Bay 41-2272 activates host defence against local and disseminated candida albicans infections

In our previous study, we have found that 5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-pyrimidin-4-ylamine (BAY 41-2272), a guanylate cyclase agonist, activates human monocytes and the THP-1 cell line to produce the superoxide anion, increasing in vitro microbicidal activity, suggesting that this drug can be used to modulate immune functioning in primary immunodeficiency patients. In the present work, we investigated the potential of the in vivo administration of BAY 41-2272 for the treatment of Candida albicans and Staphylococcus aureus infections introduced via intraperitoneal and subcutaneous inoculation. We found that intraperitoneal treatment with BAY 41-2272 markedly increased macrophage-dependent cell influx to the peritoneum in addition to macrophage functions, such as spreading, zymosan particle phagocytosis and nitric oxide and phorbol myristate acetate-stimulated hydrogen peroxide production. Treatment with BAY 41-2272 was highly effective in reducing the death rate due to intraperitoneal inoculation of C. albicans, but not S. aureus. However, we found that in vitro stimulation of peritoneal macrophages with BAY 41-2272 markedly increased microbicidal activities against both pathogens. Our results show that the prevention of death by the treatment of C. albicans-infected mice with BAY 41-2272 might occur primarily by the modulation of the host immune response through macrophage activation.In our previous study, we have found that 5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-pyrimidin-4-ylamine (BAY 41-2272), a guanylate cyclase agonist, activates human monocytes and the THP-1 cell line to produce the superoxide anion, increasing in vitro microbicidal activity, suggesting that this drug can be used to modulate immune functioning in primary immunodeficiency patients. In the present work, we investigated the potential of the in vivo administration of BAY 41-2272 for the treatment of Candida albicans and Staphylococcus aureus infections introduced via intraperitoneal and subcutaneous inoculation. We found that intraperitoneal treatment with BAY 41-2272 markedly increased macrophage-dependent cell influx to the peritoneum in addition to macrophage functions, such as spreading, zymosan particle phagocytosis and nitric oxide and phorbol myristate acetate-stimulated hydrogen peroxide production. Treatment with BAY 41-2272 was highly effective in reducing the death rate due to intraperitoneal inoculation of C. albicans, but not S. aureus. However, we found that in vitro stimulation of peritoneal macrophages with BAY 41-2272 markedly increased microbicidal activities against both pathogens. Our results show that the prevention of death by the treatment of C. albicans-infected mice with BAY 41-2272 might occur primarily by the modulation of the host immune response through macrophage activation1101758

Immunotoxicity induced by pesticides in humans

The evidence that the immune system is affected by pesticides is growing and indicates that pesticide exposure has detrimental health effects and can contribute to increased risksfor long-term diseases, including different types of psychiatric disorders, cancers, allergies, autoimmune diseases, and infectious diseases. Motivated by such studies, the present review highlights mechanisms involved in the immunological toxicity of pesticides, as well as the association between pesticide exposure and the predisposition of diseases, caused by perturbation of immune system function. A literature review was performed using the MEDLINE, PubMed, and Scopus databases with publication dates from 1986 to 2016. The following descriptors were used: “immunotoxicity”,“Pesticides”, and“immune system”. Pesticides can affect host resistance and can directly affect lymphoid tissues and/or native cells. Disorders such as immunosuppression, hypersensitivity, autoimmunity, and cancers have been cited to result from changes in the immune system. Although public health concerns regarding pesticide exposures are directed primarily at carcinogenic and neurological mutations, these compounds can cause profound effects on the immune system and may trigger several other processes by disruption of function in other physiological systems

Impact of cockroach allergens on the immune response as an asthma trigger

This work is a literature review that aims to provide a comprehensive overview of asthma and show the importance of cockroach allergens as a trigger for the disease, as well as highlight the immune mechanisms involved. Asthma is a public health problem, with a high global prevalence, especially in children and adolescents, characterized by type 1 hypersensitivity. It is a multifactorial disease triggered by environmental, genetic, and immunological factors. Several articles have correlated asthma with cockroach allergens, and their prevalence has been increasing. Environmental conditions, low income, urban centers, and lack of basic sanitation are associated with cockroach infestations that contribute to asthma attacks. Identifying cockroach proteins capable of triggering asthma, and elucidating the immunological mechanisms involved in responding to cockroach allergens is essential. This review concludes that the prevalence of asthma triggered by cockroach allergens is high. Only two allergenic cockroaches, Blatella germanica and Periplaneta americana, have been identified with 11 and 12 allergens, respectively. Furthermore, there are very few studies that detail how the immune system of asthmatic children behaves in the face of these cockroach allergens

Molecular identification of the main allergens present in household dust of asthmatic patients

The main aeroallergens present in house dust are the mites,Dermatophagoidespteronyssinus (Derp) andDermatophagoidesfarinae (Derf), and cockroaches,Periplanetaamericana (Pera). Objective: This work aims to genetically identify the allergens Derp, Derf, and Pera in household dust of asthmatic patients. Materials and methods: 29 patients, aged between 3 and 17 years, were classified as asthmatic or non-asthmatic according to the International Study of Asthma and Allergies in Childhood(ISAAC). Subjectscompleted a complementary questionnaire and skin hypersensitivity tests were performed. House dust was collected from these patients, filtered, and then DNA was extracted. Polymerase chain reactions were performed to identify Derp, Derf, and Pera in the samples. Results: There was an association between Pera sensitization and onset of asthma. There was also an association between the presence of Derp in the home of asthmatic patients and the worsening of symptoms, such as wheezing in the chest and allergic rhinitis. An association between the presence of Derf in house dust of asthmatic patients and the symptoms of allergic rhinitis was found. These data suggest that cockroach sensitization is a predominant factor in asthmatic children and the presence of mite allergens contributesto the worsening of asthma symptoms

Genetic factors, environmental exposure, immune mechanisms and development of wheezing and asthma in childhood.

Mesmo com o constante avanço no estudo da sibilância e asma, existem inúmeras controvérsias sobre a participação da exposição à endotoxina, background genético e ativação celular. Investigamos a participação da exposição à endotoxina ambiental e o papel do LPS no desenvolvimento dos fenótipos de sibilância e asma. Para tanto selecionamos crianças sibilantes e não sibilantes, e crianças asmáticas e não asmáticas, sendo seu sangue coletado e as PBMC cultivadas com LPS. O sobrenadante foi colhido para análise de citocinas por ELISA, e analisamos os polimorfismos nos genes de CD14 e TLR4 por PCR-RFLP. Não encontramos relação entre a exposição à endotoxina ambiental e o quadro de sibilância. Observamos que PBMC estimuladas ou não com LPS de crianças sibilantes e asmáticas produzem baixos níveis de IL-12 e IFN-&#947 quando comparado com crianças não sibilantes e não asmáticas. Os polimorfismos de TLR4 e CD14 não tiveram associação com sibilância ou asma. Nossos dados sugerem que não somente a polarização Th2 é importante para desenvolver essas patogenias, mas também uma diminuição na resposta Th1.Although the great advance in the study of asthma and wheezing, there are numerous controversies about the involvement of endotoxin exposure, genetic background and cellular activation. We investigated the involvement of environmental endotoxin exposure and the role of LPS in the development of phenotypes wheezing and asthma. For experiments we selected wheezing and non-wheezing, and asthmatic and non-asthmatic children, and their blood collected and the PBMC cultured with LPS. The supernatant was collected for analysis cytokines by ELISA, and analyzed CD14 and TLR4 polymorphisms by PCR-RFLP. There was no relationship between environmental endotoxin exposure and the framework of wheezing. We observed that LPS-stimulated PBMC of wheezing and asthmatic children produce lower levels of IL-12 and IFN-&#947 when compared with non-wheezing and non-asthmatic children. The polymorphisms TLR4 and CD14 were not associated with wheezing or asthma. Our data suggest that not only Th2 polarization is important to develop these diseases, but also a decrease in Th1 response

Molecular markers of susceptibility to ocular toxoplasmosis, host and guest behaving badly

Adriana Lima Vallochi1, Anna Carla Goldberg2, Angela Falcai3, Rajendranath Ramasawmy4, Jorge Kalil4, Cláudio Silveira5, Rubens Belfort Jr5, Luiz Vicente Rizzo31Oswaldo Cruz Institution (IOC), Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, RJ, Brazil; 2NUCEL – Cellular and Molecular Therapy Center, University of São Paulo, São Paulo, SP, Brazil; 3Department of Immunology, Biomedical Science Institute, University of São Paulo, São Paulo, SP, Brazil; 4Laboratory of Immunology, Heart Institute, University of São Paulo Medical School, São Paulo, SP, Brazil; 5Department of Ophthalmology, Federal University of São Paulo, São Paulo, SP, BrazilAbstract: Infection with Toxoplasma gondii results in retinochoroiditis in 6% to 20% of immunocompetent individuals. The outcome of infection is the result of a set of interactions involving host genetic background, environmental, and social factors, and the genetic background of the parasite, all of which can be further modified by additional infections or even reinfection. Genes that encode several components of the immune system exhibit polymorphisms in their regulatory and coding regions that affect level and type of expression in response to stimuli, directing the immune response into different pathways. These variant alleles have been associated with susceptibility to immune-mediated diseases and with severity of pathology. We have investigated polymorphisms in several of these genes, identified as candidates for progression to retinochoroiditis caused by toxoplasmosis, namely chemokine (C-C motif) receptor 5 (CCR5), toll-like receptor-2 (TLR2), and TLR4. Furthermore, because interleukin-12 (IL-12) has been shown to be fundamental both in mice and in man to control a protective response against T. gondii, molecules that have a key function in IL-12 production will be emphasized in this review, in addition to discussing the importance of the genetic background of the parasite in the establishment of ocular disease.Keywords: ocular toxoplasmosis, IL-12, TLR, CCR5, immunit

Leukocytes from wheezing infants release lower amounts of IL-12 and IFN-gamma compared to non-wheezing infants

Objective This study investigated environmental endotoxin exposure during early life, sensitization to aeroallergens, the production of cytokines by LPS-stimulated leukocytes, and the development of a wheezing phenotype in a prospective cohort of infants with high risk of developing allergic diseases. Materials and Methods Eighty-four infants were followed from birth until 30 months of age. We assessed endotoxin concentration in house dust of their homes during the first 6 months of life. At age 30 months they were clinically evaluated to determine the development of wheezing and other clinical events, were skin prick tested, and had blood samples collected for the evaluation of cytokine release by LPS-stimulated peripheral blood mononuclear cells (PBMC). Results the level of endotoxin exposure during early life was not associated with development of a wheezing phenotype. On the other hand a higher incidence of respiratory infections occurred among recurrent wheezing (RW) infants. PBMC from RW children exposed to higher levels of environmental endotoxin (above 50?EU/mg) released less Interleukin (IL)-12p70 and IFN-? compared to the non-RW group. TNF-a, IL-10, IL-4, IL-5, and IL17 production by LPS-stimulated PBMC from RW and non-RW children was equivalent in both groups of environmental endotoxin exposure. Conclusion in this prospective cohort of infants with high risk of developing allergic diseases we observed that RW and non-RW children were exposed to similar levels of endotoxin early in life. LPS-stimulated PBMC from RW infants exposed to higher levels of endotoxin released significantly less IL-12 and IFN-? compared to non-RW infants. Pediatr Pulmonol. 2012. 47:10541060. (C) 2012 Wiley Periodicals, Inc.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Univ São Paulo, Inst Biomed Sci, Dept Immunol, BR-05508000 São Paulo, BrazilUniversidade Federal de São Paulo, Sch Med, Dept Pediat, Div Allergy Clin Immunol & Rheumatol, São Paulo, BrazilSantos Med Sch, Santos, SP, BrazilUniversidade Federal de São Paulo, Sch Med, Dept Pediat, Div Allergy Clin Immunol & Rheumatol, São Paulo, BrazilFAPESP: 2006/6529834FAPESP: 2007/55779-1Web of Scienc