 months of treatment. In the patients who responded to treatment, the inhibitor titer was negative at 6 months on average. Conclusions: ITI is the treatment of choice for patients with hemophilia A and inhibitors persistence. ITI must be perso nalized since the time response is variable in each patient.

Retinal changes in solid organ and bone marrow transplantation patients / Alterações retinianas em pacientes de um programa de transplante de órgãos sólidos e de medula óssea

ABSTRACT Objective To evaluate retinal changes in patients who underwent solid organ or bone marrow transplantation. Methods A retrospective analysis of medical records of patients evaluated from February 2009 to December 2016. All patients included underwent funduscopy. Clinical and demographic data regarding transplantation and ophthalmological changes were collected. Results A total of 126 patients were analyzed; of these, 108 underwent transplantation and 18 were in the waiting list. Transplantation modalities were heart, lung, kidney, liver, pancreas, combined pancreas and kidney and bone marrow transplantation. The main pre-transplantation comorbidities were diabetes and arterial hypertension. Of the 108 transplanted patients, 82 (76%) had retinal changes. All patients who underwent pancreas or combined pancreas and kidney transplantation had diabetic retinopathy. The main retinal changes found were diabetic retinopathy, hypertensive retinopathy, retinal vascular occlusions, chorioretinal infections and central serous chorioretinopathy. Conclusion Retinal changes were either related to preexisting conditions, mainly diabetic retinopathy, or developed postoperatively as a complication of the surgical procedure, or as an infection related to the immunosuppressive status, or due to drug toxicity. These patients may present with complex ophthalmological changes and should be carefully evaluated prior to surgery and further followed by an ophthalmologist skilled in the management of diabetic retinopathy and posterior pole infections.

RESUMO Objetivo Analisar as alterações retinianas de pacientes submetidos a transplantes de órgãos sólidos ou de medula óssea. Métodos Análise de prontuário dos pacientes avaliados no período de fevereiro de 2009 a dezembro de 2016. Todos os pacientes incluídos foram submetidos à avaliação fundoscópica. Foram coletados dados demográficos e clínicos, referentes ao transplante e às alterações oftalmológicas encontradas. Resultados Foram avaliados 126 pacientes, sendo 108 submetidos a transplantes e 18 que aguardavam o procedimento. Foram avaliados pacientes submetidos a transplantes de coração, pulmão, rim, fígado, pâncreas, pâncreas-rim e medula óssea. As principais comorbidades pré-transplante foram diabetes e hipertensão arterial. Dos 108 pacientes transplantados, 82 (76%) apresentaram alterações retinianas. Todos os pacientes submetidos ao transplante de pâncreas ou pâncreas-rim apresentaram alterações retinianas relacionadas ao diabetes. As principais alterações retinianas detectadas foram retinopatia diabética, retinopatia hipertensiva, oclusões vasculares retinianas, infecções coriorretinianas e coriorretinopatia serosa central. Conclusão As alterações retinianas estavam relacionadas a doenças preexistentes, principalmente à retinopatia diabética, ou surgiram após o transplante, como complicação do procedimento cirúrgico, ou como complicação infecciosa associada à imunossupressão, ou ainda por toxicidade medicamentosa. Tais pacientes podem apresentar alterações oculares complexas, devendo ser submetidos à avaliação retiniana pré-operatória cuidadosa e ao acompanhamento pós-operatório por oftalmologista especializado no manejo da retinopatia diabética e de doenças infecciosas do segmento posterior ocular

Rol de la microbiota gastrointestinal en la regulación de la respuesta inmune / The role of gut microbiota in the regulation of the immune response

The gastrointestinal tract hosts around 10(14) bacterial microorganisms, in a constantly growing density from the stomach to the distal colon. This microbiota is composed by more than 500 species of bacteria, which are quickly acquired after birth, fairly stable during the host’s life, and essential for human homeostasis. These bacteria have important functions, such as stimulating the immune system, protecting the host from invading bacteria and viruses, and improving digestion, especially of complex carbohydrates. Also, the gut microbiota interacts directly with the immune system. However, the interaction of the intestinal epithelium and its microbiota with the immune system has yet to be fully understood. Secretory immunoglobulin A, produced by the plasma cells in Peyer’s patches and in the lamina propria, maintains non-invasive commensal bacteria and neutralize invasive pathogens. Dendritic cells migrate from the lamina propria of the secondary lymphoid organs to regulate gut immunity. They also have a key role maintaining luminal IgA and inducing the growth of regulatory T cells. Dendritic cells supervise the gut microenvironment too, keeping an immunological equilibrium and tolerance. The importance of the gut microbiota in regulating the immune system lies mostly in the homeostasis-or positive equilibrium. Thus, many diseases are a consequence of poor interactions or a loss of this equilibrium.

Pesticide exposure and health conditions of terrestrial pesticide applicators in Córdoba Province, Argentina / Exposición a plaguicidas y condiciones de salud de agroaplicadores terrestres de la Provincia de Córdoba, Argentina / Exposição aos agrotóxicos e condições de saúde dos aplicadores de pesticidas da Província de Córdoba, Argentina

Agricultural workers represent a population that is highly vulnerable to the toxic effects of pesticide exposure. This cross sectional study aimed to describe the health conditions of terrestrial pesticide applicators in Córdoba Province, Argentina, their work practices and socio-demographic characteristics, by means of a standardized self-administered questionnaire (n = 880). A descriptive analysis reported a high prevalence of occasional or frequent symptoms: 47.4% had symptoms of irritation, 35.5% fatigue, 40.4% headache and 27.6% nervousness or depression. Using logistic regression models, risk and protective factors were found for symptoms of irritation, medical consultation and hospitalization. Among the occupational exposure variables, marital status, length of time in the job, low level of protection with regard to the use of personal protective equipment, combined use of different pesticides and the application of the insecticide endosulfan, were associated with a higher frequency of reported symptoms and higher consultation rates and hospitalization.

Los trabajadores agrícolas son una población altamente vulnerable a los efectos tóxicos de la exposición a plaguicidas. Con el objetivo de describir las condiciones de salud de agroaplicadores terrestres de plaguicidas de la Provincia de Córdoba, Argentina, sus prácticas laborales y características sociodemográficas, se realizó un estudio transversal, mediante cuestionario (n = 880). Un análisis descriptivo reportó alta prevalencia de sintomatología ocasional o frecuente: 47,4% síntomas irritativos, 35,5% cansancio, 40,4% cefalea y 27,6% ansiedad o depresión. Mediante modelos logísticos se detectaron factores protectores y de riesgo que explican la presencia de síntomas irritativos, la consulta médica y la hospitalización. El estado civil, la antigüedad en la tarea, el nivel de protección considerando uso de equipo de protección personal, la exposición múltiple a plaguicidas y la aplicación del insecticida endosulfán, se asociaron a mayor frecuencia de reporte de síntomas, consultas médicas y hospitalizaciones por causas relacionadas con la exposición a plaguicidas.

Os trabalhadores agrícolas são uma população altamente vulnerável aos efeitos tóxicos da exposição a pesticidas. Este estudo transversal teve o objetivo de descrever as condições de saúde de aplicadores terrestres de pesticidas da Província de Córdoba, Argentina, suas práticas de trabalho e características sociodemográficas, por meio de um questionário padronizado autoadministrado (n = 880). A análise descritiva relatou alta prevalência de sintomas ocasionais ou frequentes: 47,4% sintomas irritativos, 35,5% fadiga, 40,4% dor de cabeça e 27,6% ansiedade ou depressão. Mediante modelos logísticos foram detectados os fatores protetores e do risco que explicam a presença de sintomas irritativos, consulta médica e hospitalização. O estado civil, anos de trabalho, o nível de proteção considerando o uso de equipamentos de proteção individual, a exposição a vários pesticidas e aplicação do inseticida endosulfan, foram associados com maior frequência de sintomas, consultas médicas e hospitalização por causas relacionadas à exposição ao agrotóxico.

Regulatory B cells present in lymph nodes draining a murine tumor

In cancer, B cells have been classically associated with antibody secretion, antigen presentation and T cell activation. However, a possible role for B lymphocytes in impairing antitumor response and collaborating with tumor growth has been brought into focus. Recent reports have described the capacity of B cells to negatively affect immune responses in autoimmune diseases. The highly immunogenic mouse tumor MCC loses its immunogenicity and induces systemic immune suppression and tolerance as it grows. We have previously demonstrated that MCC growth induces a distinct and progressive increase in B cell number and proportion in the tumor draining lymph nodes (TDLN), as well as a less prominent increase in T regulatory cells. The aim of this research was to study B cell characteristics and function in the lymph node draining MCC tumor and to analyze whether these cells may be playing a role in suppressing antitumor response and favoring tumor progression. Results indicate that B cells from TDLN expressed increased CD86 and MHCII co-stimulatory molecules indicating activated phenotype, as well as intracellular IL-10, FASL and Granzyme B, molecules with regulatory immunosuppressive properties. Additionally, B cells showed high inhibitory upon T cell proliferation ex vivo, and a mild capacity to secrete antibodies. Our conclusion is that even when evidence of B cell-mediated activity of the immune response is present, B cells from TDLN exhibit regulatory phenotype and inhibitory activity, probably contributing to the state of immunological tolerance characteristic of the advanced tumor condition.

Redução da inflamação das vias aéreas e da produção de anticorpos IgEatravés do uso de células dendríticas tolerogênicas pulsadas com extrato solúvel de Blomia tropicalis / Reduction in airway inflammation and the production of IgE antibodies through the use of tolerogenic dendritic cells pulsed with soluble extracts of Blomia tropicalis

As alergias afetam cerca de 20 a 30% da população mundial e sua prevalência, bem como a gravidade dos sintomas, tem aumentado nas últimas décadas. As terapias existentes para as desordens do trato respiratório ocorrem por períodos prolongados, apresentam efeitos colaterais, muitas vezes não são efetivas para pacientes graves e dependem do afastamento do alérgeno. Uma alternativa para esses pacientes seria a indução de tolerância imunológica, através da terapia celular com células dendríticas pulsadas com o alérgeno. O presente trabalho objetivou avaliar o efeito de células dendríticas mielóides sensibilizadas in vitro com extrato de B. tropicalis em modelo murino de alergia respiratória. Em modelos experimentais de alergia respiratória, células T auxiliares (Th2)...

Allergies affect about 20-30% of world population and its prevalence and severity of symptoms has increased in recent decades. Existing therapies to respiratory tract disorders are extense, with side effects, not effective for severe patients and depending on the allergen removal. An alternative for these patients is the induction of immune tolerance by cell therapy with dendritic cells pulsed with the allergen. This study aimed to evaluate the effect of myeloid dendritic cells sensitized in vitro with B. tropicalis extract in a murine model of respiratory allergy. In experimental models of respiratory allergy, T helper cells (Th2)...

Efecto inmunosupresor de la infección por Trypanosoma musculi (Mastigophora: Trypanosomatidae) en la toxoplasmosis experimental / Immunosuppressor effect of Trypanosoma musculi (Mastigophora: Trypanosomatidae) on experimental toxoplasmosis

The immunosuppression caused by species of the gender Trypanosoma has been widely documented. The influence over experimental infections with Toxoplasma gondii is evident when using Trypanosoma lewisi, a natural parasite of white rats. We decided to test the effect of Trypanosoma musculi from mice, an organism with very similar biological characteristics to T. lewisi, to see if this trypanosomatid could induce a similar effect. Four groups of Swiss mice were inoculated with T. musculi previously to infection with T. gondii, and we determined the survival of the animals, as well as the number of cysts developed in the brain of survivors. We isolated and tested different strains of T. gondii from different sources. In a first experiment, the animals were previously inoculated with T. musculi at different times prior to the infection with Toxoplasma; this allowed us to determine that the immunosuppression process resulted more evident when T. musculi inoculation was made four days before. In a second experiment, we used different inoculi dose and found that it did not influenced the process. Furthermore, the results were negative when evaluating if the amount of the inoculated trypomastigote influenced the process. In order to demonstrate if there were differences in the immnosuppressive effect, related to Toxoplasma strains, groups of mice were inoculated with brain cysts of TFC, TLP, TLW and TBT strains. Excluding the TLP strain, that resulted to be very pathogenic regardless the previous inoculation with T. lewisi, the other strains kept the same pattern of immunosuppression in mice, whose survival time was shorter as the presence of cysts in the brain was higher. These observations were in agreement with an experi- mental immunosuppression model, associated with immunosuppressive diseases, specially cancer and AIDS.

La prevalencia de infecciones por Toxoplasma gondii en el ser humano es de 5-90% según la zona geográfica; en Costa Rica por ejemplo, la seroprevalencia es de un 58%, por lo que es importante comprender algunos procesos inmunológicos, propios en estas afectaciones parasitarias. Con el objeto de determinar si el Trypanosoma musculi ejerce procesos de inmunosupresión sobre Toxoplasma gondii se realizó un experimento en el que se inocularon ratones Swiss con T. musculi cuatro, cinco, seis y siete días previos a la infección con T. gondii, ocurriendo la inmunosupresión cuando la inoculación con T. musculi fue hecha cuatro días antes. Además, la cantidad de tripomastigotos inoculados no influyó en el proceso. Se probaron tres cepas de T. gondii aisladas de las heces de un gato casero (TFC), de un Leopardus pardalis (TLP), de un Leopardus wiedii y de la carne de un Bos taurus (TBT). La cepa TLP resultó ser muy patógena, matando a los animales en un tiempo corto, independientemente de la inoculación con T. musculi; para las otras cepas se mantuvo el patrón de inmunosupresión en los ratones. Se reporta entonces un modelo experimental de inmunosupresión, aspecto muy en boga en este momento, por su relación con enfermedades que inducen esta condición en el ser humano, especialmente a enfermedades como el cáncer y el SIDA. Este modelo es más fácil de aplicar experimentalmente que el correspondiente con T. lewisi previamente descrito, el cual usa ratas blancas de más difícil manejo que los ratones usados en este estudio.

Regulatory T cells: A review.

Regulatory T cells (Tregs) play a pivotal role in the homeostasis of the immune system and in the modulation of the immune response. Tregs have emerged as key players in the development and maintenance of peripheral immune tolerance. Broadly speaking, CD4+ T cells possessing the ability to suppress immune responses can be divided into two types: naturally occurring (nTreg) and inducible (iTreg) or adaptive regulatory cells. Naturally occurring thymus-derived CD4+CD25+ Tregs are a subset of T cells which have immunosuppressive properties and are 5%–10% of the total peripheral CD4+ T cells. In normal conditions, Tregs regulate ongoing immune responses and prevent autoimmunity. Imbalanced function or number of these cells, either enhanced or decreased, might lead to tumour development and autoimmunity, respectively. These cells thus play a major role in autoimmune diseases, transplantation tolerance, infectious diseases, allergic disease and tumour immunity. These natural properties make Tregs attractive tools for novel immunotherapeutic approaches. The in vivo manipulation or depletion of Tregs may help devise effective immunotherapy for patients with cancer, autoimmunity, graftversus- host disease, infectious diseases and allergic diseases. It is crucial to understand the biology of Tregs before attempting therapies, including (i) the injection of expanded Tregs to cure autoimmune disease or prevent graft-versus-host disease or (ii) the depletion or inhibition of Tregs in cancer therapy. Recent findings in murine models and studies in humans have opened new avenues to study the biology of Tregs and their therapeutic potential. This overview provides a framework for integrating these concepts of basic and translational research.

In search of a tolerance-induction strategy for cow's milk allergies: significant reduction of beta-lactoglobulin allergenicity via transglutaminase/cysteine polymerization

OBJECTIVE: To explore the use of β-lactoglobulin polymerized using microbial transglutaminase and heating to identify whether protein polymerization could reduce in vivo allergenicity and maintain in vitro and ex vivo immunoreactivity for use in tolerance-induction protocols. METHODS: Based on previous protocols applied in mice and children, we performed in vivo challenges (using a skin prick test) with native and polymerized β-lactoglobulin in adult patients with an IgE-mediated allergy to plactoglobulin. In vitro humoral immunoreactivity was analyzed using immunoblotting. Cell-mediated immunoreactivity was analyzed using ex vivo challenges with native and polymerized β-lactoglobulin and monitored by leukocyte adherence inhibition tests. RESULTS: The skin tests demonstrated that there was a significant reduction in immediate cutaneous reactivity after polymerization. Polymerization did not decrease the immunoblotting detection of s-IgE specific to β-lactoglobulin. Cell-mediated immunoreactivity, as assessed by ex vivo challenges and leukocyte adherence inhibition tests, did not exhibit significant differences between leukocytes challenged with native versus polymerized β-lactoglobulin. CONCLUSIONS: The polymerization of β-lactoglobulin decreased in vivo allergenicity and did not decrease in vitro humoral or ex vivo cell-mediated immunoreactivity. Therefore, we conclude that inducing polymerization using transglutaminase represents a promising technique to produce suitable molecules for the purpose of designing oral/ sublingual tolerance induction protocols for the treatment of allergies.

Dynamics of immunosuppression in hamsters with experimental visceral leishmaniasis

Immunosuppression has been reported to occur during active visceral leishmaniasis and some factors such as the cytokine profile may be involved in this process. In the mouse model of cutaneous leishmaniasis using Leishmania (Leishmania) major, the Th1 response is related to protection while the Th2 response is related to disease progression. However, in hamsters, which are considered to be an excellent model for the study of visceral leishmaniasis, this dichotomy is not observed. Using outbred 45- to 60-day-old (140 to 150 g) male hamsters infected intraperitoneally with 2 x 10(7) L. (L.) chagasi amastigotes, we evaluated the immune response of spleen cells and the production of cytokines. We used 3 to 7 hamsters per group evaluated. We detected a preserved response to concanavalin A measured by index of proliferation during all periods of infection studied, while a proliferative response to Leishmania antigen was detected only at 48 and 72 h post-infection. Messenger RNA from cytokines type 1 (IL-2, TNF-α, IFN-γ) and type 2 (IL-4, IL-10 and TGF-β) detected by reverse transcriptase polymerase chain reaction and produced by spleen cells showed no qualitative difference between control non-infected hamsters and infected hamsters during any period of infection evaluated. Cytokines were measured by the DNA band intensity on agarose gel using the Image Lab 1D L340 software with no differences observed. In conclusion, the present results showed an antigen-dependent immunosuppression in hamsters with active visceral leishmaniasis that was not related to the cytokine profile.

Tolerancia inmune y trasplante hepático: introducción para clínicos / Immune tolerance and liver transplant: introduction for clinicians

Immunologic tolerance is the absence of immune response to an allograft, which is specific to graft and, therefore, implies an appropriate immune response to a third party. In clinical practice, a related concept is more frequently used: operational tolerance. Although its frequency is unknown in most of solid organ transplants it is present in the 20 percent of hepatic receptors. This means that tolerant receptors are able to maintain a normal graft function in complete absence of immunosuppressive drugs, avoiding the frequent –and sometimes severe– adverse effects related to its use. In this paper we aim to present physicians who are familiar to liver transplantation to basic concepts related to immune tolerance and operational tolerance in humans.

La tolerancia inmune es la ausencia de una respuesta efectora dirigida al injerto, la cual es específica y, por lo tanto, implica una apropiada respuesta inmune a una tercera parte. En la práctica clínica, un concepto relacionado, es frecuentemente utilizado: la tolerancia operacional. Su frecuencia es desconocida en el trasplante de la mayor parte de órganos sólidos, pero se estima que se desarrolla en el 20 por ciento de los receptores hepáticos. Estos receptores son capaces de mantener una función normal del injerto en ausencia completa e indefinida de inmunosupresores, lo cual les permite evitar los frecuentes y algunas veces graves efectos adversos relacionados con el uso de inmunosupresores. Este artículo pretende introducir a los médicos dedicados al trasplante hepático, a los conceptos básicos relacionados con la tolerancia inmune y la tolerancia operacional en humanos.

Inmunoterapia del cáncer: Importancia de controlar la inmunosupresión / Cancer immunotherapy: Importance of overcoming immune suppression

Es cada vez mayor la evidencia experimental y clínica de que el sistema inmunitario interviene activamente en la patogénesis y el control de la progresión tumoral. Una respuesta antitumoral efectiva depende de la correcta interacción de varios componentes del sistema inmunitario, como las células presentadoras de antígeno y diferentes sub-poblaciones de linfocitos T. Sin embargo, los tumores malignos desarrollan numerosos mecanismos para evadir el reconocimiento y su eliminación por parte del sistema inmunitario. En esta revisión discutiremos algunos de esos mecanismos y posibles estrategias terapéuticas para contrarrestarlos.

Increasing evidence indicates that the immune system is involved in the control of tumor progression. Effective antitumor immune response depends on the interaction between several components of the immune system, including antigen-presenting cells and different T cell subsets. However, tumor cells develop a number of mechanisms to escape recognition and elimination by the immune system. In this review we discuss these mechanisms and address possible therapeutic approaches to overcome the immune suppression generated by tumors.

Sistema imunitário: parte III. O delicado equilíbrio do sistema imunológico entre os pólos de tolerância e autoimunidade / Immune system: part III. The delicate balance of the immune system between tolerance and autoimmunity

O sistema imunológico é constituído por uma intrincada rede de órgãos, células e moléculas e tem por finalidade manter a homeostase do organismo, combatendo as agressões em geral. A imunidade inata atua em conjunto com a imunidade adaptativa e caracteriza-se pela rápida resposta à agressão, independentemente de estímulo prévio, sendo a primeira linha de defesa do organismo. Seus mecanismos compreendem barreiras físicas, químicas e biológicas, componentes celulares e moléculas solúveis. A primeira defesa do organismo frente a um dano tecidual envolve diversas etapas intimamente integradas e constituídas pelos diferentes componentes desse sistema. A presente revisão tem como objetivo resgatar os fundamentos dessa resposta, que apresenta elevada complexidade e é constituída por diversos componentes articulados que convergem para a elaboração da resposta imune adaptativa. Destacamos algumas etapas: reconhecimento molecular dos agentes agressores; ativação de vias bioquímicas intracelulares que resultam em modificações vasculares e teciduais; produção de uma miríade de mediadores com efeitos locais e sistêmicos no âmbito da ativação e proliferação celulares; síntese de novos produtos envolvidos na quimioatração e migração de células especializadas na destruição e remoção do agente agressor; e finalmente a recuperação tecidual com o restabelecimento funcional do tecido ou órgão.

The immune system consists of an intricate network of organs, cells, and molecules responsible for maintaining the body's homeostasis and responding to aggression in general. Innate immunity operates in conjunction with adaptive immunity and is characterized by rapid response to aggression, regardless of previous stimulus, being the organism first line of defense. Its mechanisms include physical, chemical and biological barriers, cellular components, as well as soluble molecules. The organism first line of defense against tissue damage involves several steps closely integrated and constituted by different components of this system. The aim of this review is to restore the foundations of this response, which has high complexity and consists of several components that converge to articulate the development of adaptive immune response. We selected some of the following steps to review: perception and molecular recognition of aggressive agents; activation of intracellular pathways, which result in vascular and tissue changes; production of a myriad of mediators with local and systemic effects on cell activation and proliferation, synthesis of new products involved in the chemoattraction and migration of cells specialized in destruction and removal of offending agent; and finally, tissue recovery with restoration of functional tissue or organ.

A imunofisiopatologia da autoimunidade / Immunophysiopathology of autoimmunity

Este artigo visa explicar conceitos básicos de imunologia de forma clara e sucinta para expor a fisiopatologia das síndromes autoimunes através de exemplos clínicos e/ou experimentais. Esperamos assim esclarecer pontos-chaves que contribuem para a instalação destas patologias.

Immune cells and oxidative stress in the endotoxin tolerance mouse model

Sepsis is a systemic inflammatory response that can lead to tissue damage and death. In order to increase our understanding of sepsis, experimental models are needed that produce relevant immune and inflammatory responses during a septic event. We describe a lipopolysaccharide tolerance mouse model to characterize the cellular and molecular alterations of immune cells during sepsis. The model presents a typical lipopolysaccharide tolerance pattern in which tolerance is related to decreased production and secretion of cytokines after a subsequent exposure to a lethal dose of lipopolysaccharide. The initial lipopolysaccharide exposure also altered the expression patterns of cytokines and was followed by an 8- and a 1.5-fold increase in the T helper 1 and 2 cell subpopulations. Behavioral data indicate a decrease in spontaneous activity and an increase in body temperature following exposure to lipopolysaccharide. In contrast, tolerant animals maintained production of reactive oxygen species and nitric oxide when terminally challenged by cecal ligation and puncture (CLP). Survival study after CLP showed protection in tolerant compared to naive animals. Spleen mass increased in tolerant animals followed by increases of B lymphocytes and subpopulation Th1 cells. An increase in the number of stem cells was found in spleen and bone marrow. We also showed that administration of spleen or bone marrow cells from tolerant to naive animals transfers the acquired resistance status. In conclusion, lipopolysaccharide tolerance is a natural reprogramming of the immune system that increases the number of immune cells, particularly T helper 1 cells, and does not reduce oxidative stress.

Effect of aging and oral tolerance on dendritic cell function

Oral tolerance can be induced in some mouse strains by gavage or spontaneous ingestion of dietary antigens. In the present study, we determined the influence of aging and oral tolerance on the secretion of co-stimulatory molecules by dendritic cells (DC), and on the ability of DC to induce proliferation and cytokine secretion by naive T cells from BALB/c and OVA transgenic (DO11.10) mice. We observed that oral tolerance could be induced in BALB/c mice (N = 5 in each group) of all ages (8, 20, 40, 60, and 80 weeks old), although a decline in specific antibody levels was observed in the sera of both tolerized and immunized mice with advancing age (40 to 80 weeks old). DC obtained from young, adult and middle-aged (8, 20, and 40 weeks old) tolerized mice were less efficient (65, 17 and 20 percent, respectively) than DC from immunized mice (P < 0.05) in inducing antigen-specific proliferation of naive T cells from both BALB/c and DO11.10 young mice, or in stimulating IFN-g, IL-4 and IL-10 production. However, TGF-â levels were significantly elevated in co-cultures carried out with DC from tolerant mice (P < 0.05). DC from both immunized and tolerized old and very old (60 and 80 weeks old) mice were equally ineffective in inducing T cell proliferation and cytokine production (P < 0.05). A marked reduction in CD86+ marker expression was observed in DC isolated from both old and tolerized mice (75 and 50 percent, respectively). The results indicate that the aging process does not interfere with the establishment of oral tolerance in BALB/c mice, but reduces DC functions, probably due to the decline of the expression of the CD86 surface marker.

Sexual orientation, handedness, sex ratio and fetomaternal tolerance-rejection

Fraternal birth order (FBO) appears as a prenatal cause of 15 percent of homosexual males (gays) through mnemonic maternal anti-male factors. Non-right-handed men seem to be protected from homosexuality. Four hypotheses are proposed: (1) androgenic factors of non-right-handedness neutralize anti-male factors; (2) non-right-handedness and homosexuality are lethal or produce mental impairment; (3) non-right-handed male embryos are insensitive to anti-male factors; (4) mothers of non-right-handed fetuses do not produce anti-male factors. Studies of the sex ratio (SR) of older and younger siblings show: (1) a significant heterogeneity in the SR of siblings of right or non-right handed heterosexual men and women; (2) lesbians are born among siblings with high SR; (3) siblings of right-handed gays show a higher SR than non-right-handed gays that present a low SR. Based on our discovery of maternal tolerance-rejection processes, associated with genetic systems (ABO, Rh), where zygotes or embryos different from their mother induce better pregnancy and maternal tolerance than do those that share antigens with their mothers, I propose a new explanation for sexual relationships, sexual orientation, handedness and sibling SR. Lesbian embryos could induce tolerance from mothers with anti-female factors. Non-right-handedness could induce maternal tolerance, or change the maternal compatibility of "gay" embryos. Alternatively, gay embryos could be poor inducers of maternal tolerance towards male traits.

The requirement of natural killer T-cells in tolerogenic APCs-mediated suppression of collagen-induced arthritis

TGF-beta-induced tolerogenic-antigen presenting cells (Tol-APCs) could induce suppression of autoimmune diseases such as collagen-induced arthritis (CIA) and allergic asthma. In contrast, many studies have shown that NKT cells are involved in the pathogenesis of Th1-mediated autoimmune joint inflammation and Th2-mediated allergic pulmonary inflammation. In this study, we investigated the effect of CD1d-restricted NKT cells in the Tol-APCs-mediated suppression of autoimmune disease using a murine CIA model. When CIA-induced mice were treated with Tol-APCs obtained from CD1d+/- or CD1d-/- mice, unlike CD1d+/- APCs, CD1d-/- Tol-APCs failed to suppress CIA. More specifically, CD1d-/- Tol-APCs failed to suppress the production of inflammatory cytokines and the induction of Th2 responses by antigen-specific CD4 T cells both in vitro and in vivo. Our results demonstrate that the presence of CD1d-restricted NKT cells is critical for the induction of Tol-APCs-mediated suppression of CIA.

Conceptos emergentes de tolerancia y autoinmunidad: Nuevos enfoques terapéuticos / Tolerance and autoimmunity: Novel therapeutic approaches

La función primaria del sistema inmune es resguardar al individuo de los patógenos potencialmente dañinos que invaden el medio ambiente en el cual nos desarrollamos. Este cuenta con dos grandes ramas, la inmunidad innata y la adaptativa, ambas con la propiedad de diferenciar lo peligroso de aquello inofensivo. Estos procesos se hallan regulados por mecanismos homeostáticos que constituyen la tolerancia inmunológica, a los fines de limitar aquellos procesos prolongados y silenciar los potencialmente autoagresivos. Ante la falla de estos mecanismos de control, surgen las enfermedades autoinmunes. Avances en el conocimiento de la fisiopatología de estas entidades, han abierto un nuevo capítulo en el terreno de la inmunofarmacología. Su prometedor potencial actualmente nos ofrece novedosas herramientas terapéuticas para controlar y atenuar el daño causado por este tipo de respuestas. No obstante, debe continuarse la investigación en el campo de los agentes biológicos, ya que ninguno de ellos se encuentra libre de inconvenientes. Seguramente, futuros hallazgos se concretarán en futuros aciertos. Y los aciertos, en Medicina, equivalen a esperanza.

The main function of the immune system is to protect the individual against potentially dangerous pathogens. It comprises innate and adaptive cellular and soluble components, both with the capacity to discriminate between harmful and harmless. These processes are regulated by homeostatic mechanisms that constitute the so-called immunological tolerance, which aims to limit the prolonged action of immune mediators and to silence the generation of potentially autoaggressive components. Failure to silence self-reactive T and B cells results in the generation of autoimmune disease. Recent advances in our knowledge of these pathological entities have opened a new chapter in the pharmacology of the immune system. Its promising potential currently offers new therapeutic agents to control and attenuate pathological tissue damage. Nevertheless, further research regarding these biologic agents is required, since they are not free from inconveniences. It is without question that upcoming findings in this field will instill hope into the quest for the "magic bullet".