RESUMO
Mast cells (MCs) are capable of executing powerful inflammatory response programs triggered by surface IgE cross-linking or through pattern recognition receptors. The question of how MCs contribute to human disease has been intensely investigated and stimulated much controversy. Correlative evidence comes from human studies, pointing to pathogenetic or protective MC functions in patients with atopic conditions, autoimmune disorders, type 2 diabetes, chronic urticaria, mastocytosis, and cancer. Experiments in MC-deficient mice underpinned key roles for MCs in patients with IgE-mediated allergic conditions. Important pathogenetic MC contributions to other inflammatory and neoplastic conditions were suggested by studies in traditional KIT mutant MC-deficient mouse strains. However, many of these findings were not reproduced in more recently developed improved mouse models of MC deficiency, largely ruling out roles for MCs in mouse models for autoimmune disease, diabetes, and cancer. We discuss limitations of studies in mice and human subjects and provide suggestions for how they can be overcome, such as through the development of specific and selective MC-targeted treatments.
Assuntos
Imunoglobulina E/imunologia , Infecções/imunologia , Inflamação/imunologia , Mastócitos/imunologia , Neoplasias/imunologia , Ferimentos e Lesões/imunologia , Animais , Quimases/imunologia , Feminino , Humanos , Infecções/patologia , Inflamação/patologia , Ativação Linfocitária , Mastócitos/patologia , Neoplasias/patologia , Gravidez , Receptores de IgE/imunologia , Células Th2/imunologia , Células Th2/patologia , Receptor 2 Toll-Like/imunologia , Microambiente Tumoral/imunologia , Ferimentos e Lesões/patologiaRESUMO
Cluster of differentiation 1c (CD1c)-dependent self-reactive T cells are abundant in human blood, but self-antigens presented by CD1c to the T-cell receptors of these cells are poorly understood. Here we present a crystal structure of CD1c determined at 2.4 Å revealing an extended ligand binding potential of the antigen groove and a substantially different conformation compared with known CD1c structures. Computational simulations exploring different occupancy states of the groove reenacted these different CD1c conformations and suggested cholesteryl esters (CE) and acylated steryl glycosides (ASG) as new ligand classes for CD1c. Confirming this, we show that binding of CE and ASG to CD1c enables the binding of human CD1c self-reactive T-cell receptors. Hence, human CD1c adopts different conformations dependent on ligand occupancy of its groove, with CE and ASG stabilizing CD1c conformations that provide a footprint for binding of CD1c self-reactive T-cell receptors.
Assuntos
Antígenos CD1/imunologia , Ésteres do Colesterol/metabolismo , Glicoproteínas/imunologia , Linfócitos T/imunologia , Antígenos CD1/química , Antígenos CD1d , Glicoproteínas/química , Humanos , Simulação de Dinâmica Molecular , Conformação ProteicaRESUMO
Lyme disease (LD) is the most common tick-borne disease in Europe, North America, and Asia. The etiologic agents of LD are spirochetes of the group Borrelia burgdorferi sensu lato, which possess a lipid content of 25-30% of the dry weight. The major glycolipid cholesteryl 6-O-acyl-beta-D-galactopyranoside (ACGal), present in B. burgdorferi sensu stricto, B. afzelii, and B. garinii, is a specific and highly prevalent antigen frequently recognized by antibodies in late-stage LD. Here we report a convenient route for the chemical synthesis of ACGal by employing a combination of chemical synthesis steps with enzymatic transformations. This synthesized molecule was compared with bacterial extracts by immunoblots with patient sera, confirming the preserved antigenicity. Next, a glycolipid library derived from the native molecules with variations in the fatty acyl moiety and derivatives in which the cholesterol has been replaced was designed and synthesized. The chemical structures were confirmed by 1D and 2D NMR spectroscopy and mass spectrometry. The native and synthetic glycolipids were utilized in immunoblots to determine the epitope recognized by antibodies in patient sera. By this method we could demonstrate that galactose, cholesterol, and a fatty acid with a minimal chain length of four carbon atoms comprises the essential structure for recognition by antibodies. Finally, this finding allowed the synthesis of a functionalized ACGal with an omega-mercapto group at the fatty acid and a facile protection and deprotection strategy. This antigenic hapten can be conjugated to a carrier protein to effect immunization against Lyme disease.
Assuntos
Antígenos de Bactérias/química , Glicolipídeos/síntese química , Glicolipídeos/imunologia , Vacinas contra Doença de Lyme/imunologia , Doença de Lyme/imunologia , Anticorpos Antibacterianos/sangue , Anticorpos Antibacterianos/metabolismo , Antígenos de Bactérias/imunologia , Antígenos de Bactérias/metabolismo , Borrelia burgdorferi/química , Colesterol/análogos & derivados , Colesterol/biossíntese , Colesterol/síntese química , Colesterol/química , Epitopos/imunologia , Epitopos/metabolismo , Glicolipídeos/biossíntese , Humanos , Doença de Lyme/prevenção & controle , EstereoisomerismoRESUMO
Experimental and clinical studies link Chlamydia pneumoniae infection to atherogenesis and atherothrombotic events, but the underlying mechanisms are unclear. We tested the hypothesis that C. pneumoniae-induced acceleration of atherosclerosis in apolipoprotein E (ApoE)(-/-) mice is reciprocally modulated by activation of TLR-mediated innate immune and liver X receptor alpha (LXRalpha) signaling pathways. We infected ApoE(-/-) mice and ApoE(-/-) mice that also lacked TLR2, TLR4, MyD88, or LXRalpha intranasally with C. pneumoniae followed by feeding of a high fat diet for 4 mo. Mock-infected littermates served as controls. Atherosclerosis was assessed in aortic sinuses and in en face preparation of whole aorta. The numbers of activated dendritic cells (DCs) within plaques and the serum levels of cholesterol and proinflammatory cytokines were also measured. C. pneumoniae infection markedly accelerated atherosclerosis in ApoE-deficient mice that was associated with increased numbers of activated DCs in aortic sinus plaques and higher circulating levels of MCP-1, IL-12p40, IL-6, and TNF-alpha. In contrast, C. pneumoniae infection had only a minimal effect on atherosclerosis, accumulation of activated DCs in the sinus plaques, or circulating cytokine increases in ApoE(-/-) mice that were also deficient in TLR2, TLR4, or MyD88. However, C. pneumoniae-induced acceleration of atherosclerosis in ApoE(-/-) mice was further enhanced in ApoE(-/-)LXRalpha(-/-) double knockout mice and was accompanied by higher serum levels of IL-6 and TNF-alpha. We conclude that C. pneumoniae infection accelerates atherosclerosis in hypercholesterolemic mice predominantly through a TLR/MyD88-dependent mechanism and that LXRalpha appears to reciprocally modulate and reduce the proatherogenic effects of C. pneumoniae infection.
Assuntos
Aterosclerose/microbiologia , Infecções por Chlamydia/complicações , Proteínas de Ligação a DNA/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Transdução de Sinais/fisiologia , Receptores Toll-Like/metabolismo , Animais , Aorta/imunologia , Aorta/patologia , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Aterosclerose/metabolismo , Infecções por Chlamydia/metabolismo , Chlamydophila pneumoniae , Citocinas/sangue , Citocinas/imunologia , Proteínas de Ligação a DNA/genética , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Imunofluorescência , Expressão Gênica , Fator Estimulador de Colônias de Granulócitos e Macrófagos/biossíntese , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Hipercolesterolemia/complicações , Imuno-Histoquímica , Receptores X do Fígado , Camundongos , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/genética , Análise de Sequência com Séries de Oligonucleotídeos , Receptores Nucleares Órfãos , Receptores Citoplasmáticos e Nucleares/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Receptores Toll-Like/genéticaRESUMO
BACKGROUND: The original hygiene hypothesis predicts that infections should protect against asthma but does not account for increasing evidence that certain infections might also promote asthma development. A mechanistic reconciliation of these findings has not yet emerged. In particular, the role of innate immunity in this context is unclear. OBJECTIVE: We sought to test whether bacterial respiratory tract infection causes airway sensitization toward an antigen encountered in parallel and to elucidate the contribution of innate immune responses. METHODS: Mice were infected with different doses of Chlamydia pneumoniae, followed by exposure to human serum albumin (HSA) and challenge with HSA 2 weeks later. Airway inflammation, immunoglobulins, and lymph node cytokines were assessed. Furthermore, adoptive transfer of dendritic cells (DCs) and depletion of regulatory T (Treg) cells was performed. RESULTS: C pneumoniae-induced lung inflammation triggered sensitization toward HSA, resulting in eosinophilic airway inflammation after HSA challenge. Airway sensitization depended on the severity and timing of infection: low-dose infection and antigen exposure within 5 days of infection induced allergic sensitization, whereas high-dose infection or antigen exposure 10 days after infection did not. Temporal and dose-related effects reflected DC activation and could be reproduced by means of adoptive transfer of HSA-pulsed lung DCs from infected mice. MyD88 deficiency in DCs abolished antigen sensitization, and depletion of Treg cells prolonged the time window in which sensitization could occur. CONCLUSIONS: We conclude that moderate, but not severe, pulmonary bacterial infection can induce allergic sensitization to inert inhaled antigens through a mechanism that requires MyD88-dependent DC activation and is controlled by Treg cells.
Assuntos
Infecções por Chlamydophila/imunologia , Células Dendríticas/imunologia , Imunidade Inata , Pulmão/imunologia , Hipersensibilidade Respiratória/imunologia , Infecções Respiratórias/imunologia , Linfócitos T Reguladores/imunologia , Animais , Chlamydophila pneumoniae/imunologia , Células Dendríticas/metabolismo , Eosinófilos/imunologia , Eosinófilos/metabolismo , Humanos , Imunoglobulina E/sangue , Inflamação/complicações , Inflamação/imunologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/deficiência , Fator 88 de Diferenciação Mieloide/metabolismo , Hipersensibilidade Respiratória/complicações , Infecções Respiratórias/complicações , Infecções Respiratórias/microbiologia , Albumina Sérica/imunologia , Linfócitos T Reguladores/metabolismoRESUMO
Major barriers separating the blood from tissue compartments in the body are composed of endothelial cells. Interaction of bacteria with such barriers defines the course of invasive infections, and meningitis has served as a model system to study endothelial cell injury. Here we report the impressive ability of Streptococcus pneumoniae, clinically one of the most important pathogens, to induce 2 morphologically distinct forms of programmed cell death (PCD) in brain-derived endothelial cells. Pneumococci and the major cytotoxins H2O2 and pneumolysin induce apoptosis-like PCD independent of TLR2 and TLR4. On the other hand, pneumococcal cell wall, a major proinflammatory component, causes caspase-driven classical apoptosis that is mediated through TLR2. These findings broaden the scope of bacterial-induced PCD, link these effects to innate immune TLRs, and provide insight into the acute and persistent phases of damage during meningitis.
Assuntos
Apoptose , Cerebelo/fisiopatologia , Células Endoteliais/metabolismo , Meningite Pneumocócica/fisiopatologia , Streptococcus pneumoniae , Animais , Apoptose/efeitos dos fármacos , Proteínas de Bactérias/farmacologia , Caspases/metabolismo , Parede Celular/metabolismo , Células Cultivadas , Cerebelo/citologia , Cerebelo/patologia , Células Endoteliais/microbiologia , Células Endoteliais/patologia , Peróxido de Hidrogênio/farmacologia , Glicoproteínas de Membrana/deficiência , Glicoproteínas de Membrana/metabolismo , Meningite Pneumocócica/microbiologia , Meningite Pneumocócica/patologia , Camundongos , Camundongos Knockout , Ratos , Ratos Wistar , Receptores de Superfície Celular/deficiência , Receptores de Superfície Celular/metabolismo , Estreptolisinas/farmacologia , Receptor 2 Toll-Like , Receptor 4 Toll-Like , Receptores Toll-LikeRESUMO
The class of Spirochetes comprises a wide array of clinically important pathogens, including Treponema pallidum causing syphilis as well as Borrelia burgdorferi, the agent of Lyme disease (LD). Diseases caused by spirochetes are characterized by specific sequelae of host reactions, and also by characteristic antibody response patterns. Over the last decades, research on the interaction of spirochetes with the host's immune system had a strong emphasis on outer membrane lipoproteins. In fact, these structures have been convincingly shown to activate immune cells via CD14 and Toll-like receptor (TLR)-2, and recent data also indicate an interaction with lipopolysaccharide (LPS)-binding protein (LBP). In particular, the interaction of B. burgdorferi with TLR-2 could not only be demonstrated in mice, but was also supported by data showing that genetic variants of TLR-2 in humans influenced the clinical course of LD. However, there is increasing evidence that next to lipoproteins, glycolipids may also play an important role in responses of the immune system towards spirochetes. Diacylglycerol-containing glycolipids exhibiting similarities with lipoteichoic acid (LTA) of Gram-positive bacteria have been demonstrated in various Treponema species, whereas LPS-like glycolipids have been shown to be present in Leptospira. Treponema glycolipids, comparably to lipoproteins and LTA, interact with LBP, CD14 and TLRs. In contrast, complex glycolipids of high molecular weight could not be demonstrated in Borrelia, whereas these bacteria exhibit a number of unique low molecular weight glycolipids. Some of these glycolipids cause strong immediate immune responses, while others appear to be potent antigens for induction of an adaptive immune response. This review summarizes data obtained so far on amphiphilic and hydrophobic molecules from spirochetes regarding structure and influence on innate as well as adaptive immune responses.
Assuntos
Glicolipídeos/metabolismo , Sistema Imunitário , Imunidade Inata , Lipoproteínas/metabolismo , Doença de Lyme/microbiologia , Proteínas de Fase Aguda/metabolismo , Animais , Borrelia burgdorferi/metabolismo , Proteínas de Transporte/metabolismo , Diglicerídeos/metabolismo , Relação Dose-Resposta a Droga , Humanos , Células Matadoras Naturais/imunologia , Leptospira/metabolismo , Glicoproteínas de Membrana/metabolismo , Modelos Biológicos , Treponema/metabolismoRESUMO
Infectious diseases have a major impact on both the development and the severity of asthma. The rise in incidence of asthma in industrialized countries over the last decades has been attributed to increased hygiene standards as well as the concomitant usage of antibiotics, which together lower the incidence of infections. Although this point of view is supported by both clinical studies and experimental approaches in mice, an increasing body of evidence suggests that certain infectious diseases may predispose for the development of asthma, thus challenging the ;hygiene hypothesis' in its classical form. Toll-like receptors (TLRs) are centrally involved in orchestrating immune responses towards various micro-organisms. Because of this, it is tempting to speculate that signaling through TLRs may be involved in mechanisms provoking Th1- or Th2-biased immune responses and may, therefore, be an important factor in either preventing or promoting allergic airway disease. This review summarizes clinical and experimental data from mouse models focused on the impact of TLR-signaling on allergic asthma.
Assuntos
Asma/imunologia , Imunidade Inata/imunologia , Transdução de Sinais/imunologia , Receptores Toll-Like/imunologia , Animais , Asma/tratamento farmacológico , Asma/microbiologia , Modelos Animais de Doenças , Humanos , Ligantes , Camundongos , Transdução de Sinais/genética , Receptores Toll-Like/genética , Vacinas/uso terapêuticoRESUMO
Restenosis is a major problem for patients undergoing percutaneous transluminal coronary angioplasty (PTCA). Inflammatory processes and genetic factors have been suggested to be involved in the pathogenesis of both atherosclerosis and restenosis. The recently discovered family of Toll-like receptors (TLRs) consists of molecules that initiate signaling after host-pathogen interactions. Recently it has been shown that the TLRs are involved in the development and progression of atherosclerosis by interfering with lipid metabolisms and by mediating inflammation. TLR-2 is a key innate immunity receptor for sensing both endogenous inflammatory mediators and ligands of several microbial pathogens postulated to be involved in atherosclerosis. A frequent single nucleotide polymorphism (SNP) for the TLR-2 gene, resulting in a non-functional receptor, has been described. By genotyping two independent groups of patients receiving PTCA, followed by stent implantation in one group, we found a significantly enhanced frequency of the TLR-2 Arg753Gln SNP in patients with restenosis as compared to those without restenosis (PTCA: 7.21 versus 2.45%, P = 0.014; PTCA/stent: 6.86 versus 1.53%, P = 0.013). In contrast, a common TLR-4 SNP was similarly distributed among the patient groups investigated. We furthermore compared the frequency of both SNPs in the patients with an age-matched group of individuals without atherosclerosis and found a trend towards a lower frequency of the TLR-4 SNP in the atherosclerotic group (PTCA: 5.58; PTCA/stent: 3.85 versus 7.14%). We conclude that in restenosis a functional TLR-2 is protective and potentially involved in a reaction pattern preventing restenosis. Screening for the TLR-2 Arg753Gln SNP may be of importance for stratifying a patient's risk and for preventive and therapeutic measures.
Assuntos
Reestenose Coronária/genética , Glicoproteínas de Membrana/genética , Polimorfismo de Nucleotídeo Único , Receptores de Superfície Celular/genética , Reestenose Coronária/etiologia , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Mutação Puntual , Estudos Prospectivos , Fatores de Risco , Receptor 2 Toll-Like , Receptor 4 Toll-Like , Receptores Toll-Like , População Branca/genéticaRESUMO
LPS binding protein (LBP) was discovered about 20 years ago because of its ability to bind to bacterial lipopolysaccharide (LPS). We have shown that in addition to its complex function of transferring LPS to its cellular receptor into the cell or into lipoproteins, LBP also binds to other bacterial compounds and can modulate their ability to stimulate the host's innate immune system. The majority of compounds found to also interact with LBP are amphiphilic molecules such as glycolipids or lipoproteins. Lipoteichoic acid (LTA) of different Gram-positive bacteria is recognized by LBP and both its complexation with CD14 and biological activity towards immune cells is modulated by LBP. LTA-like glycolipids isolated from spirochetes are recognized by LBP and initiate signaling in the presence of LBP. Lipopeptides corresponding to lipoproteins present in spirochetes, Mycobacterium spp. and Gram-negative bacteria as well as Mycoplasma spp. are also recognized by LBP. Together with the growing number of related proteins of the BPI-PLUNC family, LBP apparently as soluble mediator has the important ability to recognize a variety of bacterial pathogens before cellular contact has been established. The different sources of LBP in tissues such as lung and intestine further support its role as an important defense molecule.
Assuntos
Proteínas de Fase Aguda/imunologia , Proteínas de Transporte/imunologia , Lipopolissacarídeos/imunologia , Glicoproteínas de Membrana/imunologia , Animais , Proteínas de Bactérias/imunologia , Previsões , Humanos , Receptores de Lipopolissacarídeos/imunologia , Lipoproteínas/imunologia , Modelos Imunológicos , Ligação Proteica/imunologiaRESUMO
Toll-like receptors (TLRs) play an important part in the innate immune recognition of invading microorganisms, initiating sufficient immune responses. Growing amounts of data suggest that the ability of certain individuals to respond properly to TLR ligands may be impaired by single nucleotide polymorphisms (SNPs) within TLR genes, resulting in an altered susceptibility to, or course of, infectious or inflammatory disease. Most studies have focused on two cosegregating SNPs-Asp299gly and Thr399Ile-within the gene encoding TLR4, the receptor for bacterial lipopolysaccharide. These SNPs are present in approximately 10% of white individuals, and have been found to be positively correlated with several infectious diseases. However, these SNPs seem to protect from atherosclerosis and related diseases, which is reviewed in this article also. Meanwhile, SNPs of genes encoding other TLRs-eg, TLR2, which recognises a wide variety of microbial ligands-have been reported, and preliminary studies indicate an impact on susceptibility to infectious and inflammatory diseases as well. This review summarises and discusses the results obtained, and draws conclusions from these data.
Assuntos
Doenças Transmissíveis/genética , Glicoproteínas de Membrana/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores de Superfície Celular/genética , Estudos de Casos e Controles , Doenças Transmissíveis/imunologia , Variação Genética , Humanos , Glicoproteínas de Membrana/imunologia , Glicoproteínas de Membrana/fisiologia , Polimorfismo de Nucleotídeo Único/imunologia , Polimorfismo de Nucleotídeo Único/fisiologia , Receptores de Superfície Celular/imunologia , Receptores de Superfície Celular/fisiologia , Receptor 2 Toll-Like , Receptor 4 Toll-Like , Receptores Toll-LikeRESUMO
The recently described family of Toll-like receptors (TLRs) plays a major role in innate immunity by mediating inflammatory reactions against a wide array of pathogens. TLR-2 is reported to interact with various bacterial partial structures including lipoproteins, peptidoglycan, and lipoteichoic acid. Two polymorphisms of the TLR-2 gene have recently been described: Arg753Gln, correlated with the incidence of sepsis in a white population, and Arg677Trp, correlated with the incidence of lepromatous leprosy in an Asian population. Both polymorphisms, when inserted into expression vectors encoding for human TLR-2, reduced stimulation of Chinese hamster ovary cells by synthetic lipopeptides. We furthermore developed a rapid and inexpensive method for the detection of both single nucleotide polymorphisms based on restriction fragment length polymorphism. While no individuals carrying the Arg677Trp SNP were identified in a large group of whites, 9.4% of the study population were found to be heterozygous for the Arg753Gln polymorphism. This ratio is significantly higher than previously reported, and therefore detection of this polymorphism among patients may yield important information for the assessment of risk profiles regarding susceptibility to bacterial infections.
Assuntos
Frequência do Gene/genética , Glicoproteínas de Membrana/genética , Reação em Cadeia da Polimerase/métodos , Polimorfismo de Nucleotídeo Único , Receptores de Superfície Celular/genética , Alelos , Animais , Células CHO , Cricetinae , Primers do DNA , Feminino , Frequência do Gene/imunologia , Genótipo , Humanos , Masculino , Glicoproteínas de Membrana/fisiologia , Polimorfismo de Fragmento de Restrição , Receptores de Superfície Celular/fisiologia , Receptor 2 Toll-Like , Receptores Toll-LikeRESUMO
Pipestem-capillaries in necrotizing myopathy, have been reported as a feature of a distinct type of myopathy. Here, we analyze four muscle biopsy specimens from patients exhibiting endomysial fibrosis associated with pipestem capillaries using histological and electronmicroscopic techniques. However, only one case displayed all of the originally described features, including necrotic fibres, capillary thickening and lack of a significant lymphocytic inflammation, while one case exhibited striking capillary pathology with minimal necrosis and absence of inflammation, and the other two cases were accompanied by additional pathological features. These data support the existence of a microangiopathy with pipestem capillaries as a characteristic and distinct histopathological pattern, and indicate that it occurs in the context of a variety of muscular disorders broader than initially suspected. Furthermore, we show that the pipestem-capillary associated decrease in fibre size is at least in part a result of hypoxic changes.
Assuntos
Capilares/patologia , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/patologia , Doenças Musculares/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Complexo de Ataque à Membrana do Sistema Complemento/metabolismo , Creatina Quinase/metabolismo , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/metabolismo , NecroseRESUMO
Chlamydia pneumoniae (CP) is associated with induction and exacerbation of asthma. CP infection can induce allergic airway sensitization in mice in a dose- and time-dependent manner. Allergen exposure 5 days after a low dose (mild-moderate), but not a high dose (severe) CP infection induces antigen sensitization in mice. Innate immune signals play a critical role in controlling CP infection induced allergic airway sensitization, however these mechanisms have not been fully elucidated. Wild-type, TLR2-/-, and TLR4-/- mice were infected intranasally (i.n.) with a low dose of CP, followed by i.n. exposure to human serum albumin (HSA) and challenged with HSA 2 weeks later. Airway inflammation, immunoglobulins, eosinophils, and goblet cells were measured. Low dose CP infection induced allergic sensitization in TLR2-/- mice, but not in TLR4-/- mice, due to differential Treg responses in these genotypes. TLR2-/- mice had reduced numbers of Tregs in the lung during CP infection while TLR4-/- mice had increased numbers. High dose CP infection resulted in an increase in Tregs and pDCs in lungs, which prevented antigen sensitization in WT mice. Depletion of Tregs or pDCs resulted in allergic airway sensitization. We conclude that Tregs and pDCs are critical determinants regulating CP infection-induced allergic sensitization. Furthermore, TLR2 and TLR4 signaling during CP infection may play a regulatory role through the modulation of Tregs.
Assuntos
Chlamydophila pneumoniae/imunologia , Células Dendríticas/imunologia , Imunização , Pneumonia Bacteriana/imunologia , Pneumonia Bacteriana/microbiologia , Hipersensibilidade Respiratória/imunologia , Linfócitos T Reguladores/imunologia , Animais , Antígenos de Bactérias/imunologia , Bordetella/imunologia , Bordetella/efeitos da radiação , Chlamydophila pneumoniae/efeitos da radiação , Eosinófilos/patologia , Humanos , Inflamação/complicações , Inflamação/microbiologia , Inflamação/patologia , Pulmão/imunologia , Pulmão/microbiologia , Pulmão/patologia , Depleção Linfocítica , Camundongos , Viabilidade Microbiana/efeitos da radiação , Pneumonia Bacteriana/complicações , Pneumonia Bacteriana/patologia , Hipersensibilidade Respiratória/complicações , Hipersensibilidade Respiratória/microbiologia , Hipersensibilidade Respiratória/patologia , Albumina Sérica/imunologia , Transdução de Sinais/imunologia , Transdução de Sinais/efeitos da radiação , Fatores de Tempo , Receptor 2 Toll-Like/deficiência , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/deficiência , Receptor 4 Toll-Like/metabolismo , Raios UltravioletaRESUMO
Lyme disease (LD) is the most common tick-borne disease in the Northern hemisphere. It is caused by Borrelia burgdorferi sensu lato, in particular, B. burgdorferi sensu stricto, Borrelia garinii, and Borrelia afzelii. However, other genospecies have been implicated as causative factors of LD as well. Borrelia burgdorferi exhibits numerous immunogenic lipoproteins, but due to strong heterogeneity, the use of these proteins for serodiagnosis and vaccination is hampered. We and others have identified acylated cholesteryl galactosides (ACGal) as a novel glycolipid present in B. burgdorferi sensu stricto, B. afzelii, and B. garinii. ACGal is a strong antigen and the majority of patients display anti-ACGal antibodies in the chronic stages of LD. However, it is unknown whether ACGal is present in other presumably pathogenic B. burgdorferi genospecies. Therefore, we performed an analysis of the total lipid extracts of a wide spectrum of genospecies of B. burgdorferi sensu lato using thin-layer chromatography as well as Western blot and dot-blot assays. We show that ACGal is present in substantial quantities in all B. burgdorferi genospecies tested. Therefore, this molecule might improve the serological detection of rarely pathogenic genospecies, and may be used as a protective vaccine regardless of the prevailing genospecies.
Assuntos
Antígenos de Bactérias/análise , Grupo Borrelia Burgdorferi/química , Ésteres do Colesterol/análise , Galactosídeos/análise , Glicolipídeos/análise , Acilação , Western Blotting , Cromatografia em Camada Fina , HumanosRESUMO
PURPOSE OF REVIEW: The increase in prevalence of allergic diseases, in particular of asthma, poses great difficulties to healthcare institutions in industrialized countries. According to the hygiene hypothesis, a linkage exists between exposure towards microbes in early childhood and the development of allergies; however, the original view that stimulation of the host's immune system by microbes exclusively protects against the development of allergies and asthma has been challenged by recent studies, which are summarized in this review. RECENT FINDINGS: Recent studies in mice revealed that infection with a series of microbes in the context of allergen exposure enhances antigen sensitization. Furthermore, in studies using purified toll-like receptor ligands and live bacteria, innate immune activation via MyD88 has been shown to be a causative factor in sensitization. The view that innate immune activation, under circumstances yet to be elucidated, may be a causative factor for the development of allergies is backed by epidemiologic data showing a protective effect of genetic variants, which impair toll-like receptor signaling. CONCLUSION: Recent studies in mice suggest that innate immune stimulation via microbes or their compounds, in a dose and time-dependent manner, can cause allergen sensitization, and this notion has lately been supported by epidemiologic data.
Assuntos
Asma/imunologia , Asma/microbiologia , Imunidade Inata , Alérgenos/imunologia , Animais , Células Dendríticas/imunologia , Modelos Animais de Doenças , Humanos , Camundongos , Infecções Respiratórias/imunologia , Infecções Respiratórias/microbiologia , Receptores Toll-Like/imunologiaRESUMO
Borrelia burgdorferi sensu lato is the causative agent of Lyme disease (LD), an infectious disease occurring in North America, Europe, and Asia in different clinical stages. B. burgdorferi sensu lato encompasses at least 12 species, with B. burgdorferi sensu stricto, B. garinii, and B. afzelii being of highest clinical importance. Immunologic testing for LD as well as recent vaccination strategies exclusively refer to proteinaceous antigens. However, B. burgdorferi sensu stricto exhibits glycolipid antigens, including 6-O-acylated cholesteryl beta-D-galactopyranoside (ACGal), and first the data indicated that this compound may act as an immunogen. Here we investigated whether B. garinii and B. afzelii also possess this antigen, and whether antibodies directed against these compounds are abundant among patients suffering from different stages of LD. Gas-liquid chromatography/mass spectroscopy and NMR spectroscopy showed that both B. garinii and B. afzelii exhibit ACGal in high quantities. In contrast, B. hermsii causing relapsing fever features 6-O-acylated cholesteryl beta-D-glucopyranoside (ACGlc). Sera derived from patients diagnosed for LD contained antibodies against ACGal, with 80% of patients suffering from late stage disease exhibiting this feature. Antibodies reacted with ACGal from all three B. burgdorferi species tested, but not with ACGlc from B. hermsii. These data show that ACGal is present in all clinically important B. burgdorferi species, and that specific antibodies against this compound are frequently found during LD. ACGal may thus be an interesting tool for improving diagnostics as well as for novel vaccination strategies.
Assuntos
Anticorpos Antibacterianos/imunologia , Borrelia burgdorferi/imunologia , Glicolipídeos/imunologia , Vacinas contra Doença de Lyme/imunologia , Doença de Lyme/imunologia , Anticorpos Antibacterianos/sangue , Humanos , Doença de Lyme/sangue , Doença de Lyme/diagnóstico , Doença de Lyme/prevenção & controle , Especificidade da EspécieRESUMO
Emerging evidence implicating the participation of dendritic cells (DCs) and T cells in various vascular inflammatory diseases such as giant cell arteritis, Takayasu's arteritis, and atherosclerosis led us to hypothesize that they might also participate in the pathogenesis of coronary arteritis in Kawasaki disease (KD). Coronary artery specimens from 4 patients with KD and 6 control patients were obtained. Immunohistochemical and computer-assisted histomorphometric analyses were performed to detect all myeloid DCs (S-100(+), fascin(+)), all plasmacytoid DCs (CD123(+)) as well as specific DC subsets (mature myeloid DCs [CD83(+)], myeloid [BDCA-1(+)] and plasmacytoid DC precursors [BDCA-2(+)]), T cells (CD3(+)), and all antigen-presenting cells (HLA-DR(+)). Co-localization of DCs with T cells was assessed using double immunostaining. Significantly more myeloid DCs at a precursor, immature or mature stage were found in coronary lesions of KD patients than in controls. Myeloid DC precursors were distributed equally in the intima and adventitia. Mature myeloid DCs were particularly abundant in the adventitia. There was a significant correlation between mature DCs and HLA-DR expression. Double immunostaining demonstrated frequent contacts between myeloid DCs and T cells in the outer media and adventitia. Plasmacytoid DC precursors were rarely found in the adventitia. In conclusion, coronary artery lesions of KD patients contain increased numbers of mature myeloid DCs with high HLA-DR expression and frequent T cell contacts detected immunohistochemically. This suggests that mature arterial myeloid DCs might be activating T cells in situ and may be a significant factor in the pathogenesis of coronary arteritis in KD.
Assuntos
Complexo CD3/metabolismo , Doença da Artéria Coronariana/metabolismo , Células Dendríticas/metabolismo , Síndrome de Linfonodos Mucocutâneos/metabolismo , Células Mieloides/metabolismo , Linfócitos T/metabolismo , Aneurisma/patologia , Diferenciação Celular , Criança , Pré-Escolar , Doença da Artéria Coronariana/patologia , Células Dendríticas/citologia , Feminino , Antígenos HLA-DR/metabolismo , Humanos , Imuno-Histoquímica , Lactente , Masculino , Síndrome de Linfonodos Mucocutâneos/patologia , Células Mieloides/citologia , Linfócitos T/citologiaRESUMO
Genetic host factors play a substantial role in susceptibility to and severity of malaria, which continues to cause at least one million deaths per year. Recently, members of the toll-like receptor (TLR) family have been shown to be involved in recognition of the etiologic organism Plasmodium falciparum: The glycosylphosphatidylinositol anchor induces signaling in host cells via TLR-2 and -4, whereas hemozoin-induced immune activation involves TLR-9. Binding of microbial ligands to the respective TLRs triggers the release of proinflammatory cytokines via the TLR/IL-1 receptor (TIR) domain and may contribute to the host response in malaria, including cytokine induction and fever. In a case-control study among 870 Ghanaian children, we examined the influence of TLR-2, -4, and -9 polymorphisms in susceptibility to severe malaria. TLR-2 variants common in Caucasians and Asians were completely absent. However, we found a rare previously undescribed mutation (Leu658Pro), which impairs signaling via TLR-2. We failed to detect any polymorphisms within the TLR-9 Toll/IL-1 receptor domain. Two frequent TLR-9 promoter polymorphisms did not show a clear association with malaria severity. In contrast, the TLR-4-Asp299Gly variant occurred at a high rate of 17.6% in healthy controls and was even more frequent in severe malaria patients (24.1%, P < 0.05). Likewise, TLR-4-Thr399Ile was seen in 2.4% of healthy children and in 6.2% of patients (P = 0.02). TLR-4-Asp299Gly and TLR-4-Thr399Ile conferred 1.5- and 2.6-fold increased risks of severe malaria, respectively. These findings suggest TLR4-mediated responses to malaria in vivo and TLR-4 polymorphisms to be associated with disease manifestation.