The pattern of immune cell infiltration in chromoblastomycosis: involvement of macrophage inflammatory protein-1 alpha/CCL3 and fungi persistence

Chromoblastomycosis (CR) is a subcutaneous chronic mycosis characterized by a granulomatous inflammatory response. However, little is known regarding the pattern of leukocyte subsets in CR and the pathways involved in their recruitment. The objective of this study was to assess the cellular subsets, chemokine, chemokine receptors and enzymes in CR. The inflammatory infiltrate was characterized by immunohistochemistry using antibodies against macrophages (CD68), Langerhans'cells (S100), lymphocytes (CD3, CD4, CD8, CD45RO, CD20 and CD56) and neutrophils (CD15). The expression of MIP-1alpha (Macrophage inflammatory protein-1alpha), chemokine receptors (CXCR3 and CCR1) and enzymes (superoxide dismutase-SOD and nitric oxide synthase-iNOS) was also evaluated by the same method. We observed an increase in all populations evaluated when compared with the controls. Numbers of CD15+ and CD56+ were significantly lower than CD3+, CD4+, CD20+ and CD68+ cells. Statistical analysis revealed an association of fungi numbers with CD3, CD45RO and iNOS-positive cells. Furthermore, MIP-1alpha expression was associated with CD45RO, CD68, iNOS and CXCR3. Our results suggest a possible role of MIP-1alpha and fungi persistence in the cell infiltration in CR sites.

Evaluation of CD4+CD25+ T lymphocyte response time kinetics in patients with chronic Chagas disease after in vitro stimulation with recombinant Trypanosoma cruzi antigens

Introduction CD4+CD25+ T lymphocytes have been implicated in the regulation of host inflammatory response against Trypanosoma cruzi, and may be involved in the clinical course of the disease. Methods Peripheral blood mononuclear cells from patients with chronic Chagas disease were cultured in the presence of T. cruzi recombinant antigens and assayed for lymphocytes at distinct time points. Results It was possible to differentiate clinical forms of chronic Chagas disease at days 3 and 5 according to presence of CD4+CD25+ T cells in cell cultures. Conclusions Longer periods of cell culture proved to be potentially valuable for prospective evaluations of CD4+CD25+ T lymphocytes in patients with chronic Chagas disease.

Inflammatory bowel diseases: principles of nutritional therapy

Inflammatory Bowel Diseases - ulcerative colitis and Crohn's disease- are chronic gastrointestinal inflammatory diseases of unknown etiology. Decreased oral intake, malabsorption, accelerated nutrient losses, increased requirements, and drug-nutrient interactions cause nutritional and functional deficiencies that require proper correction by nutritional therapy. The goals of the different forms of nutritional therapy are to correct nutritional disturbances and to modulate inflammatory response, thus influencing disease activity. Total parenteral nutrition has been used to correct and to prevent nutritional disturbances and to promote bowel rest during active disease, mainly in cases of digestive fistulae with high output. Its use should be reserved for patients who cannot tolerate enteral nutrition. Enteral nutrition is effective in inducing clinical remission in adults and promoting growth in children. Due to its low complication rate and lower costs, enteral nutrition should be preferred over total parenteral nutrition whenever possible. Both present equal effectiveness in primary therapy for remission of active Crohn's disease. Nutritional intervention may improve outcome in certain individuals; however, because of the costs and complications of such therapy, careful selection is warranted, especially in patients presumed to need total parenteral nutrition. Recent research has focused on the use of nutrients as primary treatment agents. Immunonutrition is an important therapeutic alternative in the management of inflammatory bowel diseases, modulating the inflammation and changing the eicosanoid synthesis profile. However, beneficial reported effects have yet to be translated into the clinical practice. The real efficacy of these and other nutrients (glutamine, short-chain fatty acids, antioxidants) still need further evaluation through prospective and randomized trials.

Behavior of inflammatory markers of myocardial injury in cardiac surgery: laboratory correlation with the clinical picture of postpericardiotomy syndrome

OBJECTIVE: To verify the association of serum markers of myocardial injury, such as troponin I, creatinine kinase, and creatinine kinase isoenzyme MB, and inflammatory markers, such as tumor necrosis factor alpha (TNF-alpha), C-reactive protein, and the erythrocyte sedimentation rate in the perioperative period of cardiac surgery, with the occurrence of possible postpericardiotomy syndrome. METHODS: This was a cohort study with 96 patients undergoing cardiac surgery assessed at the following 4 different time periods: the day before surgery (D0); the 3rd postoperative day (D3); between the 7th and 10th postoperative days (D7-10); and the 30th postoperative day (D30). During each period, we evaluated demographic variables (sex and age), surgical variables (type and duration , extracorporeal circulation), and serum dosages of the markers of myocardial injury and inflammatory response. RESULTS: Of all patients, 12 (12.5%) met the clinical criteria for a diagnosis of postpericardiotomy syndrome, and their mean age was 10.3 years lower than the age of the others (P=0.02). The results of the serum markers for tissue injury and inflammatory response were not significantly different between the 2 assessed groups. No significant difference existed regarding either surgery duration or extracorporeal circulation. CONCLUSION: The patients who met the clinical criteria for postpericardiotomy syndrome were significantly younger than the others were. Serum markers for tissue injury and inflammatory response were not different in the clinically affected group, and did not correlate with the different types and duration of surgery or with extracorporeal circulation.

Modulación de la activación de células dendríticas por antígenos de Fasciola hepatica y ligandos para receptores Toll: Potencial terapéutico en respuestas anti-inflamatorias. Fasciola hepatica antigens and TLR ligands modulate dendritic cells activation: therapeutic potential in anti-inflammatory responses.

Antecedentes: En nuestro laboratorio hemos demostrado que antígenos (Ags) de Fasciola hepatica inducen en células dendríticas murinas (CD), diferentes propiedades tolerogénicas como la incapacidad por si mismos de inducir la maduración de las células, la resistencia a la maduración por ligandos de TLR, el incremento en la producción de IDO y también la capacidad de esta estas células de dirigir la respuesta inmune hacia un perfil Th2 y T reg. Por otra parte ha sido bien documentado que CD con características tolerogénicas, ya sea inmaduras o semimaduras, son útiles para reducir respuestas inflamatorias excesivas tales como las que ocurren en enfermedades autoinmunes. Además hemos demostrado que CD tratadas con Ags del parásito en conjunto con un ligando Toll (CpG-ODN) producen altos niveles de citoquinas anti-inflamatorias (IL-10 y TGF-) bajos de citoquinas proinflamatorias (TNF, IL-6, IL-12). Hipótesis: El fenotipo semimaduro alcanzado en las CDpodría ser utilizado para reducir la inflamación en un modelo de enfermedad autoinmune en donde existe una exacerbada respuesta Th1 y Th17, ya que la producción elevada de IL-10 y TGF- podría inhibir o controlar estas respuestas de manera directa o a través de la inducción de células T regulatorias. Objetivos: En este proyecto nosotros proponemos la inmunización de animales susceptibles (ratones DBA1/j), al desarrollo de artritis inducida por colágeno (AIC) con CD tratadas con Ags de F. hepatica en conjunto con CpG-ODN para reducir los síntomas clínicos de la enfermedad. Materiales a utilizar: En nuestro laboratorio hemos desarrollado un modelo de artritis inducida por colágeno (AIC) mediante dos inmunizaciones de ratones DBA1/j con colágeno tipo II bovino y adyuvante de Freund. El modelo permitió establecer un índice clínico mediante la hinchazón en las patas de los animales. Doce días posteriores a la primera inmunización los animales serán inyectados con CD tratadas con: 1. PBS, 2.Extracto total de F.hepatica (TE) + CII, 3. CpG + CII, 4. TE+CpG+CII Se realizará la observación macroscópica diaria, a partir de los 7 días de la 2a inmunización Luego del sacrificio las articulaciones de las patas se prepararán para realizar un análisis histológico. Se detectará en suero los niveles de anticuerpos IgG1 (perfil Th2) y de IgG2a (perfil Th1) mediante la técnica de ELISA. Se detectará también el perfil de citoquinas en los nódulos drenantes por la técnica de ELISA y adicionalmente la poblaciónes celulares de células T regulatorias (Treg) CD4+CD25+Foxp3 o células Tr1. Resultados esperados: Pensamos que el tratamiento de los animales que desarrollan AIC con CD semimaduras (por el tratamiento con TE y CpG), serán capaces de migrar a los órganos linfaticos y secretar TGF-be(inductora de células T reg), IL-10 (inductoras de células Tr1), IDO inhibitoria de la respuesta de Li T y promotor de células T reg, también podría generarse una respuesta Th2 (por la presencia de antígenos del parásito), y estas respuestas aisladas o en forma sinérgica podrían inhibir las respuestas de tipo Th17 y Th1 asociadas a la patología en esta enfermedad. Importancia del proyecto: En el desarrollo de la artritis existe un aumento de la inmunidad mediada por células, asi como de la respuesta inmune humoral hacia componentes de la matriz del cartílago. El tratamiento convencional de la artritis recae en general en el uso de inmunosupresores no-específicos, los cuales poseen una variedad de efectos adversos y la inhibición de la respuesta inflamatoria no es específica. En este proyecto proponemos el uso de CD tratadas con antígenos del helminto F. hepatica y CpG ligando Tol que capacita a estas células para generar una respuesta adaptativa de tipo regulatoria, útil en la inhibición de las respuestas inflamatorias como la que ocurre durante la progresión de artritis reumatoidea en un modelo experimental en ratones. We have shown that F. hepatica Ags-treated dendritic cells (DC) together with a TLRl ligand (CpG-ODN) produce high levels of anti-inflammatory cytokines (IL-10 and TGF-Beta) and low of proinflammatory cytokines (TNF, IL-6, IL -12). Hypothesis: The semimature phenotype achieved by DC, could be used to reduce inflammation in a model of autoimmune disease. The high production of IL-10 and TGF-Beta by these cells could directly or through the induction of T reg cells inhibit the inflammatory response. Objective: In this project we propose the immunization of DBA1 / j mice, susceptible to the development of collagen-induced arthritis (CIA) with F. hepatica-treated DC in conjunction with CpG-ODN to reduce clinical signs of disease. Materials: In our laboratory, we developed the CIA model by two immunizations of DBA1 / j mice with bovine type II collagen and Freund's adjuvant. The model allowed to stablish a clinical index by swelling in the legs of animals. Twelve days after the first immunization the animals are injected with DC treated with: 1. PBS 2. F.hepatica Extract (TE) + CII, 3. CpG + CII, 4. TE + CpG + CII Macroscopic observation will take place daily from 7 days of the 2nd immunization. After sacrifice the joints of the legs will be prepared for histological analysis. Serum levels of IgG1 antibodies (Th2 profile) and IgG2a (Th1 profile) will be detected by ELISA. It will also detected the cytokine profile in draining lymph nodes by ELISA and additionally the cell populations of regulatory T cells (Treg) CD4 + CD25 + Foxp3 or Tr1 cells. Expected results: We believe that the treatment of animals that had developed CIA with DC will be able to migrate to lymphatic organs and secrete TGF-B (T reg cell-inducing), IL-10 (inducing Tr1 cells), IDO (inhibitory of T cells and inducing of T reg cells) could alone or in synergy inhibit Th17-type responses and Th1 associated with the pathology in this disease.

MC1R-dependent, melanin-based colour polymorphism is associated with cell-mediated response in the Eleonora's falcon.

Colour polymorphism in vertebrates is usually under genetic control and may be associated with variation in physiological traits. The melanocortin 1 receptor (Mc1r) has been involved repeatedly in melanin-based pigmentation but it was thought to have few other physiological effects. However, recent pharmacological studies suggest that MC1R could regulate the aspects of immunity. We investigated whether variation at Mc1r underpins plumage colouration in the Eleonora's falcon. We also examined whether nestlings of the different morphs differed in their inflammatory response induced by phytohemagglutinin (PHA). Variation in colouration was due to a deletion of four amino acids at the Mc1r gene. Cellular immune response was morph specific. In males, but not in females, dark nestling mounted a lower PHA response than pale ones. Although correlative, our results raise the neglected possibility that MC1R has pleiotropic effects, suggesting a potential role of immune capacity and pathogen pressure on the maintenance of colour polymorphism in this species.

Blunting the response to endotoxin in healthy subjects: effects of various doses of intravenous fish oil.

To test the dose response effect of infused fish oil (FO) rich in n-3 PUFAs on the inflammatory response to endotoxin (LPS) and on membrane incorporation of fatty acids in healthy subjects. Prospective, sequential investigation comparing three different FO doses. Three groups of male subjects aged 26.8 +/- 3.2 years (BMI 22.5 +/- 2.1). One of three FO doses (Omegaven10%) as a slow infusion before LPS: 0.5 g/kg 1 day before LPS, 0.2 g/kg 1 day before, or 0.2 g/kg 2 h before. Temperature, hemodynamic variables, indirect calorimetry and blood samples (TNF-alpha, stress hormones) were collected. After LPS temperature, ACTH and TNF-alpha concentrations increased in the three groups: the responses were significantly blunted (p < 0.0001) compared with the control group of the Pluess et al. trial. Cortisol was unchanged. Lowest plasma ACTH, TNF-alpha and temperature AUC values were observed after a single 0.2 g/kg dose of FO. EPA incorporation into platelet membranes was dose-dependent. Having previously shown that the response to LPS was reproducible, this study shows that three FO doses blunted it to various degrees. The 0.2 g/kg perfusion immediately before LPS was the most efficient in blunting the responses, suggesting LPS capture in addition to the systemic and membrane effects.

Schistosoma mansoni infection modulates the immune response against allergic and auto-immune diseases

Chronic Schistosoma mansoni infection leads to a type 2-immune response with increased production of interleukin (IL-10). Evidence indicates chronic exposure to S. mansoni down regulates the type 1 immune response and prevents the onset of Th1-mediated diseases such as multiple sclerosis, diabetes mellitus and Cronh's disease. Furthermore, our own studies have revealed that chronic exposure to S. mansoni also down regulates atopic disease, Th2-mediated diseases. Our studies show an inverse association between the skin prick test reactivity and infection with S. mansoni and show the severity of asthma is reduced in subjects living in an endemic area of S. mansoni. Moreover, we hypothesize the mechanisms involved in the modulation of inflammatory response in atopic individuals, is likely dependent on IL-10 production, an anti-inflammatory cytokine elevated during helminth infections. Patients with asthma and helminth infections produced less IL-5 than patients with asthma without helminth infections, and this down regulation could, in part, be mediated by IL-10. In conclusion, helminthic infections, through induction of regulatory mechanisms, such as IL-10 production, are able to modulate the inflammatory immune response involved in the pathology of auto-immune and allergic disease.

Immune response in cervical dysplasia induced by human papillomavirus: the influence of human immunodeficiency virus-1 co-infection - review

Human immunodeficiency virus (HIV-1) has become an important risk factor for human papillomavirus (HPV) infection and the development of HPV associated lesions in the female genital tract. HIV-1 may also increase the oncogenicity of high risk HPV types and the activation of low risk types. The Center for Disease Control and Prevention declared invasive cervical cancer an acquired immunodeficience virus (AIDS) defining illness in HIV positive women. Furthermore, cervical cancer happens to be the second most common female cancer worldwide. The host's local immune response plays a critical factor in controlling these conditions, as well as in changes in the number of professional antigen-presenting cells, cytokine, and MHC molecules expression. Also, the production of cytokines may determine which arm of the immune response will be stimulated and may influence the magnitude of immune protection. Although there are many studies describing the inflammatory response in HPV infection, few data are available to demonstrate the influence of the HIV infection and several questions regarding the cervical immune response are still unknown. In this review we present a brief account of the current understanding of HIV/HPV co-infection, emphasizing cervical immune response.

An overview of the effects of annexin 1 on cells involved in the inflammatory process

The concept of anti-inflammation is currently evolving with the definition of several endogenous inhibitory circuits that are important in the control of the host inflammatory response. Here we focus on one of these pathways, the annexin 1 (ANXA1) system. Originally identified as a 37 kDa glucocorticoid-inducible protein, ANXA1 has emerged over the last decade as an important endogenous modulator of inflammation. We review the pharmacological effects of ANXA1 on cell types involved in inflammation, from blood-borne leukocytes to resident cells. This review reveals that there is scope for more research, since most of the studies have so far focused on the effects of the protein and its peptido-mimetics on neutrophil recruitment and activation. However, many other cells central to inflammation, e.g. endothelial cells or mast cells, also express ANXA1: it is foreseen that a better definition of the role(s) of the endogenous protein in these cells will open the way to further pharmacological studies. We propose that a more systematic analysis of ANXA1 physio-pharmacology in cells involved in the host inflammatory reaction could aid in the design of novel anti-inflammatory therapeutics based on this endogenous mediator.

Tissue and serum immune response in chronic hepatitis C with mild histological lesions

The immunopathogenesis of chronic hepatitis C virus (HCV) infection is a matter of great controversy and has been suggested to involve a complex balance between cytokines with pro and anti-inflammatory activity. We investigated the expression of inflammatory cells and cytokines in the liver and serum of 51 chronically HCV infected patients and compared them to data from two sets of normal controls: 51 healthy blood donors and 33 liver biopsies of healthy liver donors. We also assessed the relationship between selected cytokines and cell populations in hepatic compartments and the disease stage. Compared with controls, hepatitis C patients had a greater expression of portal TNF-α, TGF-β and CD4+ and acinar IFN-γ, TNF-α, IL-1β and IL-4, as well as a higher serum concentration of IL-2, IL-10 and TGF-β. Significant positive correlations were found between portal CD4+ and TNF-α, portal CD8+ and TGF-β, portal CD45+RO and TNF-α, acinar CD45+RO and IFN-γ and acinar CD57+ and TGF-β. In conclusion, we have shown that (i) in this sample of predominantly mild disease, the immune response was associated with a pro-inflammatory response pattern, (ii) CD4+ T-lymphocytes played a major role in orchestrating the immune response and (iii) these events primarily took place in the portal space.

Schistosoma mansoni antigens alter the cytokine response in vitro during cutaneous leishmaniasis

Schistosoma mansoni infection or associated products are able to down-modulate the type 1 CD4+ T cell inflammatory response characteristic of autoimmune diseases. In this study, we evaluated how S. mansoni antigens altered the immune response that was induced by the soluble Leishmania antigen (SLA) from cutaneous leishmaniasis (CL) patients. Cytokines were measured from the supernatants of peripheral blood mononuclear cell cultures stimulated with SLA. This was performed using the sandwich enzyme linked immunosorbent assay technique in the presence or absence of S. mansoni recombinant antigens Sm29, SmTSP-2 and PIII. The addition of S. mansoni antigens to the cultures resulted in the reduction of interferon gamma (IFN-γ) levels in 37-50% of patients. Although to a lesser extent, the antigens were also able to decrease the production of tumour necrosis factor-alpha (TNF-α). We compared patients that either had or did not have reduction in IFN-γ and TNF-α production in cultures stimulated with SLA in the presence of S. mansoni antigens. We found that there was no significant difference in the levels of interleukin (IL)-10 and IL-5 in response to S. mansoni antigens between the groups. The antigens used in this study down-modulated the in vitro proinflammatory response induced by SLA in a group of CL patients through a currently undefined mechanism.

Short-term therapy with simvastatin reduces inflammatory mediators and heart inflammation during the acute phase of experimental Chagas disease

Trypanosoma cruzi infection induces progressive cardiac inflammation that leads to fibrosis and modifications in the heart architecture and functionality. Statins, such as 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors, have been studied due to their pleiotropic roles in modulating the inflammatory response. Our goal was to evaluate the effects of simvastatin on the cardiac inflammatory process using a cardiotropic strain of T. cruzi in a murine model of Chagas cardiomyopathy. C57BL/6 mice were infected with 500 trypomastigotes of the Colombian strain of T. cruzi and treated with an oral dose of simvastatin (20 mg/Kg/day) for one month and inflammatory and morphometric parameters were subsequently evaluated in the serum and in the heart, respectively. Simvastatin reduced the total cholesterol and inflammatory mediators (interferon-gamma, tumour necrosis factor-alpha, CCL2 and CCL5) in the serum and in the heart tissue at 30 days post-infection. Additionally, a proportional reduction in heart weight and inflammatory infiltration was observed. Simvastatin also reduced epimastigote proliferation in a dose-dependent manner in vitro and was able to reduce blood trypomastigotes and heart amastigote nests during the acute phase of Chagas disease in vivo. Based on these data, we conclude that simvastatin exerts a modulatory effect on the inflammatory mediators that are elicited by the Colombian strain of T. cruzi and ameliorates the heart damage that is observed in a murine model of Chagas disease.

Rethinking the triggering inflammatory processes of chronic periaortitis.

Chronic periaortitis (CP) is an uncommon inflammatory disease which primarily involves the infrarenal portion of the abdominal aorta. However, CP should be regarded as a generalized disease with three different pathophysiological entities, namely idiopathic retroperitoneal fibrosis (RPF), inflammatory abdominal aortic aneurysm and perianeurysmal RPF. These entities share similar histopathological characteristics and finally will lead to fibrosis of the retroperitoneal space. Beside fibrosis, an infiltrate with variable chronic inflammatory cell is present. The majority of these cells are lymphocytes and macrophages as well as vascular endothelial cells, most of which are HLA-DR-positive. B and T cells are present with a majority of T cells of the T-helper phenotype. Cytokine gene expression analysis shows the presence of interleukin (IL)-1alpha, IL-2, IL-4, interferon-gamma and IL-2 receptors. Adhesion molecules such as E-selectin, intercellular adhesion molecule-1 and the vascular cell adhesion molecule-1 were also found in aortic tissue, and may play a significant role in CP pathophysiology. Although CP pathogenesis remains unknown, an exaggerated inflammatory response to advanced atherosclerosis (ATS) has been postulated to be the main process. Autoimmunity has also been proposed as a contributing factor based on immunohistochemical studies. The suspected allergen may be a component of ceroid, which is elaborated within the atheroma. We review the pathogenesis and the pathophysiology of CP, and its potential links with ATS. Clinically relevant issues are summarized in each section with regard to the current working hypothesis of this complex inflammatory disease.

Neutrophils contribute to development of a protective immune response during onset of infection with Leishmania donovani.

Neutrophils are key components of the inflammatory response and as such contribute to the killing of microorganisms. In addition, recent evidence suggests their involvement in the development of the immune response. The role of neutrophils during the first weeks post-infection with Leishmania donovani was investigated in this study. When L. donovani-infected mice were selectively depleted of neutrophils with the NIMP-R14 monoclonal antibody, a significant increase in parasite numbers was observed in the spleen and bone marrow and to a lesser extent in the liver. Increased susceptibility was associated with enhanced splenomegally, a delay in the maturation of hepatic granulomas, and a decrease in inducible nitric oxide synthase expression within granulomas. In the spleen, neutrophil depletion was associated with a significant increase in interleukin 4 (IL-4) and IL-10 levels and reduced gamma interferon secretion by CD4(+) and CD8(+) T cells. Increased production of serum IL-4 and IL-10 and higher levels of Leishmania-specific immunoglobulin G1 (IgG1) versus IgG2a revealed the preferential induction of Th2 responses in neutrophil-depleted mice. Altogether, these data suggest a critical role for neutrophils in the early protective response against L. donovani, both as effector cells involved in the killing of the parasites and as significant players influencing the development of a protective Th1 immune response.