HCV感染过程中的相关免疫反应

丙型肝炎病毒(Hepatitis C Virus,HCV)是慢性丙型病毒性肝炎的主要病因,也是引发肝硬化和肝癌的主要诱因。在HCV感染过程中,伴随着干扰素信号通路的激活和干扰素刺激基因(IFN-stimulated gene,ISG)的持续表达,且有HCV独特的免疫逃逸和免疫细胞的功能损伤。现就HCV感染过程中机体的固有免疫反应和适应性免疫反应的研究进展作一综述。     

The ecology of host immune responses to chronic avian haemosporidian infection

Host responses to parasitism in the wild are often studied in the context of single host–parasite systems, which provide little insight into the ecological dynamics of host–parasite interactions within a community. Here we characterized immune system responses to mostly low-intensity, chronic infection by haemosporidian parasites in a sample of 424 individuals of 22 avian host species from the same local assemblage in the Missouri Ozarks. Two types of white blood cells (heterophils and lymphocytes) were elevated in infected individuals across species, as was the acute-phase protein haptoglobin, which is associated with inflammatory immune responses. Linear discriminant analysis indicated that individuals infected by haemosporidians occupied a subset of the overall white blood cell multivariate space that was also occupied by uninfected individuals, suggesting that these latter individuals might have harbored other pathogens or that parasites more readily infect individuals with a specific white blood cell profile. DNA sequence-defined lineages of haemosporidian parasites were sparsely distributed across the assemblage of hosts. In one well-sampled host species, the red-eyed vireo (Vireo olivaceus), heterophils were significantly elevated in individuals infected with one but not another of two common parasite lineages. Another well-sampled host, the yellow-breasted chat (Icteria virens), exhibited no differences in immune response to different haemosporidian lineages. Our results indicate that while immune responses to infection may be generalized across host species, parasite-specific immune responses may also occur.     

Toll-like receptor 4 mediates innate immune responses to Haemophilus influenzae infection in mouse lung.

Toll-like receptors (TLRs) have been implicated in the regulation of host responses to microbial Ags. This study characterizes the role of TLR4 in the innate immune response to intrapulmonary administration of Haemophilus influenzae in the mouse. Two different strains of mice efficiently cleared aerosolized H. influenzae concurrent with a brisk elaboration of IL-1beta, IL-6, TNF-alpha, macrophage-inflammatory protein (MIP)-1alpha, and MIP-2 in bronchoalveolar lavage and a corresponding mobilization of intrapulmonary neutrophils. Congenic strains of mice deficient in TLR4 demonstrated a substantial delay in clearance of H. influenzae with diminished IL-1beta, IL-6, TNF-alpha, MIP-1alpha, and MIP-2 in bronchoalveolar lavage and a notable absence of intrapulmonary neutrophils. In TLR4-expressing animals, but not TLR4-deficient animals, TNF-alpha and MIP-1alpha expression was up-regulated in epithelial cells of the conducting airway in response to H. influenzae which was preceded by an apparent activation of the NF-kappaB pathway in these cells based on the findings of decreased overall IkappaB and an increase in its phosphorylated form. This study demonstrates a critical role of TLR4 in mediating an effective innate immune response to H. influenzae in the lung. This suggests that the airway epithelia might contribute to sensing of H. influenzae infection and signaling the innate immune response.     

Clara cell secretory protein modulates lung inflammatory and immune responses to respiratory syncytial virus infection

Clara cell secretory protein (CCSP) has been shown to have anti-inflammatory and immunomodulatory functions in the lung. Respiratory syncytial virus (RSV) is the most common cause of respiratory infection in infants and young children. RSV usually infects small airways and likely interacts with the Clara cells of bronchioles. To determine a possible role for CCSP during acute RSV infection, CCSP-deficient (CCSP(-/-)) and wild-type (WT) mice were intratracheally infected with RSV and the lung inflammatory and immune responses to RSV infection were assessed. RSV-F gene expression was increased in the lungs of CCSP(-/-) mice as compared with WT mice following RSV infection, consistent with increased viral persistence. Lung inflammation was significantly increased in CCSP(-/-) mice as compared with WT mice after infection. Moreover, although the levels of Th1 cytokines were similar, the levels of Th2 cytokines and neutrophil chemokines were increased in the lungs of CCSP(-/-) mice following infection. Physiologic endpoints of exacerbated lung disease, specifically airway reactivity and mucus production, were increased in CCSP(-/-) mice after RSV infection. Importantly, restoration of CCSP in the airways of CCSP(-/-) mice abrogated the increased viral persistence, lung inflammation, and airway reactivity. These findings suggest a role for CCSP and Clara cells in regulating lung inflammatory and immune responses to RSV infection.     

Parasite glycans and antibody-mediated immune responses in Schistosoma infection

Schistosome infections in humans are characterized by the development of chronic disease and high re-infection rates after treatment due to the slow development of immunity. It appears that anti-schistosome antibodies are at least partially mediating protective mechanisms. Efforts to develop a vaccine based on immunization with surface-exposed or secreted larval or worm proteins are ongoing. Schistosomes also express a large number of glycans as part of their glycoprotein and glycolipid repertoire, and antibody responses to those glycans are mounted by the infected host. This observation raises the question if glycans might also form novel vaccine targets for immune intervention in schistosomiasis. This review summarizes current knowledge of antibody responses and immunity in experimental and natural infections with Schistosoma, the expression profiles of schistosome glycans (the glycome), and antibody responses to individual antigenic glycan motifs. Future directions to study anti-glycan responses in schistosomiasis in more detail in order to address more precisely the possible role of glycans in antibody-mediated immunity are discussed.     

Immunoglobulin carbohydrate requirement for formation of an IgG-IgG complex.

In addition to their Fc oligosaccharides, some immunoglobulin molecules have oligosaccharides linked to variable segments of H or L chains. These Fab oligosaccharides are potential determinants of antibody specificity. This possibility was considered in a study of the IgG antiglobulin from a patient with IgG-IgG complexes. F(ab')2 fragments of the antiglobulin retained the ability to form complexes with normal IgG as detected by analytical ultracentrifugation. Removal of F(ab')2 sialic acids by neuraminidase abolished complex formation. Recombination experiments further localized antiglobulin activity to the L chains. Antiglobulin activity of the recombinant molecules was shown by analytical ultracentrifugation and by column chromatography with molecules containing 125I-labeled L chains. L chains from the subject's IgG were enriched in sialic acids. Thus, a sialic acid-containing oligosaccharide on the L chain of this antiglobulin is required for its binding action.     

Orientia tsutsugamushi infection: overview and immune responses

Orientia tsutsugamushi, an obligate intracellular bacterium, was isolated for the first time in 1930. Infections by virulent strains are characterized by fever, rash, eschar, pneumonia, myocarditis, and disseminated intravascular coagulation. Here we review the general aspects of O. tsutsugamushi and immune responses in terms of inflammation, protective immune mechanisms, and immunogenic antigens.     

Aging and the immune response. I. Antibody formation and chronic infection in Toxoplasma gondii-infected mice

Studies were performed to determine the effect of aging on the antibody response and cyst formations after infection with a relatively avirulent strain of the intracellular parasite Toxoplasma gondii. When compared with young mice (4 months), aged mice showed a significant decrease in the magnitude of humoral immune response to infection. This decrease was observed at the peak of the acute infection and also during chronic infection. Evaluation of the presence of Toxoplasma cysts, a measure of the latent infection, revealed that the numbers of tissue cysts present 11 weeks after infection increased with the age of the mice at time of infection. The larger numbers of cysts in older mice which had received the same inoculum size of T. gondii as young mice, together with our previous observations of increased susceptibility of these older mice to T. gondii, suggest that an age-related decrease in the early immune response to this infection allows an increased multiplication of the organism in vivo, leading to increased cyst numbers or death.     

Innate immune responses to Pseudomonas aeruginosa infection

Innate immune responses play a critical role in controlling acute infections due to Pseudomonas aeruginosa in both mice and in humans. In this review we focus on innate immune recognition and clearance mechanisms that are important for controlling P. aeruginosa in the mammalian lung, with particular attention to those that influence the outcome of in vivo infection in murine models.     

Circulating and tissue-bound immune complex formation in murine malaria.

Immune complex formation during Plasmodium berghei infection of OF1 mice was investigated. Circulating immune complexes (CIC) were detected by the Clg-binding assay and the conglutinin-binding solid-phase assay in lethal or drug-limited infections. CIC appeared on day 9 of infection, peaked on day 11, and disappeared only after complete cure of the infection. Analysis of the immune complexes detected by the Clq-binding assay revealed the following characteristics: sedimentation coefficients of 13S to 21S, resistance to DNAse, and selective removal by filtration through protein A bound to Sepharose. Glomerular deposits of IgM preceded the appearance of CIC, whereas deposits of IgG and C3 were concomitant with the appearance of CIC. Tissue-bound immunoglobulins were also found in the choroid plexus. The appearance of anti-malarial antibodies and malarial antigens in the serum was closely associated with a depression of C3 levels and the presence of CIC. Drug treatment was followed by normalization of C3 levels, and clearance of both CIC and malarial antigens.     

Mediators and regulation of neutrophil accumulation in inflammatory responses in lung: insights from the IgG immune complex model

Neutrophil trafficking in lung involves transendothelial migration, migration in tissue interstitium, and transepithelial migration. In a rat model of IgG immune complex-induced lung injury, it was demonstrated that neutrophil emigration involves regulatory mechanisms including complement activation, cytokine regulation, chemokine production, activation of adhesion molecules, and their respective counter receptors. The process is presumably initiated and modulated by the production of early response cytokines and chemokines from lung cells, especially from alveolar macrophages. TNF-alpha and IL-1 up-regulate intracellular adhesion molecule-1 (ICAM-1) and E-selectin, setting the stage for neutrophil migration through endothelium. The CXC chemokines, such as macrophage inflammatory protein (MIP)-2 and cytokine-inducible neutrophil chemoattractant (CINC), constitute chemokine gradient to orchestrate neutrophil migration in lung. Complement activation induced by IgG immune complex deposition is another important event leading to neutrophil accumulation in lung. Complement activation product C5a not only plays an important role in chemoattracting neutrophils into lung, but regulates adhesion molecules, chemokines, and cytokines expression. In addition, oxidative stress may regulate neutrophil accumulation in lung by modulation of adhesion molecule activation and chemokine production. In this review, we focus on the current knowledge of the mechanisms leading to accumulation of neutrophils during acute lung injury.     

Perillyl alcohol suppresses antigen-induced immune responses in the lung

Perillyl alcohol (POH) is an isoprenoid which inhibits farnesyl transferase and geranylgeranyl transferase, key enzymes that induce conformational and functional changes in small G proteins to conduct signal production for cell proliferation. Thus, it has been tried for the treatment of cancers. However, although it affects the proliferation of immunocytes, its influence on immune responses has been examined in only a few studies. Notably, its effect on antigen-induced immune responses has not been studied. In this study, we examined whether POH suppresses Ag-induced immune responses with a mouse model of allergic airway inflammation. POH treatment of sensitized mice suppressed proliferation and cytokine production in Ag-stimulated spleen cells or CD4⁺ T cells. Further, sensitized mice received aerosolized OVA to induce allergic airway inflammation, and some mice received POH treatment. POH significantly suppressed indicators of allergic airway inflammation such as airway eosinophilia. Cytokine production in thoracic lymph nodes was also significantly suppressed. These results demonstrate that POH suppresses antigen-induced immune responses in the lung. Considering that it exists naturally, POH could be a novel preventive or therapeutic option for immunologic lung disorders such as asthma with minimal side effects.     

Differential tissue-specific regulation of antiviral CD8+ T-cell immune responses during chronic viral infection

The hallmarks of the immune response to viral infections are the expansion of antigen-specific CD8(+) cytotoxic T lymphocytes (CTLs) after they encounter antigen-presenting cells in the lymphoid tissues and their subsequent redistribution to nonlymphoid tissues to deal with the pathogen. Control mechanisms exist within CTL activation pathways to prevent inappropriate CTL responses against disseminating infections with a broad distribution of pathogen in host tissues. This is demonstrated during overwhelming infection with the noncytolytic murine lymphocytic choriomeningitis virus, in which clonal exhaustion (anergy and/or deletion) of CTLs prevents immune-mediated pathology but allows persistence of the virus. The mechanism by which the immune system determines whether or not to mount a full response to such infections is unknown. Here we present data showing that the initial encounter of specific CTLs with infected cells in lymphoid tissues is critical for this decision. Whether the course of the viral infection is acute or persistent for life primarily depends on the degree and kinetics of CTL exhaustion in infected lymphoid tissues. Virus-driven CTL expansion in lymphoid tissues resulted in the migration of large quantities of CTLs to nonlymphoid tissues, where they persisted at stable levels. Surprisingly, although virus-specific CTLs were rapidly clonally exhausted in lymphoid tissues under conditions of chronic infection, a substantial number of them migrated to nonlymphoid tissues, where they retained an effector phenotype for a long time. However, these cells were unable to control the infection and progressively lost their antiviral capacities (cytotoxicity and cytokine secretion) in a hierarchical manner before their eventual physical elimination. These results illustrate the differential tissue-specific regulation of antiviral T-cell responses during chronic infections and may help us to understand the dynamic relationship between antigen and T-cell populations in many persistent infections in humans.     

Cell-mediated immune responses in human infection with Onchocerca volvulus

Mechanisms involved in modulation of the immune response in persons with chronic Onchocerca volvulus infection are poorly understood. In this study in vitro reactivity of PBMC to O. volvulus antigen (Ovag), streptolysin O (SL-O) and the mitogen PHA was tested in 62 infected individuals (INF), 17 persons living in the endemic area with exposure to the infection, but with no detectable infection (END), and 7 healthy controls (CTRL) in Liberia, West Africa. Mean blastogenic responses to Ovag were minimal and did not differ between the groups. There was, however, heterogenous reactivity to Ovag in the INF and END. For example, individuals with a history of therapy, and half of those less than 17 yr old who were tested, showed high responses. No significant differences in the response to SL-O or PHA were detected between the groups. IL-2 production in response to Ovag was minimal in the majority of infected subjects. Exogenous IL-2 was found to cause a significant increase in mean responses to Ovag and SL-O in INF and END only. Similarly, Ovag did not stimulate IL-1 production in most INF, whereas stimulation with LPS led to significantly greater production of IL-1. Depletion of plastic and nylon wool adherent cells did not increase responses to parasite-related antigen in INF, END or CTRL; however, responses to SL-O were augmented in INF, an effect that was also observed in CTRL. Finally, depletion of CD8 or CD16 cells in INF by C lysis did not increase blastogenic responses. These results indicate that cell-mediated immunity to parasite-related Ag as reflected in lymphocyte responses in vitro is diminished in infected individuals, and that this may be caused by defects in T cell activation.     

Human cellular immune responses to Bordetella pertussis infection

Abstract We have compared the responses of peripheral blood leucocytes from three groups (i) patients suffering from pertussis (whooping cough), (ii) clinical staff caring for those patients and laboratory staff working with Bordetella pertussis , and (iii) staff with no known recent contact with B. pertussis . In vitro stimulation with filamentous haemagglutinin (FHA) caused significant increases in proliferation of only the patient group's lymphocytes. In vitro stimulation with pertussis toxin (PT) caused a large increase in proliferation of lymphocytes from all three groups and in the patient group the increase in proliferation was related to the dose of PT. Interleukin 2 (IL-2) production by leucocytes from all three groups was significantly increased following challenge with FHA or PT. The increases in IL-2 production were greatest in lymphocytes from patients with pertussis. Challenge with toxoided pertussis toxin had no effect on either proliferation or IL-2 production in any of the groups.     

Scaling of immune responses against intracellular bacterial infection

Macrophages detect bacterial infection through pattern recognition receptors (PRRs) localized at the cell surface, in intracellular vesicles or in the cytosol. Discrimination of viable and virulent bacteria from non-virulent bacteria (dead or viable) is necessary to appropriately scale the anti-bacterial immune response. Such scaling of anti-bacterial immunity is necessary to control the infection, but also to avoid immunopathology or bacterial persistence. PRR-mediated detection of bacterial constituents in the cytosol rather than at the cell surface along with cytosolic recognition of secreted bacterial nucleic acids indicates viability and virulence of infecting bacteria. The effector responses triggered by activation of cytosolic PRRs, in particular the RIG-I-induced simultaneous rapid type I IFN induction and inflammasome activation, are crucial for timely control of bacterial infection by innate and adaptive immunity. The knowledge on the PRRs and the effector responses relevant for control of infection with intracellular bacteria will help to develop strategies to overcome chronic infection.     

Persistent activation of an innate immune response translates respiratory viral infection into chronic lung disease

To understand the pathogenesis of chronic inflammatory disease, we analyzed an experimental mouse model of chronic lung disease with pathology that resembles asthma and chronic obstructive pulmonary disease (COPD) in humans. In this model, chronic lung disease develops after an infection with a common type of respiratory virus is cleared to only trace levels of noninfectious virus. Chronic inflammatory disease is generally thought to depend on an altered adaptive immune response. However, here we find that this type of disease arises independently of an adaptive immune response and is driven instead by interleukin-13 produced by macrophages that have been stimulated by CD1d-dependent T cell receptor-invariant natural killer T (NKT) cells. This innate immune axis is also activated in the lungs of humans with chronic airway disease due to asthma or COPD. These findings provide new insight into the pathogenesis of chronic inflammatory disease with the discovery that the transition from respiratory viral infection into chronic lung disease requires persistent activation of a previously undescribed NKT cell-macrophage innate immune axis.