RESUMO
Vaccines or early childhood exposure to infection mediate immunity, that is, improved resistance against disease and death caused by a second infection with the same agent. This has been explained by and equaled to immunological memory, that is, an "altered immune system behavior" that is maintained in a presumably antigen-independent fashion. This review summarizes epidemiological and experimental data, that largely falsify this idea and that show that periodic re-exposure to antigen either, artificially as vaccines or naturally as low-level persisting antigens or infections, or immune complexes on follicular dendritic cells or endemic re-exposure is necessary for protection. Both, the huge success of vaccines in controlling childhood infections, the reduction in clinical disease and the chance of endemically re-exposure, have gradually reduced periodical re-exposure to infections and thereby endangered protective herd immunity. In parallel, vaccine deniers have created susceptibility islands even in an otherwise well vaccinated population, thereby creating a very new situation when compared to the later parts of the 20th century. If protective Immunity is-as emphasized here-antigen driven, then increasingly frequent revaccinations will be necessary (even more so with too much attenuated vaccines) to maintain both herd immunity and individual resistance to acute infections. Of course, this rule also applies to tumor vaccines.
Assuntos
Antígenos/imunologia , Linfócitos B/imunologia , Imunidade , Memória Imunológica , Linfócitos T/imunologia , Animais , Linfócitos B/metabolismo , Suscetibilidade a Doenças , Humanos , Linfócitos T/metabolismoRESUMO
Immunological memory is considered to be one of the cardinal features of the adaptive immune system. Despite being a recognized phenomenon since the time of the ancient Greeks, immunologists are yet to fully appreciate the mechanisms that control memory responses in the immune system. Furthermore, our definition of immunological memory itself continues to evolve, with recent suggestions that innate immune cells also show memory-like behaviour. In this Viewpoint article, Nature Reviews Immunology invites five leading immunologists to share their thoughts on our current understanding of the nature of immunological memory. Our experts highlight some of the seminal studies that have shaped the immune memory field and offer contrasting views on the key questions that remain to be addressed.
Assuntos
Imunidade Inata/imunologia , Memória Imunológica/imunologia , Linfócitos T/imunologia , Alergia e Imunologia/história , Alergia e Imunologia/tendências , História do Século XX , História do Século XXI , Humanos , Subpopulações de Linfócitos T/imunologiaRESUMO
So-called 'immunological memory' is, in my view, a typical example where a field of enquiry, i.e. to understand long-term protection to survive reexposure to infection, has been overtaken by 'l'art pour l'art' of 'basic immunology'. The aim of this critical review is to point out some key differences between academic text book-defined immunological memory and protective immunity as viewed from a co-evolutionary point of view, both from the host and the infectious agents. A key conclusion is that 'immunological memory' of course exists, but only in particular experimental laboratory models measuring 'quicker and better' responses after an earlier immunization. These often do correlate with, but are not the key mechanisms of, protection. Protection depends on pre-existing neutralizing antibodies or pre-activated T cells at the time of infection-as documented by the importance of maternal antibodies around birth for survival of the offspring. Importantly, both high levels of antibodies and of activated T cells are antigen driven. This conclusion has serious implications for our thinking about vaccines and maintaining a level of protection in the population to deal with old and new infectious diseases.
Assuntos
Formação de Anticorpos , Memória Imunológica , Modelos Imunológicos , Animais , Evolução Biológica , Humanos , Imunidade ColetivaRESUMO
The acquisition of pathogen-derived antigen by dendritic cells (DCs) is a key event in the generation of cytotoxic CD8(+) T cell responses. In mice, the intracellular bacterium Listeria monocytogenes is directed from the blood to splenic CD8α(+) DCs. We report that L. monocytogenes rapidly associated with platelets in the bloodstream in a manner dependent on GPIb and complement C3. Platelet association targeted a small but immunologically important portion of L. monocytogenes to splenic CD8α(+) DCs, diverting bacteria from swift clearance by other, less immunogenic phagocytes. Thus, an effective balance is established between maintaining sterility of the circulation and induction of antibacterial immunity by DCs. Other gram-positive bacteria also were rapidly tagged by platelets, revealing a broadly active shuttling mechanism for systemic bacteria.
Assuntos
Plaquetas/microbiologia , Antígenos CD8/metabolismo , Complemento C3/metabolismo , Células Dendríticas/imunologia , Listeria monocytogenes/imunologia , Complexo Glicoproteico GPIb-IX de Plaquetas/metabolismo , Glicoproteínas da Membrana de Plaquetas/metabolismo , Animais , Plaquetas/metabolismo , Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/metabolismo , Células Dendríticas/microbiologia , Listeriose/imunologia , Listeriose/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Agregação Plaquetária/imunologia , Baço/imunologia , Baço/microbiologiaRESUMO
UNLABELLED: The innate immune response plays an essential role in the prevention of early viral dissemination. We used the lymphocytic choriomeningitis virus model system to analyze the role of tissue macrophages/Kupffer cells in this process. Our findings demonstrated that Kupffer cells are essential for the efficient capture of infectious virus and for preventing viral replication. The latter process involved activation of Kupffer cells by interferon (IFN)-I and prevented viral spread to neighboring hepatocytes. In the absence of Kupffer cells, hepatocytes were not able to suppress virus replication, even in the presence of IFN-I, leading to prolonged viral replication and severe T cell-dependent immunopathology. CONCLUSION: Tissue-resident macrophages play a crucial role in early viral capture and represent the major liver cell type exhibiting responsiveness to IFN-I and providing control of viral replication.
Assuntos
Hepatite/imunologia , Doenças do Sistema Imunitário/imunologia , Interferon Tipo I/imunologia , Células de Kupffer/imunologia , Fígado/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Modelos Animais de Doenças , Hepatite/patologia , Hepatite/virologia , Fígado/patologia , Fígado/virologia , Vírus da Coriomeningite Linfocítica/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Replicação ViralRESUMO
Newborn higher vertebrates are largely immuno-incompetent and generally survive infections--including poxviruses--by maternal antibody protection. Here, we show that mice survived epidemics as adults only if exposed to lethal orthopoxvirus infections during infancy under the umbrella of maternal protective antibodies. This implies that both the absence of exposure to infection during early infancy or of effective vaccination renders the population highly susceptible to new or old re-emerging pathogens.
Assuntos
Anticorpos Antivirais/imunologia , Ectromelia Infecciosa/imunologia , Imunidade Materno-Adquirida , Animais , Animais Recém-Nascidos , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Taxa de SobrevidaRESUMO
Neutrophils are the most abundant leukocytes in circulation and provide a primary innate immune defense function against bacterial pathogens before development of a specific immune response. These specialized phagocytes are short lived (12-24 hours) and continuously replenished from bone marrow. We found that if the host is overwhelmed by a high inoculum of Listeria monocytogenes, neutrophils are depleted despite high granulocyte-colony stimulating factor induction. In contrast to a low-dose innocuous L. monocytogenes infection, high-dose Listeria challenge blocks neutrophil recruitment to infectious abscesses and bacterial proliferation is not controlled, resulting in lethal outcomes. Administering synthetic TLR2-ligand or heat-killed bacteria during the innocuous L. monocytogenes infection reproduced these effects, once again leading to overwhelming bacterial propagation. The same stimuli also severely aggravated Salmonella typhimurium, Staphylococcus aureus, and Streptococcus pyogenes systemic infection. These data implicate systemic innate immune stimulation as a mechanism of bone marrow neutrophil exhaustion which negatively influences the outcome of bacterial infections.
Assuntos
Apoptose/imunologia , Medula Óssea/imunologia , Infecções por Bactérias Gram-Positivas/imunologia , Imunidade Inata/imunologia , Neutrófilos/citologia , Neutrófilos/imunologia , Salmonelose Animal/imunologia , Animais , Listeriose/imunologia , Camundongos , Camundongos Knockout , Infecções Estafilocócicas/imunologia , Infecções Estreptocócicas/imunologia , Fatores de Tempo , Receptor 2 Toll-Like/deficiência , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/imunologia , Receptor 2 Toll-Like/metabolismoRESUMO
Retroviruses have the potential to acquire host cell-derived genetic material during reverse transcription and can integrate into the genomes of larger, more complex DNA viruses. In contrast, RNA viruses were believed not to integrate into the host's genome under any circumstances. We found that illegitimate recombination between an exogenous nonretroviral RNA virus, lymphocytic choriomeningitis virus, and the endogenous intracisternal A-type particle (IAP) retrotransposon occurred and led to reverse transcription of exogenous viral RNA. The resulting complementary DNA was integrated into the host's genome with an IAP element. Thus, RNA viruses should be closely scrutinized for any capacity to interact with endogenous retroviral elements before their approval for therapeutic use in humans.
Assuntos
DNA Complementar/genética , Genes de Partícula A Intracisternal/genética , Vírus da Coriomeningite Linfocítica/genética , RNA Viral/genética , Recombinação Genética , Transcrição Reversa , Integração Viral , Animais , Infecções por Arenaviridae/virologia , Sequência de Bases , Linhagem Celular , Glicoproteínas/genética , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Transfecção , Proteínas Virais/genéticaRESUMO
Anti-helminth immunity involves CD4+ T cells, yet the precise effector mechanisms responsible for parasite killing or expulsion remain elusive. We now report an essential role for antibodies in mediating immunity against the enteric helminth Heligmosomoides polygyrus (Hp), a natural murine parasite that establishes chronic infection. Polyclonal IgG antibodies, present in naive mice and produced following Hp infection, functioned to limit egg production by adult parasites. Comparatively, affinity-matured parasite-specific IgG and IgA antibodies that developed only after multiple infections were required to prevent adult worm development. These data reveal complementary roles for polyclonal and affinity-matured parasite-specific antibodies in preventing enteric helminth infection by limiting parasite fecundity and providing immune protection against reinfection, respectively. We propose that parasite-induced polyclonal antibodies play a dual role, whereby the parasite is allowed to establish chronicity, while parasite load and spread are limited, likely reflecting the long coevolution of helminth parasites with their hosts.
Assuntos
Anticorpos Anti-Helmínticos/imunologia , Enteropatias Parasitárias/imunologia , Nematospiroides dubius/imunologia , Infecções por Strongylida/imunologia , Animais , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Contagem de Ovos de ParasitasRESUMO
More than 500 million people worldwide are persistently infected with hepatitis B virus or hepatitis C virus. Although both viruses are poorly cytopathic, persistence of either virus carries a risk of chronic liver inflammation, potentially resulting in liver steatosis, liver cirrhosis, end-stage liver failure or hepatocellular carcinoma. Virus-specific T cells are a major determinant of the outcome of hepatitis, as they contribute to the early control of chronic hepatitis viruses, but they also mediate immunopathology during persistent virus infection. We have analyzed the role of platelet-derived vasoactive serotonin during virus-induced CD8(+) T cell-dependent immunopathological hepatitis in mice infected with the noncytopathic lymphocytic choriomeningitis virus. After virus infection, platelets were recruited to the liver, and their activation correlated with severely reduced sinusoidal microcirculation, delayed virus elimination and increased immunopathological liver cell damage. Lack of platelet-derived serotonin in serotonin-deficient mice normalized hepatic microcirculatory dysfunction, accelerated virus clearance in the liver and reduced CD8(+) T cell-dependent liver cell damage. In keeping with these observations, serotonin treatment of infected mice delayed entry of activated CD8(+) T cells into the liver, delayed virus control and aggravated immunopathological hepatitis. Thus, vasoactive serotonin supports virus persistence in the liver and aggravates virus-induced immunopathology.
Assuntos
Plaquetas/química , Hepatite Viral Animal/patologia , Coriomeningite Linfocítica/patologia , Serotonina/deficiência , Serotonina/metabolismo , Animais , Linfócitos T CD8-Positivos/metabolismo , Meia-Vida , Hepatite Viral Animal/imunologia , Hepatite Viral Animal/virologia , Fígado/irrigação sanguínea , Fígado/imunologia , Fígado/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microcirculação , Contagem de Plaquetas , Serotonina/genéticaRESUMO
Many vaccination strategies and immune cell therapies aim at increasing the numbers of memory T cells reactive to protective antigens. However, the differentiation lineage and therefore the optimal generation conditions of CD4 memory cells remain controversial. Linear and divergent differentiation models have been proposed, suggesting CD4 memory T cell development from naive precursors either with or without an effector-stage intermediate, respectively. Here, we address this question by using newly available techniques for the identification and isolation of effector T cells secreting effector cytokines. In adoptive cell transfers into normal, nonlymphopenic mice, we show that long-lived virus-specific memory T cells can efficiently be generated from purified interferon gamma-secreting T helper (Th) type 1 and interleukin (IL)-4- or IL-10-secreting Th2 effectors primed in vitro or in vivo. Importantly, such effector-derived memory T cells were functional in viral challenge infections. They proliferated vigorously, rapidly modulated IL-7 receptor expression, exhibited partial stability and flexibility of their cytokine patterns, and exerted differential effects on virus-induced immunopathology. Thus, cytokine-secreting effectors can evade activation-induced cell death and develop into long-lived functional memory cells. These findings demonstrate the efficiency of linear memory T cell differentiation and encourage the design of vaccines and immune cell therapies based on differentiated effector T cells.
Assuntos
Memória Imunológica , Linfócitos T/fisiologia , Células Th1/fisiologia , Células Th2/fisiologia , Animais , Diferenciação Celular , Citocinas/metabolismo , Citometria de Fluxo , Interferon gama/metabolismo , Interleucina-10/metabolismo , Interleucina-4/metabolismo , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Biológicos , Linfócitos T/virologia , Células Th1/virologia , Células Th2/virologiaRESUMO
Maternal antibodies protect newborns whilst they are immunologically immature. This study shows that maternal antibodies can also shape the B cell repertoire of the offspring long after the maternal antibodies themselves become undetectable. V(H)DJ(H) gene-targeted (VI10) mice expressing a heavy chain specific for vesicular stomatitis virus (VSV) produce a 20-fold increased spontaneous titer of VSV-neutralizing antibodies. When transferred from mother to offspring, these antibodies prevented accumulation of Ag-specific transitional type 2 and marginal zone B cells with an activated phenotype and favored selection to the B cell follicles. This effect was B cell-intrinsic and lasted up to adulthood. The pups nursed by mothers producing specific antibodies developed higher endogenous antibody titers of this specificity which perpetuated the effects of specific B cell selection into the mature follicular compartment, presumably by blocking auto-Ag-dependent development of transitional type 2 B cells in the spleen. This repertoire change was functional, as following infection of adult mice with VSV, those pups that had received specific maternal antibodies as neonates had increased pre-immune titers and mounted strong early IgG neutralizing antibodies.
Assuntos
Anticorpos/imunologia , Linfócitos B/imunologia , Impressão Genômica/imunologia , Sistema Imunitário/crescimento & desenvolvimento , Switching de Imunoglobulina/imunologia , Transferência Adotiva , Animais , Animais Recém-Nascidos , Anticorpos Antivirais/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Camundongos , Infecções por Rhabdoviridae/imunologia , Tempo , Vírus da Estomatite Vesicular Indiana/imunologiaRESUMO
The prion protein (PrP) is crucially involved in transmissible spongiform encephalopathies (TSE), but neither its exact role in disease nor its physiological function are known. Here we show for mice, using histological, immunochemical and PCR-based methods, that stimulation of innate resistance was followed by appearance of numerous endogenous retroviruses and ensuing PrP up-regulation in germinal centers of the spleen. Subsequently, the activated retroviruses disappeared in a PrP-dependent manner. Our results reveal the regular involvement of endogenous retroviruses in murine immune responses and provide evidence for an essential function of PrP in the control of the retroviral activity. The interaction between PrP and ubiquitous endogenous retroviruses may allow new interpretations of TSE pathophysiology and explain the evolutionary conservation of PrP.
Assuntos
Príons/fisiologia , Retroviridae/fisiologia , Baço/virologia , Animais , Sequência de Bases , Western Blotting , Primers do DNA , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Microscopia de Fluorescência , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Baço/imunologia , Ativação ViralRESUMO
T helper cells can support the functions of CD8(+) T cells against persistently infecting viruses such as murine lymphocytic choriomeningitis virus (LCMV), cytomegalovirus, hepatitis C virus and HIV. These viruses often resist complete elimination and remain detectable at sanctuary sites, such as the kidneys and other extralymphatic organs. The mechanisms underlying this persistence are not well understood. Here we show that mice with potent virus-specific T-cell responses have reduced levels and delayed formation of neutralizing antibodies, and these mice fail to clear LCMV from extralymphatic epithelia. Transfer of virus-specific B cells but not virus-specific T cells augmented virus clearance from persistent sites. Virus elimination from the kidneys was associated with the formation of IgG deposits in the interstitial space, presumably from kidney-infiltrating B cells. CD8(+) T cells in the kidneys of mice that did not clear virus from this site were activated but showed evidence of exhaustion. Thus, we conclude that in this model of infection, site-specific virus persistence develops as a consequence of potent immune activation coupled with reductions in virus-specific neutralizing antibodies. Our results suggest that sanctuary-site formation depends both on organ anatomy and on the induction of different adaptive immune effector mechanisms. Boosting T-cell responses alone may not reduce virus persistence.
Assuntos
Sistema Linfático/imunologia , Ativação Linfocitária/imunologia , Vírus da Coriomeningite Linfocítica/imunologia , Linfócitos T/imunologia , Latência Viral/imunologia , Replicação Viral/imunologia , Animais , Linhagem Celular , Cricetinae , Rim/imunologia , Rim/virologia , Fígado/imunologia , Fígado/virologia , Pulmão/imunologia , Pulmão/virologia , Sistema Linfático/virologia , Vírus da Coriomeningite Linfocítica/crescimento & desenvolvimento , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Especificidade de Órgãos/imunologia , Linfócitos T/virologiaRESUMO
BACKGROUND: Cooperation of CD4+ T helper cells with specific B cells is crucial for protective vaccination against pathogens by inducing long-lived neutralizing antibody responses. During infection with persistence-prone viruses, prolonged virus replication correlates with low neutralizing antibody responses. We recently described that a viral mutant of lymphocytic choriomeningitis virus (LCMV), which lacks a T helper epitope, counterintuitively induced an enhanced protective antibody response. Likewise, partial depletion of the CD4+ T cell compartment by using anti-CD4 antibodies enhanced protective antibodies. PRINCIPAL FINDINGS: Here we have developed a protocol to selectively reduce the CD4+ T cell response against viral CD4+ T cell epitopes. We demonstrate that in vivo treatment with LCMV-derived MHC-II peptides induced non-responsiveness of specific CD4+ T cells without affecting CD4+ T cell reactivity towards other antigens. This was associated with accelerated virus-specific neutralizing IgG-antibody responses. In contrast to a complete absence of CD4+ T cell help, tolerisation did not impair CD8+ T cell responses. CONCLUSIONS: This result reveals a novel "negative vaccination" strategy where specific CD4+ T cell unresponsiveness may be used to enhance the delayed protective antibody responses in chronic virus infections.
Assuntos
Anticorpos Antivirais/biossíntese , Linfócitos T CD4-Positivos/imunologia , Tolerância Imunológica , Sequência de Aminoácidos , Animais , Anticorpos Antivirais/imunologia , Separação Celular , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Testes de NeutralizaçãoRESUMO
Germinal centers are structures that promote humoral memory cell formation and affinity maturation, but the triggers for their development are not entirely clear. Activated extrafollicular B cells can form IgM-producing plasmablasts or enter a germinal center reaction and differentiate into memory or plasma cells, mostly of the IgG isotype. Vesicular stomatitis virus (VSV) induces both types of response, allowing events that promote each of these pathways to be studied. In this work, extrafollicular vs germinal center responses were examined at a cellular level, analyzing VSV-specific B cells in infected mice. We show that VSV-specific germinal centers are transiently formed when insufficient proportions of specific T cell help is available and that strong B cell activation in cells expressing high levels of the VSV-specific BCR promoted their differentiation into early blasts, whereas moderate stimulation of B cells or interaction with Th cells restricted extrafollicular responses and promoted germinal center formation.
Assuntos
Linfócitos B/imunologia , Centro Germinativo/imunologia , Ativação Linfocitária/imunologia , Infecções por Rhabdoviridae/imunologia , Vírus da Estomatite Vesicular Indiana/imunologia , Animais , Cálcio/metabolismo , Linhagem Celular , Camundongos , Receptores de Antígenos de Linfócitos B/imunologia , Infecções por Rhabdoviridae/virologiaRESUMO
Lymphocytic choriomeningitis virus (LCMV) is a murine arenavirus whose glycoprotein consists of a transmembrane subunit (GP-2) and a receptor-binding subunit (GP-1). LCMV-neutralizing antibodies (nAbs) are directed against a single site on GP-1 and occur 1 month after the infection of cytotoxic-T-lymphocyte (CTL) deficient mice. In wild-type mice, however, CTLs control early infection, and weak nAb titers emerge very late (after 70 to 150 days) if at all. Production of recombinant GP-1 in native conformation enabled us to study the emergence of GP-1-binding antibodies directed against the neutralizing epitope. By combining binding and neutralization assays, we correlated the development of binding antibodies versus nAbs in wild-type and CTL-deficient mice after infection with different LCMV doses. We found that wild-type mice developed GP-1-specific antibodies already by day 8 after exposure to high but not low doses, demonstrating that naive GP-1-specific B cells were infrequent. Furthermore, the induced antibodies bound to the neutralizing GP-1 epitope but failed to neutralize the virus and therefore were of low affinity. In CTL-deficient mice, where massive viremia quickly levels initial differences in viral load, low and high doses induced low-affinity non-neutralizing GP-1-binding antibodies with kinetics similar to high-dose-infected wild-type mice. Only in CTL-deficient mice, however, the GP-1-specific antibodies developed into nAbs within 1 month. We conclude that LCMV uses a dual strategy to evade nAb responses in wild-type mice. First, LCMV exploits a "hole" in the murine B-cell repertoire, which provides only a small and narrow initial pool of low-affinity GP-1-specific B cells. Second, affinity maturation of the available low-affinity non-neutralizing antibodies is impaired.
Assuntos
Epitopos/química , Vírus da Coriomeningite Linfocítica/metabolismo , Animais , Anticorpos Monoclonais/química , Anticorpos Antivirais/química , Ensaio de Imunoadsorção Enzimática , Mapeamento de Epitopos , Glicoproteínas/química , Coriomeningite Linfocítica/prevenção & controle , Coriomeningite Linfocítica/virologia , Camundongos , Camundongos Endogâmicos C57BL , Conformação Molecular , Nucleoproteínas/química , Estrutura Terciária de Proteína , Fatores de TempoRESUMO
Recent studies indicate that T cell cross-priming preferentially occurs against long-lived, stable proteins. We have studied cross-priming by using the glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV), a protein that normally is not MHC class I cross-presented. This study shows that a C-terminally truncated, noncleavable variant of LCMV-GP led to the accumulation of stable, soluble GP trimers in the endoplasmic reticulum (ER) of the antigen donor cell, and thereby converted LCMV-GP into a potent immunogen for cytotoxic T lymphocyte cross-priming. Immunization of mice with tumor cells expressing an ER-retained LCMV-GP variant cross-primed protective antiviral cytotoxic T lymphocyte responses in vivo at least 10,000-fold better than immunization with cells expressing the cross-presentation-"resistant" wild-type LCMV-GP. Thus the ER is a cellular compartment that can provide antigen for cross-presentation, and modifications affecting stability and subcellular localization of the antigen significantly increase its availability for MHC class I cross-presentation. These findings impinge on vaccine strategies.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Retículo Endoplasmático/metabolismo , Glicoproteínas/imunologia , Vírus da Coriomeningite Linfocítica/metabolismo , Proteínas Virais/imunologia , Animais , Western Blotting , Citometria de Fluxo , Células HeLa , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos TransgênicosRESUMO
MyD88 is a key adaptor molecule in innate resistance, engaged in most Toll-like receptor, as well as IL-1 and IL-18, signalling. Here, we analyzed the role of MyD88 in innate resistance during infection with vesicular stomatitis virus (VSV) using myd88(-/-) mice. We found an increased susceptibility to VSV in myd88(-/-) mice, which was not explained by reduced type I IFN or neutralizing antibody responses. Susceptibility of myd88(-/-) mice correlated with impaired recruitment of immune cells to the site of infection. In the absence of MyD88 signalling, VSV rapidly spread to the spinal cord and brain causing lethal encephalitis.
Assuntos
Encefalite Viral/metabolismo , Encefalite Viral/patologia , Fator 88 de Diferenciação Mieloide/metabolismo , Vírus da Estomatite Vesicular Indiana/fisiologia , Animais , Anticorpos/imunologia , Linhagem Celular , Quimiocinas/metabolismo , Cricetinae , Encefalite Viral/imunologia , Encefalite Viral/virologia , Interferon Tipo I/metabolismo , Interleucina-1/biossíntese , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/deficiência , Fator 88 de Diferenciação Mieloide/genética , Transdução de Sinais , Taxa de SobrevidaRESUMO
Identification and characterization of IgE-inducing antigens are important for elucidating the mechanisms involved in IgE-mediated immune responses in allergic diseases and parasite infections. While many allergens have been characterized, little is known about parasite antigens inducing specific IgE following infection. In order to identify antigens from the nematode Nippostrongylus brasiliensis, we generated an IgE-producing B cell hybridoma from N. brasiliensis-infected C57BL/6 mice and constructed a cDNA phage display library from N. brasiliensis. We successfully cloned and expressed an N. brasiliensis antigen (Nb-Ag1) that showed specific binding to anti-N. brasiliensis IgE. Nb-Ag1 localized to the pharynx of adult N. brasiliensis, suggesting that Nb-Ag1 is a potential pharyngeal gland antigen. Nb-Ag1-specific IgE could be detected in the serum of N. brasiliensis-infected mice, but only for a short time and only following a challenge infection. In contrast, local administration of Nb-Ag1 during primary, secondary and tertiary infections induced Nb-Ag1-specific IgE-mediated active cutaneous anaphylaxis. Therefore, amongst the high amounts of polyclonal total IgE, low levels of parasite-specific IgE responses are induced during primary helminth infections. Here, we show that even such low levels of parasite-specific IgE are sufficient to prime mast cells in vivo and mediate degranulation.