Receptors for immunoglobulin G (FcyR)

Os receptores para IgG fazem uma importante ligação entre as respostas imunes humoral e celular. Estes receptores medeiam várias respostas biológicas tais como: fagocitose, endocitose, captura e clearance de imunocomplexos, citotoxicidade e liberação de mediadores inflamatórios. Os FcyR humanos pertencem à superfamília das imunoglobulinas e três classes principais destes receptores são descritas, as quais apresentam várias isoformas. Estas moléculas diferem quanto à afinidade e especificidade para os isotipos de IgG, distribuição celular, sinalização intracelular e pesos moleculares. Além disso, o polimorfismo genético é responsável por variações entre os indivíduos. A diversidade estrutural e funcional dos FcyR faz destas moléculas importantes alvos para a imunoterapia. A ativação e desativação de células efetoras via FcyR pode ser explorada para o desenvolvimento de novas terapias para o câncer, doenças infecciosas e desordens auto-imunes. Esta revisão descreve detalhes estruturais e funcionais, relevância clínica e alguns usos terapêuticos dos FcyR.Receptors for immunoglobulin G (FcyR) provide an important link between the humoral and cellular branches of the immune response. These receptors can trigger a variety of biological responses such as phagocytosis, endocytosis, capture and clearance of immune complexes, antibody-dependent cell citotoxicity and release of inflammatory mediators. Human FcyR belong to the Ig superfamily and three classes of these receptors are distinguished specifying many receptor isoforms. These molecules differ in affinity and specificity for IgG isotypes, cell distribution patterns, intracellular signal delivery and molecular weights. Moreover, the genetic polymorphism introduces variations among individuals. The structural and functional diversity makes these receptors potential targets for immunotherapy. Activation and deactivation of effector cells via FcyR can be exploited to develop novel therapies for cancer, infectious diseases and autoimmune disorders. This review describes structural and functional details, clinical relevance and some therapeutic use of the FcyR molecules.  &nbsp

Clearance of immune complexes: role of complement and polymorphonuclear neutrophils

O sistema complemento desempenha um papel importante no transporte e eliminação de imunocomplexos (IC) circulantes. No entanto, existem circunstâncias em que os mecanismos envolvidos não são eficientes, favorecendo a deposição dos IC em órgãos específicos. Tais complexos depositados estimulam a fagocitose pelos polimorfonucleares neutrófilos, com conseqüente produção de radicais de oxigênio e liberação de enzimas lisossomais, e contribuem para a lesão tecidual local. Nesta revisão, damos ênfase ao papel do complemento, bem como dos neutrófilos, na patogênese das doenças por imunocomplexos.The complement system plays an important role in the transport and elimination of circulating immune complexes (IC). However, there are circunstances where the envolved mechanisms fail, leading to deposition of IC at specific organs. The deposited complexes stimulate phagocytosis by polymorphonuclear neutrophils, with production of oxygen radicals and release of lysossomal enzymes, thus contributing to tissular injury. In this review, we discuss the role of complement and neutrophils in pathogenesis of immune complexes diseases

Propranolol does not affect the oxidative burst of rat neutrophils or complement serum opsonizing capacity in in vivo and in vitro experiments

Propranolol is a ß-adrenergic antagonist used for the treatment of a variety of cardiac conditions and has a palliative value when used in situations in which adrenergic signals and symptoms are involved. It is used as a co-adjuvant in hyperthyroidism to decrease heart rate and output, as well as the tremor. The aim of this work was to study the effect of propranolol treatment on the oxidative burst of rat peripheral blood neutrophils and on the complement system.In the in vivo study, Wistar male rats were treated with propranolol by gavage for 16 days with 220 or 440 μg/animal/day. These doses are equivalent to 80 or 160 mg/adult human (~70 day/kg), respectively. Neutrophils were obtained and stimulated with opsonized immune complexes (opIC). The oxidative burst of control (from water treated rats) or propranolol-treated rat cells was measured by luminol- and lucigenin-dependent chemiluminescence (CL). The CL of treated rat neutrophils was not affected by any of the propranolol doses studied when compared to the control responses.In the in vitro study whole blood and serum from Wistar male rats were incubated for 1 h at 37C° with propranolol at three different concentrations (17.5, 35 and 70 μg/mL). After incubation, neutrophils were isolated from whole blood and stimulated with opIC while treated sera were used to opsonize IC. IC opsonized with treated sera were used to stimulate neutrophils from normal rats. In both cases oxidative burst was measured by luminol- and lucigenin-dependent CL. No differences in responses or activities were detected between in vitro treated neutrophils or sera and their respective controls.These results suggest that this drug, at the concentrations studied and with the experimental approach used, had no effect on the oxidative burst during phagocytosis of opIC or on the complement opsonization capacity of the sera

Sensibilização de hemácias de carneiro e restrição à lise pelo sistema complemento do soro eqüino e de carneiro

The effect of the degree of sheep red cell sensitisation by antibody in the resistance to lysis by sheep and horse complement was analysed. The results showed that, as the level of sensitisation increased, so did the homologous complement activity, eventually leading to one hundred percent of lysis; the same was observed for horse serum, generally considered as not efficient at lysing these cells. Therefore, the homologous and heterologous restriction can be overridden by this treatment. This may be of interest for the comprehension of the mechanisms involved in the modulation of the restriction phenomenon in health an in diseases involving complement in domestic animals and in human, as well as in laboratory diagnosis where hemolytic assays are used for measurement of complement activity and evaluation of presence of antibodies in serum samples.Neste trabalho foi analisado o efeito do grau de sensibilização de hemácias de carneiro por anticorpo, na resistência à lise pelo complemento do soro eqüino e de carneiro. Os resultados mostraram que, à medida que houve um aumento do nível de sensibilização, ocorreu também um aumento da atividade do complemento homólogo, levando a 100% de lise; o mesmo foi observado para o complemento do soro eqüino, geralmente considerado ineficiente na lise destas células. A restrição à lise pode, assim, ser sobrepujada por este tratamento. Estes dados podem ser de interesse para a compreensão dos mecanismos envolvidos na modulação do fenômeno de restrição, na saúde e em doenças envolvendo o sistema complemento em animais domésticos e no homem, bem como em diagnóstico laboratorial, onde são utilizados ensaios hemolíticos para medida de atividade do complemento e pesquisa de anticorpos em amostras de soro

Modulatory effects of rutin on biochemical and hematological parameters in hypercholesterolemic Golden Syrian hamsters

Flavonoids have been reported to exhibit several pharmacological properties, mainly in cardiovascular and inflammatory diseases. In the present study, we observed that rutin, a known glycosylated flavonoid isolated from Dimorphandra mollis, had a lowering effect on plasma triglyceride levels of diet-induced hypercholesterolemic Golden Syrian hamsters, but did not change total cholesterol and high-density lipoprotein cholesterol levels. Moreover, high-fat or rutin supplemented diets showed no immunotoxic effects, since no significant changes were observed on total white blood cells, granulocytes and mononuclear cells, as well as on the neutrophil apoptosis degree, when compared to untreated animals. Therefore, rutin seems to be a selective and non-toxic modulator of hypercholesterolemia, which can be promising for the development of new drugs.Os flavonóides possuem diversas propriedades farmacológicas, principalmente nas doenças cardiovasculares e inflamatórias. No presente estudo, observamos que a rutina, um conhecido flavonóide glicosilado isolado da Dimorphandra mollis, diminuiu o nível de triglicerídeos plasmáticos em hamsters Golden Syrian hipercolesterolêmicos sem alterar os níveis de colesterol total e colesterol HDL. Além disso, observamos que dietas hipercolesterolêmicas ou suplementadas com rutina não apresentaram efeito imunotóxico, uma vez que nenhuma alteração significativa foi observada nos leucócitos totais, granulócitos e células mononucleares, bem como no grau de neutrófilos em apoptose, quando comparado com animais não tratados. Portanto, a rutina parece ser um modulador seletivo e não tóxico da hipercolesterolemia, o que pode ser promissor para o desenvolvimento de novos fármacos.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), São Paulo State, Brazi

Evaluation of the Potential of Brazilian Propolis against UV-Induced Oxidative Stress

This study investigated the potential use of topically and orally administered propolis extracts to prevent UV irradiation-induced oxidative stress in skin. The results illustrated that green propolis extract (GPE) contained greater amounts of polyphenols, coumaric acid, drupanin, baccharin and artepillin C than did brown propolis extract (BPE). GPE showed higher antioxidant activity than BPE when the IC50 (concentration that caused 50% inhibition) values were compared. Interesting, the oral treatment of hairless mice demonstrated a recovery of 30.0% for GPE and 22.8% for BPE with respect to UV irradiation-induced GSH depletion. The topical pretreatment of animals with both propolis extract solutions recovered around 14.0% of the depleted GSH. However, the employed treatments did not inhibit the increase of cutaneous proteinase secretion/activity caused by irradiation. These findings indicate that despite differences in composition and antioxidant properties, GPE and BPE both successfully prevent UV-induced GSH depletion in vivo and are both promising antioxidant systems against oxidative stress in skin. Based on these findings, complementary studies should be performed to enhance our understanding of the protective effects of propolis extracts in skin

Fc γ

Rheumatoid arthritis (RA) is a highly disabling disease that affects all structures of the joint and significantly impacts on morbidity and mortality in RA patients. RA is characterized by persistent inflammation of the synovial membrane lining the joint associated with infiltration of immune cells. Eighty to 90% of the leukocytes infiltrating the synovia are neutrophils. The specific role that neutrophils play in the onset of RA is not clear, but recent studies have evidenced that they have an important participation in joint damage and disease progression through the release of proteolytic enzymes, reactive oxygen species (ROS), cytokines, and neutrophil extracellular traps, in particular during frustrated phagocytosis of immune complexes (ICs). In addition, the local and systemic activation of the complement system contributes to the pathogenesis of RA and other IC-mediated diseases. This review discusses (i) the participation of Fcγ and complement receptors in mediating the effector functions of neutrophils in RA; (ii) the contribution of the complement system and ROS-dependent and ROS-independent mechanisms to joint damage in RA; and (iii) the use of plant extracts, dietary compounds, and isolated natural compounds in the treatment of RA, focusing on modulation of the effector functions of neutrophils and the complement system activity and/or activation

Salmonella Typhi Bactericidal Antibodies Reduce Disease Severity but Do Not Protect against Typhoid Fever in a Controlled Human Infection Model

Effective vaccines against Salmonella Typhi, a major cause of febrile illness in tropical regions, can have a significant effect as a disease control measure. Earlier work has shown that immunization with either of two Salmonella Typhi vaccines, licensed Ty21a or candidate M01ZH09, did not provide full immunity in a controlled human infection model. Here, we describe the human humoral immune responses to these oral vaccines and their functional role in protection after challenge with S. Typhi. Serum, obtained from healthy volunteers before and after vaccination with Ty21a or M01ZH09 or placebo and before and after oral challenge with wild-type S. Typhi, was assessed for bactericidal activity. Single-dose vaccination with M01ZH09 induced an increase in serum bactericidal antibodies (p = 0.001) while three doses of Ty21a did not. No association between bactericidal activity and protection against typhoid after challenge was seen in either vaccine arm. Bactericidal activity after vaccination correlated significantly with delayed disease onset (p = 0.013), lower bacterial burden (p = 0.006), and decreased disease severity scores (p = 0.021). Depletion of antibodies directed against lipopolysaccharide significantly reduced bactericidal activity (p =  0.009). We conclude that antibodies induced after ingestion of oral live-attenuated typhoid vaccines or after challenge with wild-type S. Typhi exhibit bactericidal activity. This bactericidal activity is mediated by anti-O:LPS antibodies and significantly reduces clinical symptoms but does not provide sterile immunity. This directs future vaccine studies toward other antigens or mechanisms of protection against typhoid