RESUMO
The complement system is activated in tuberculous pleural effusion (TPE), with increased levels of the anaphylatoxins stimulating pleural mesothelial cells (PMCs) to secrete chemokines, which recruit nonclassical monocytes to the pleural cavity. The differentiation and recruitment of naive CD4+ T cells are induced by pleural cytokines and PMC-produced chemokines in TPE. However, it is unclear whether anaphylatoxins orchestrate CD4+ T cell response via interactions between PMCs and monocytes in TPE. In this study, CD16+ and CD16- monocytes isolated from TPE patients were cocultured with PMCs pretreated with anaphylatoxins. After removing the PMCs, the conditioned monocytes were cocultured with CD4+ T cells. The levels of the cytokines were measured in PMCs and monocyte subsets treated separately with anaphylatoxins. The costimulatory molecules were assessed in conditioned monocyte subsets. Furthermore, CD4+ T cell response was evaluated in different coculture systems. The results indicated that anaphylatoxins induced PMCs and CD16+ monocytes to secrete abundant cytokines capable of only inducing Th17 expansion, but Th1 was feeble. In addition, costimulatory molecules were more highly expressed in CD16+ than in CD16- monocytes isolated from TPE. The interactions between monocytes and PMCs enhanced the ability of PMCs and monocytes to produce cytokines and that of monocytes to express HLA-DR, CD40, CD80 and CD86, which synergistically induced Th17 expansion. In the above process, anaphylatoxins enhanced the interactions between monocytes and PMCs by increasing the level of the cytokines IL-1ß, IL-6, IL-23 and upregulating the phenotype of CD40 and CD80 in CD16+ monocytes. Collectively, these data indicate that anaphylatoxins play a central role in orchestrating Th17 response mainly via interactions between CD16+ monocytes and PMCs in TPE.
Assuntos
Anafilatoxinas/imunologia , Epitélio/imunologia , Monócitos/imunologia , Derrame Pleural/imunologia , Células Th17/imunologia , Tuberculose/imunologia , Adulto , Linfócitos T CD4-Positivos , Citocinas/imunologia , Células Epiteliais/imunologia , Células Epiteliais/microbiologia , Epitélio/microbiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/fisiologia , Derrame Pleural/microbiologia , Receptores de IgG/imunologia , Tuberculose/microbiologiaRESUMO
The vascular endothelium has been discovered in the past several years to be important in shaping the cellular immune response. During the immune response the vascular endothelium is constantly perturbed by biologically potent molecules, including the complement activation peptides, C3a and C5a. Despite the importance of C3a and C5a in inflammation and immunity, their role in modulating lymphocyte function via activation of vascular endothelial cells is unknown. Accordingly, we investigated the regulated expression of the C3a and C5a receptors (complement anaphylatoxin C3a receptor [C3aR] and complement anaphylatoxin C5a receptor 1 [C5aR1]) on human umbilical vascular endothelial cells (HUVECs) and examined how C3a or C5a activation of HUVECs affects the activation and polarization of lymphatic cells. Our findings demonstrated that C3a and C5a increase C3aR and C5aR1 expression by HUVECs as well as directing their cellular transmigration and spreading through transwell filters. Moreover, C3a- or C5a-stimulated endothelial cells: (1) caused activation of B-lymphoblasts with significant increase in Fas Ligand (CD95L) (FasL), CD69, and IL-R1 expression, and (2) skewed T-lymphoblast cells toward a Th1 subtype, (CD4+ /CCR5+ ) that correlated with significant increase of IFN-γ. Collectively, these data indicate that C3a and C5a signaling is important in the activation and polarization of lymphocytes as they traffic through the vascular endothelium during the immune response.
Assuntos
Anafilatoxinas/imunologia , Linfócitos B/imunologia , Complemento C3a/imunologia , Complemento C5a/imunologia , Peptídeos/imunologia , Linfócitos T/imunologia , Células Cultivadas , Ativação do Complemento/imunologia , Endotélio Vascular/imunologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Inflamação/imunologia , Receptor da Anafilatoxina C5a/imunologia , Receptores de Complemento/imunologia , Transdução de Sinais/imunologiaRESUMO
The complement system is pivotal in the defense against invasive disease caused by Neisseria meningitidis (Nme, meningococcus), particularly via the membrane attack complex. Complement activation liberates the anaphylatoxins C3a and C5a, which activate three distinct G-protein coupled receptors, C3aR, C5aR1 and C5aR2 (anaphylatoxin receptors, ATRs). We recently discovered that C5aR1 exacerbates the course of the disease, revealing a downside of complement in Nme sepsis. Here, we compared the roles of all three ATRs during mouse nasal colonization, intraperitoneal infection and human whole blood infection with Nme. Deficiency of complement or ATRs did not alter nasal colonization, but significantly affected invasive disease: Compared to WT mice, the disease was aggravated in C3ar-/- mice, whereas C5ar1-/- and C5ar2-/- mice showed increased resistance to meningococcal sepsis. Surprisingly, deletion of either of the ATRs resulted in lower cytokine/chemokine responses, irrespective of the different susceptibilities of the mice. This was similar in ex vivo human whole blood infection using ATR inhibitors. Neutrophil responses to Nme were reduced in C5ar1-/- mouse blood. Upon stimulation with C5a plus Nme, mouse macrophages displayed reduced phosphorylation of ERK1/2, when C5aR1 or C5aR2 were ablated or inhibited, suggesting that both C5a-receptors prime an initial macrophage response to Nme. Finally, in vivo blockade of C5aR1 alone (PMX205) or along with C5aR2 (A8Δ71-73) resulted in ameliorated disease, whereas neither antagonizing C3aR (SB290157) nor its activation with a "super-agonist" peptide (WWGKKYRASKLGLAR) demonstrated a benefit. Thus, C5aR1 and C5aR2 augment disease pathology and are interesting targets for treatment, whereas C3aR is protective in experimental meningococcal sepsis.
Assuntos
Infecções Meningocócicas/imunologia , Neisseria meningitidis/imunologia , Receptor da Anafilatoxina C5a/imunologia , Receptores de Complemento/imunologia , Anafilatoxinas/imunologia , Animais , Quimiocinas/imunologia , Citocinas/imunologia , Humanos , Macrófagos/imunologia , Macrófagos/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neisseria meningitidis/patogenicidade , Neutrófilos/imunologia , Neutrófilos/microbiologia , Receptor da Anafilatoxina C5a/genética , Receptores de Complemento/genética , SepseRESUMO
Cysteine-rich secretory proteins (CRISPs) are commonly described as part of the protein content of snake venoms, nevertheless, so far, little is known about their biological targets and functions. Our study describes the isolation and characterization of Bj-CRP, the first CRISP isolated from Bothrops jararaca snake venom, also aiming at the identification of possible targets for its actions. Bj-CRP was purified using three chromatographic steps (Sephacryl S-200, Source 15Q and C18) and showed to be an acidic protein of 24.6kDa with high sequence identity to other snake venom CRISPs. This CRISP was devoid of proteolytic, hemorrhagic or coagulant activities, and it did not affect the currents from 13 voltage-gated potassium channel isoforms. Conversely, Bj-CRP induced inflammatory responses characterized by increase of leukocytes, mainly neutrophils, after 1 and 4h of its injection in the peritoneal cavity of mice, also stimulating the production of IL-6. Bj-CRP also acted on the human complement system, modulating some of the activation pathways and acting directly on important components (C3 and C4), thus inducing the generation of anaphylatoxins (C3a, C4a and C5a). Therefore, our results for Bj-CRP open up prospects for better understanding this class of toxins and its biological actions.
Assuntos
Bothrops , Venenos de Crotalídeos/química , Peptídeos/isolamento & purificação , Sequência de Aminoácidos , Anafilatoxinas/biossíntese , Anafilatoxinas/imunologia , Animais , Coagulação Sanguínea/efeitos dos fármacos , Células Cultivadas , Ativação do Complemento/efeitos dos fármacos , Eletroforese em Gel de Poliacrilamida , Hemorragia/induzido quimicamente , Humanos , Técnicas In Vitro , Masculino , Camundongos Endogâmicos C57BL , Peso Molecular , Oócitos/efeitos dos fármacos , Oócitos/metabolismo , Técnicas de Patch-Clamp , Peptídeos/farmacologia , Peptídeos/toxicidade , Canais de Potássio de Abertura Dependente da Tensão da Membrana/antagonistas & inibidores , Proteínas de Répteis/isolamento & purificação , Proteínas de Répteis/farmacologia , Proteínas de Répteis/toxicidade , Venenos de Víboras/isolamento & purificação , Venenos de Víboras/farmacologia , Venenos de Víboras/toxicidade , Xenopus laevisRESUMO
Acquired demyelinating syndromes (ADS) in children evolve either as a monophasic disease diagnosed as acute demyelinating encephalomyelitis (ADEM), transverse myelitis (TM) or optic neuritis (ON), or a multiphasic one with several relapses most often leading to the diagnosis of multiple sclerosis (MS) or neuromyelitis optica (NMO). These neuroinflammatory disorders are increasingly associated with autoantibodies against proteins such as aquaporin-4 in rare instances, and more frequently against myelin oligodendrocyte glycoprotein (MOG). Recently, in adult NMO patients, C5a levels were shown to be elevated in cerebrospinal fluid (CSF) during acute exacerbation. We investigated the CSF levels of anaphylatoxins and pro-inflammatory cytokines, and plasma MOG antibodies in onset samples from children with ADS. Thirty four children presenting with a first episode of ADS, 17 with monophasic ADS (9 with ADEM, 4 with TM and 4 with ON) and 17 with MS, who had paired blood and CSF samples at onset were included and compared to 12 patients with other non-inflammatory neurological disorders (OND). Cytokines and anaphylatoxins in CSF were measured by Cytometric Bead Array immunoassay. MOG antibody titers in plasma were tested by flow cytometry using a stable cell line expressing full-length human MOG. We found a significant increase in C5a levels in the CSF of patients with monophasic ADS (n=17) compared to OND (n=12, p=0.0036) and to MS (n=17, p=0.0371). The C5a levels in MS were higher than in OND without reaching significance (p=0.2). CSF IL-6 levels were significantly increased in monophasic ADS compared to OND (p=0.0027) and to MS (p=0.0046). MOG antibody plasma levels were significantly higher in monophasic ADS (p<0.0001) and, to a lesser extent, in MS compared to OND (p=0.0023). Plasma MOG antibodies and CSF IL-6 levels were significantly correlated (r=0.51, p=0.018). CSF C5a and IL-6 levels are increased in monophasic ADS but not in MS when compared to OND, suggesting that these markers may help to predict monophasic or relapsing fate of ADS at onset. MOG antibody titers, which were higher in monophasic ADS than in MS, correlated with IL-6 levels, but not with C5a, suggesting an association between MOG antibodies and neuroinflammation in pediatric ADS.
Assuntos
Doenças Desmielinizantes , Imunoglobulina G/sangue , Interleucina-6/imunologia , Esclerose Múltipla , Glicoproteína Mielina-Oligodendrócito/imunologia , Adolescente , Anafilatoxinas/líquido cefalorraquidiano , Anafilatoxinas/imunologia , Anafilatoxinas/metabolismo , Criança , Citocinas/metabolismo , Doenças Desmielinizantes/sangue , Doenças Desmielinizantes/líquido cefalorraquidiano , Doenças Desmielinizantes/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Interleucina-6/sangue , Interleucina-6/líquido cefalorraquidiano , Estudos Longitudinais , Masculino , Esclerose Múltipla/sangue , Esclerose Múltipla/líquido cefalorraquidiano , Esclerose Múltipla/imunologia , Glicoproteína Mielina-Oligodendrócito/sangue , Glicoproteína Mielina-Oligodendrócito/líquido cefalorraquidiano , Estudos RetrospectivosRESUMO
Listeria monocytogenes is a major cause of mortality resulting from food poisoning in the United States. In mice, C5 has been genetically linked to host resistance to listeriosis. Despite this genetic association, it remains poorly understood how C5 and its activation products, C5a and C5b, confer host protection to this Gram-positive intracellular bacterium. In this article, we show in a systemic infection model that the major receptor for C5a, C5aR1, is required for a normal robust host immune response against L. monocytogenes. In comparison with wild-type mice, C5aR1(-/-) mice had reduced survival and increased bacterial burden in their livers and spleens. Infected C5aR1(-/-) mice exhibited a dramatic reduction in all major subsets of splenocytes, which was associated with elevated caspase-3 activity and increased TUNEL staining. Because type 1 IFN has been reported to impede the host response to L. monocytogenes through the promotion of splenocyte death, we examined the effect of C5aR1 on type 1 IFN expression in vivo. Indeed, serum levels of IFN-α and IFN-ß were significantly elevated in L. monocytogenes-infected C5aR1(-/-) mice. Similarly, the expression of TRAIL, a type 1 IFN target gene and a proapoptotic factor, was elevated in NK cells isolated from infected C5aR1(-/-) mice. Treatment of C5aR1(-/-) mice with a type 1 IFNR blocking Ab resulted in near-complete rescue of L. monocytogenes-induced mortality. Thus, these findings reveal a critical role for C5aR1 in host defense against L. monocytogenes through the suppression of type 1 IFN expression.
Assuntos
Interferon-alfa/genética , Interferon beta/genética , Listeria monocytogenes/imunologia , Listeriose/imunologia , Baço/imunologia , Anafilatoxinas/imunologia , Animais , Anticorpos/farmacologia , Apoptose , Carga Bacteriana , Caspase 3/genética , Caspase 3/imunologia , Complemento C5a/genética , Complemento C5a/imunologia , Complemento C5b/genética , Complemento C5b/imunologia , Expressão Gênica , Interferon-alfa/imunologia , Interferon beta/imunologia , Listeriose/tratamento farmacológico , Listeriose/microbiologia , Listeriose/mortalidade , Fígado/imunologia , Fígado/microbiologia , Fígado/patologia , Linfócitos/imunologia , Linfócitos/microbiologia , Linfócitos/patologia , Masculino , Camundongos , Camundongos Knockout , Receptor da Anafilatoxina C5a/genética , Receptor da Anafilatoxina C5a/imunologia , Receptores de Interferon/antagonistas & inibidores , Receptores de Interferon/genética , Receptores de Interferon/imunologia , Baço/microbiologia , Baço/patologia , Análise de Sobrevida , Ligante Indutor de Apoptose Relacionado a TNF/genética , Ligante Indutor de Apoptose Relacionado a TNF/imunologiaRESUMO
Polyreactive antibodies are a major component of the natural antibody repertoire and are capable of binding a variety of structurally unrelated antigens. Many of the properties attributed to natural antibodies, in fact, are turning out to be due to polyreactive antibodies. In humans, each day, billions of cells undergo apoptosis. In the present experiments, we show by ImageStream technology that although polyreactive antibodies do not bind to live T cells they bind to both the plasma membrane and cytoplasm of late apoptotic cells, fix complement, generate the anaphylatoxin C5a and increase by as much as 5 fold complement-mediated phagocytosis by macrophages. Of particular importance, T cells undergoing apoptosis following infection with HIV also bind polyreactive antibodies and are phagocytosed. We conclude that the polyreactive antibodies in the natural antibody repertoire contribute in a major way to the clearance of cells made apoptotic by a variety of natural and infectious processes.
Assuntos
Anticorpos/imunologia , Apoptose/imunologia , Apoptose/efeitos da radiação , Proteínas do Sistema Complemento/imunologia , Fagocitose/imunologia , Anafilatoxinas/imunologia , Animais , Anticorpos/metabolismo , Complemento C5a/imunologia , Proteínas do Sistema Complemento/metabolismo , HIV/fisiologia , Humanos , Imunoglobulina M/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Linfócitos T/imunologia , Linfócitos T/patologia , Linfócitos T/efeitos da radiação , Raios Ultravioleta/efeitos adversosRESUMO
Complement receptors are expressed on cells of the innate and the adaptive immune system. They play important roles in pathogen and danger sensing as they translate the information gathered by complement fluid phase sensors into cellular responses. Further, they control complement activation on viable and apoptotic host cells, clearance of immune complexes and mediate opsonophagocytosis. More recently, evidence has accumulated that complement receptors form a complex network with other innate receptors systems such as the Toll-like receptors, the Notch signaling system, IgG Fc receptors and C-type lectin receptors contributing to the benefit and burden of innate and adaptive immune responses in autoimmune and allergic diseases as well as in cancer and transplantation. Here, we will discuss recent developments and emerging concepts of complement receptor activation and regulation with a particular focus on the differentiation, maintenance and contraction of effector and regulatory T cells.
Assuntos
Receptores de Complemento/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Anafilatoxinas/imunologia , Anafilatoxinas/metabolismo , Animais , Diferenciação Celular/imunologia , Ativação do Complemento/imunologia , Homeostase/imunologia , Humanos , Ativação Linfocitária/imunologia , Proteína Cofatora de Membrana/metabolismo , Receptores de Complemento/imunologia , Transdução de Sinais , Linfócitos T/citologia , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismoRESUMO
The complement system and Toll-like receptors (TLR) are key innate defense systems which might interact synergistically on dendritic cells (DC) to reinforce adaptive immunity. In a previous work, we found that the extra domain A from fibronectin EDA (an endogenous ligand for TLR4) can favour antigen delivery to DC and induce their maturation. Given the potential of anaphylatoxins to cause inflammation and activation of myeloid cells, we hypothesized that a fusion protein between EDA, and anaphylatoxins C3a, C4a or C5a together with an antigen might improve the immunogenicity of the antigen. Naked DNA immunization with a construct expressing the fusion protein between C5a, EDA and the cytotoxic T cell epitope SIINFEKL from ovalbumin, induced strong antigen specific T cell responses. The purified recombinant fusion protein EDA-SIINFEKL-C5a induced activation of dendritic cells, the production of proinflammatory cytokines/chemokines and stimulated antigen presenting cell migration and NK cell activation. As compared to EDA-SIINFEKL, the fusion protein EDA-SIINFEKL-C5a did not induce the production of the immunosuppressive molecules IL-10, CCL17, CCL1, CXCL12 or XCL1 by DC. Moreover, EDA-SIINFEKL-C5a induced strong specific T cell responses in vivo and protected mice against E.G7-OVA tumor growth more efficiently than EDA-SIINFEKL or SIINFEKL-C5a recombinant proteins. Our results suggest that fusion proteins containing EDA, the anaphylatoxin C5a and the antigen may serve as a suitable strategy for the development of anti-tumor or anti-viral vaccines.
Assuntos
Anafilatoxinas/imunologia , Complemento C5a/imunologia , Ectodisplasinas/imunologia , Linfócitos T Citotóxicos/imunologia , Receptor 4 Toll-Like/agonistas , Anafilatoxinas/genética , Animais , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/imunologia , Complemento C5a/genética , Citocinas/metabolismo , Ectodisplasinas/genética , Epitopos de Linfócito T/genética , Epitopos de Linfócito T/imunologia , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias/imunologia , Neoplasias/prevenção & controle , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Vacinas de DNA/administração & dosagem , Vacinas de DNA/imunologiaRESUMO
Activation of complement is one of the earliest immune responses to exogenous threats, resulting in various cleavage products including anaphylatoxin C3a. In addition to its contribution to host defense, C3a has been shown to mediate Th2 responses in animal models of asthma. However, the role of C3a on pulmonary Th17 responses during allergic inflammation remains unclear. Here, we show that mice deficient in C3a receptor (C3aR) exhibited (i) higher percentages of endogenous IL-17-producing CD4(+) T cells in the lungs, (ii) higher amounts of IL-17 in the bronchoalveolar lavage fluid, and (iii) more neutrophils in the lungs than wild-type mice when challenged with intranasal allergens. Moreover, adoptive transfer experiments showed that the frequencies of antigen-specific IL-17-producing CD4(+) T cells were significantly higher in the lungs and bronchial lymph nodes of C3aR-deficient recipients than those of wild-types recipients. Bone-marrow reconstitution study indicated that C3aR-deficiency on hematopoietic cells was required for the increased Th17 responses. Furthermore, C3aR-deficient mice exhibited increased percentages of Foxp3(+) regulatory T cells; however, depletion of these cells minimally affected the induction of antigen-specific Th17 cell population in the lungs. Neutralization of IL-17 significantly reduced the number of neutrophils in bronchoalveolar lavage fluid of C3aR-deficient mice. Our findings demonstrate that C3a signals negatively regulate antigen-specific Th17 responses during allergic lung inflammation and the size of Foxp3(+) regulatory T cell population in the periphery.
Assuntos
Anafilatoxinas/imunologia , Complemento C3a/imunologia , Hipersensibilidade/imunologia , Pneumonia/imunologia , Células Th17/imunologia , Alérgenos/administração & dosagem , Alérgenos/imunologia , Animais , Complemento C3a/metabolismo , Modelos Animais de Doenças , Fatores de Transcrição Forkhead/metabolismo , Hipersensibilidade/metabolismo , Interleucina-17/biossíntese , Camundongos , Camundongos Knockout , Infiltração de Neutrófilos/imunologia , Neutrófilos/imunologia , Pneumonia/genética , Receptores de Complemento/genética , Receptores de Complemento/imunologia , Receptores de Complemento/metabolismo , Transdução de Sinais , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismoRESUMO
Reperfusion of an organ following prolonged ischemia instigates the pro-inflammatory and pro-coagulant response of ischemia / reperfusion (IR) injury. IR injury is a wide-spread pathology, observed in many clinically relevant situations, including myocardial infarction, stroke, organ transplantation, sepsis and shock, and cardiovascular surgery on cardiopulmonary bypass. Activation of the classical, alternative, and lectin complement pathways and the generation of the anaphylatoxins C3a and C5a lead to recruitment of polymorphonuclear leukocytes, generation of radical oxygen species, up-regulation of adhesion molecules on the endothelium and platelets, and induction of cytokine release. Generalized or pathway-specific complement inhibition using protein-based drugs or low-molecular-weight inhibitors has been shown to significantly reduce tissue injury and improve outcome in numerous in-vitro, ex-vivo, and in-vivo models. Despite the obvious benefits in experimental research, only few complement inhibitors, including C1-esterase inhibitor, anti-C5 antibody, and soluble complement receptor 1, have made it into clinical trials of IR injury. The results are mixed, and the next objectives should be to combine knowledge and experience obtained in the past from animal models and channel future work to translate this into clinical trials in surgical and interventional reperfusion therapy as well as organ transplantation.
Assuntos
Anafilatoxinas/antagonistas & inibidores , Ativação do Complemento/efeitos dos fármacos , Proteínas do Sistema Complemento/uso terapêutico , Isquemia/complicações , Traumatismo por Reperfusão/tratamento farmacológico , Anafilatoxinas/imunologia , Anafilatoxinas/metabolismo , Ativação do Complemento/imunologia , Proteínas do Sistema Complemento/imunologia , Proteínas do Sistema Complemento/farmacologia , Humanos , Fatores Imunológicos/uso terapêutico , Isquemia/tratamento farmacológico , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/prevenção & controleRESUMO
Anaphylatoxins are a group of small peptides (i.e. C3a, C4a and C5a) generated by complement activation and play important roles in innate immunity through the initiation and regulation of inflammatory responses. More recent studies have revealed that, in addition to their traditional roles in inflammation, anaphylatoxins also significantly influence the adaptive immune response. It does so through a number of mechanisms and by targeting various cells. One important mechanism is that anaphylatoxins (C3a, C5a) act on their receptors expressed on innate immune cells such as dendritic cells. This modulates cell activation and their functions in initiating and regulating T cell responses and thus influencing T cell immunity. This review provides an overview of anaphylatoxins in adaptive immune regulation focusing on their roles in modulating dendritic cell and macrophage functions and the importance of local production of complement in this regulation.
Assuntos
Imunidade Adaptativa , Anafilatoxinas/imunologia , Ativação do Complemento/imunologia , Animais , Células Dendríticas/imunologia , Humanos , Inflamação/imunologia , Ativação Linfocitária/imunologia , Macrófagos/imunologia , Camundongos , Linfócitos T Auxiliares-Indutores/imunologiaRESUMO
The incidence rate of anaphylaxis is increasing, particularly during the first 2 decades of life. Common triggers include foods, medications, and insect stings. Clinical diagnosis is based on a meticulous history of an exposure or event preceding characteristic symptoms and signs, sometimes but not always supported by a laboratory test such as an elevated serum total tryptase level. Physician-initiated investigation of patients with anaphylaxis whose symptoms and signs are atypical sometimes leads to important insights into previously unrecognized triggers and mechanisms. In idiopathic anaphylaxis, in which no trigger can be confirmed by means of skin testing or measurement of specific IgE, the possibility of mastocytosis or a clonal mast cell disorder must be considered in addition to the possibility of a previously unrecognized trigger. Long-term risk reduction in patients with anaphylaxis focuses on optimal management of relevant comorbidities such as asthma and other respiratory diseases, cardiovascular disease, and mastocytosis or a clonal mast cell disorder; avoidance of the relevant confirmed allergen trigger; and relevant immunomodulation such as medication desensitization, venom immunotherapy, and possibly in the future, immunotherapy with food. Emergency preparedness for recurrence of anaphylaxis in community settings includes having epinephrine (adrenaline) autoinjectors available, knowing when and how to use them, and having a written, personalized anaphylaxis emergency action plan and up-to-date medical identification. Randomized controlled trials of the pharmacologic interventions used in an acute anaphylaxis episode are needed.
Assuntos
Alérgenos/imunologia , Anafilatoxinas/imunologia , Anafilaxia/diagnóstico , Anafilaxia/terapia , Mastócitos/imunologia , Anafilatoxinas/metabolismo , Anafilaxia/epidemiologia , Animais , Antialérgicos/uso terapêutico , Complexo Antígeno-Anticorpo/imunologia , Citocinas/sangue , Humanos , Imunoglobulina E/sangue , Mastócitos/metabolismo , Fatores de RiscoRESUMO
BACKGROUND: Complement activation contributes to the regulation of liver regeneration after liver resection (LR) in mice. METHODS: We hypothesized that complement activation and changes in C5a-receptors (C5aR, C5L2) on polymorphonuclear cells (PMN) and monocytes are important in clinical LR. Anaphylatoxin and C5b9 plasma levels were measured (bead-array, ELISA) (25 patients) and receptor expression was assessed after LR (19 patients) (FACS). In vitro PMN C5a-dependent chemotactic response (7 patients) as well as L-selectin shedding and Mac-1 expression (3 patients) was determined. RESULTS: C3a increased after LR (31.1 +/- 4 before LR vs. 41.6 +/- 5 ng/ml, 30 min after LR, P < 0.01), as did C5b9 (12.7 +/- 1 before LR vs. 26.9 +/- 3 ng/ml, 60 min after LR, P < 0.001). C4a and C5a decreased after LR, by 25% 24 h after LR and 30% 2 h after LR, respectively (P < 0.01). C5L2 expression decreased at 4 h, rising at 24 h after LR (PMN: 6.3 +/- 1 before LR, 3.1 +/- 1, 4 h, 8.3 +/- 2, 24 h; P < 0.01). The receptor-related changes accompanied a diminished C5a-dependent chemotactic response by PMN (42.1 +/- 17 before LR vs. 2.1 +/- 3 4 h after LR; P < 0.01) and a reduction of activation upon C5a-R stimulation as measured by L-selectin shedding and Mac-1 expression on PMN. Changes in C5L2 expression on monocytes paralleled postoperative impairment of liver function. CONCLUSIONS: These results indicate that complement components are released after clinical LR and subsequently PMN display altered C5a-dependent functional responses.
Assuntos
Proteínas do Sistema Complemento/imunologia , Regeneração Hepática/imunologia , Fígado/imunologia , Neutrófilos/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anafilatoxinas/imunologia , Animais , Hepatectomia , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Monócitos/imunologiaRESUMO
The anaphylatoxin (AT) C3a, C5a and C5a-desArg are generally considered pro-inflammatory polypeptides generated after proteolytic cleavage of C3 and C5 in response to complement activation. Their well-appreciated effector functions include chemotaxis and activation of granulocytes, mast cells and macrophages. Recent evidence suggests that ATs are also generated locally within tissues by pathogen-, cell-, or contact system-derived proteases. This local generation of ATs is important for their pleiotropic biologic effects beyond inflammation. The ATs exert most of the biologic activities through ligation of three cognate receptors, i.e. the C3a receptor, the C5a receptor and the C5a receptor-like, C5L2. Here, we will discuss recent findings suggesting that ATs regulate cell apoptosis, lipid metabolism as well as innate and adaptive immune responses through their impact on antigen-presenting cells and T cells. As we will outline, such regulatory functions of ATs and their receptors play important roles in the pathogenesis of allergy, autoimmunity, neurodegenerative diseases, cancer and infections with intracellular pathogens.
Assuntos
Anafilatoxinas/imunologia , Hipersensibilidade/imunologia , Inflamação/imunologia , Neoplasias/imunologia , Sepse/imunologia , Linfócitos T/imunologia , Anafilatoxinas/metabolismo , Animais , Apoptose/imunologia , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/metabolismo , Ativação do Complemento/imunologia , Humanos , Hipersensibilidade/metabolismo , Imunidade Ativa/imunologia , Imunidade Inata/imunologia , Inflamação/metabolismo , Camundongos , Neoplasias/metabolismo , Neurogênese/imunologia , Sepse/metabolismo , Linfócitos T/metabolismoRESUMO
Upon crossing the endothelial barrier of the host, HIV initiates immediate responses of the immunity system. Among its components, the complement system is one of the first the first elements, which are activated to affect HIV propagation. Complement participates not only in the early phase of the immune response, but its effects can be observed continuously and also concern the induction and modification of the adaptive immune response. Here we discuss the role of complement in early and late stages of HIV pathogenesis and review the escape mechanisms, which protect HIV from destruction by the complement system.
Assuntos
Ativação do Complemento , Proteínas do Sistema Complemento/imunologia , Infecções por HIV/imunologia , HIV/imunologia , Anafilatoxinas/imunologia , Animais , Células Dendríticas/imunologia , Células Dendríticas/virologia , Infecções por HIV/sangue , Interações Hospedeiro-Patógeno , Humanos , Tecido Linfoide/imunologia , Tecido Linfoide/virologia , Mucosa/imunologia , Mucosa/virologia , Proteínas Opsonizantes/imunologia , Ligação ViralRESUMO
A relative lack of neutrophils around Streptococcus pyogenes is observed in streptococcal toxic shock syndrome (STSS). Because the bacteria spread rapidly into various organs in STSS, we speculated that S. pyogenes is equipped with molecules to evade the host innate immune system. Complement C3b opsonizes the pathogen to facilitate phagocytosis, and a complex of C3b converts C5 into anaphylatoxin. Because we found that C3 (C3b) is degraded in sera from patients with STSS, we investigated the mechanism of C3 (C3b) degradation by S. pyogenes. We incubated human C3b or serum with recombinant SpeB (rSpeB), a wild-type S. pyogenes strain isolated from an STSS patient or its isogenic DeltaspeB mutant and examined the supernatant by Western blotting with anti-human C3b. Western blot and Biacore analyses revealed that rSpeB and wild-type S. pyogenes rapidly degrade C3b. Additionally, C3 (C3b) was not detected in sera collected from infected areas of STSS patients. Furthermore, the survival rate in human blood and in mice was lower for the DeltaspeB mutant than the wild-type strain. Histopathological observations demonstrated that neutrophils were recruited to and phagocytosed the DeltaspeB mutant, whereas with the wild-type strain, few neutrophils migrated to the site of infection, and the bacteria spread along the fascia. We observed the degradation of C3 (C3b) in sera from STSS patients and the degradation of C3 (C3b) by rSpeB. This suggests that SpeB contributes to the escape of S. pyogenes from phagocytosis at the site of initial infection, allowing it to invade host tissues during severe infections.
Assuntos
Proteínas de Bactérias/imunologia , Complemento C3b/imunologia , Exotoxinas/imunologia , Neutrófilos/imunologia , Fagocitose/imunologia , Choque Séptico/imunologia , Streptococcus pyogenes/imunologia , Adulto , Anafilatoxinas/análise , Anafilatoxinas/imunologia , Animais , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Complemento C3b/análise , Complemento C5/análise , Complemento C5/imunologia , Exotoxinas/genética , Exotoxinas/metabolismo , Feminino , Deleção de Genes , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Neutrófilos/metabolismo , Fagocitose/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/metabolismo , Choque Séptico/sangueRESUMO
The complement system, which plays an important role in inmate immunity, is considered to be important in the pathophysiology of allergic asthma. A patient with allergic asthma shows the reversible characteristic system of bronchoconstriction, increased mucus secretion, and complicated airway inflammation. Various cytokines secreted from Th2 cells contribute to the system. Cysteinyl-leukotrienes (CysLTs) are also considered to be one of the important mediators involved in asthmatic pathophysiology. However, the effects of a drug on humans may not be the same as those on animals due to species differences in complement-related molecules. In this series of experiments, we tried to establish a model in which the effects of a drug on the production of CysLTs from human lung preparations were evaluated following an anaphylactic reaction. CysLT production increased when the passively sensitized lung tissues were stimulated with anti-IgE antibody. The coaddition of anaphylatoxin, C5a, with the anti-IgE antibody potentiated CysLT production. The response to C3a was weaker when compared with that to C5a. In addition, increased production of CysLTs by adding serum at a specific ratio was dose dependently inhibited by nonpeptide C5a receptor antagonist, W-54011, or a novel complementary peptide inhibitor of C5a, acetyl peptide A. From these results, it is suggested that C5a potentiates cysLT production from human lung tissues and contributes to allergic inflammation like asthma, and thus acetylated peptide A and W-54011 are useful for suppressing allergic inflammation in the lungs.
Assuntos
Compostos de Anilina/uso terapêutico , Asma/tratamento farmacológico , Asma/etiologia , Cisteína/biossíntese , Hipersensibilidade/tratamento farmacológico , Hipersensibilidade/etiologia , Leucotrienos/biossíntese , Pulmão/metabolismo , Proteína Oncogênica pp60(v-src)/uso terapêutico , Fragmentos de Peptídeos/uso terapêutico , Receptor da Anafilatoxina C5a/antagonistas & inibidores , Tetra-Hidronaftalenos/uso terapêutico , Anafilatoxinas/imunologia , Complemento C5a/antagonistas & inibidores , Complemento C5a/fisiologia , Humanos , Imunoglobulina E/imunologia , Técnicas In Vitro , Modelos BiológicosRESUMO
Tumor treatment by photodynamic therapy (PDT) provokes a host-protective inflammatory and acute-phase response and an immune reaction. Neutrophilia manifested in this context is driven by multiple mediators of neutrophil chemotaxis orchestrated by an activated complement system. Mouse FsaR fibrosarcoma was used in this study to further investigate neutrophilia induced by Photofrin-based PDT. The complement anaphylatoxin C3a was identified as a major chemoattractant in the advanced phase of PDT-induced neutrophilia, because injecting mice with antibodies blocking its receptor C3aR significantly inhibited the increase in neutrophil levels 8 h after PDT. At the same time point, an increased C3aR expression was detected in neutrophils, monocytes and B lymphocytes in the blood of host mice. Peritoneal macrophages and mast cells harvested from treatment-naive mice exhibited elevated C3aR expression after coincubation in vitro for 8 h with PDT-treated FsaR cells. Thus, C3a emerges as one of the key effector molecules engaged in PDT-induced host response.
Assuntos
Anafilatoxinas/imunologia , Linfócitos B/imunologia , Complemento C3a/imunologia , Mastócitos/imunologia , Monócitos/imunologia , Neutrófilos/imunologia , Fotoquimioterapia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Linfócitos B/fisiologia , Fibrossarcoma/tratamento farmacológico , Fibrossarcoma/patologia , Macrófagos Peritoneais/patologia , Mastócitos/fisiologia , Camundongos , Monócitos/fisiologia , Neutrófilos/fisiologia , Fatores de Tempo , Células Tumorais CultivadasRESUMO
The contribution of complement activation to allergic asthma remains controversial. In order to elucidate the role played by the complement split products, anaphylatoxins C3a and C5a, we evaluated their effects on production of cysteinyl-leukotrienes (cysLTs) by human lung fragments following an anaphylactic reaction. The lung tissues obtained from two patients with lung cancer showed C5aR-, C5L2R-, and C3aR-mRNA expression. When the chopped lung fragments passively sensitized with human IgE were incubated with anti-human IgE antibody, a significant amount of cysLTs was generated in comparison with the control (without anti-IgE antibody). The co-addition of human C5a at doses of 0.1 to 10 ng/ml to the anti-IgE antibody potentiated cysLT production. The response was bell-shaped in distribution, significant, and peaked at a C5a concentration of 1 ng/ml. The co-addition of human C3a up to 1,000 ng/ml seemed to increase cysLT production, but not to any significant extent. A novel C5a receptor complementary peptide, acetylated peptide A, dose-dependently inhibited cysLT production by the human lung fragments following the anaphylactic reaction in the presence of 1 ng/ml C5a. However, this peptide did not inhibit cysLT production in the presence of 100 ng/ml C3a. It is suggested that the anaphylatoxin C5a potentiates cysLT production in human lung tissues and contributes to allergic inflammation in disorders such as asthma, thus acetylated peptide A may be useful for suppressing allergic inflammation in the lungs.