Ⅰ型变态反应与呼吸道合胞病毒毛细支气管炎喘鸣的关系

本文从RSV特异的IgE抗体(RSV-IgE),嗜硷粒细胞和组织胺三方面,探讨了RSV毛细支气管炎喘鸣的发病机理。实验发现,RSV毛细支气管炎患儿的鼻咽分泌液(NPS)中RSV-IgE和组织胺显著升高,外周血嗜硷粒细胞绝对数升高,对 RSV抗原敏感性高,脱颗粒阳性率高。初步证实 IgE介导Ⅰ型变态反应参与了 RSV毛细支气管炎的发病。同时发现,RSV-IgE在患儿体内持续存在,这可能是 RSV毛细支气管炎喘鸣患儿在病后数年中反复出现喘鸣的原因之一。     

Production of interferon gamma in respiratory syncytial virus infection of humans is not associated with interleukins 12 and 18

In order to understand early events in the immune response to respiratory syncytial virus (RSV) infection, we studied the presence of various chemokines and cytokines in respiratory secretions of human infants with RSV infection. Interferon gamma (IFNgamma) was present in 30/39 (76.9%) subjects tested, but the IFNgamma-inducing cytokines interleukin (IL)12 and IL18 were detectable in 6/40 (15%) and 11/38 (28.9%) subjects, respectively. Quantities of IL12 and IL18 did not correlate with those of IFNgamma. IL18, but neither IFNgamma nor IL12 was found in significantly greater concentrations in subjects with mild, nonhypoxic forms of bronchiolitis than in those with upper respiratory illness alone or hypoxic bronchiolitis. The findings suggest that IFNgamma may be induced independently of the activities of IL12 and IL18 during RSV infection. Immune responses characterized by relatively greater release of IL18 may be associated with milder forms of bronchiolitis.     

Influence of atopy on the clinical manifestations of coronavirus infection in adult volunteers

In an attempt to understand the relationship between viral upper respiratory tract infection and the underlying virological and immunological mechanisms, thirty-four volunteers were inoculated intranasally with coronavirus 229E; subsequent virus shedding and/or antibody rises, indicating active infection, were observed in twenty-nine. There was a greater increase in independently measured scores of clinical severity, e.g. cold symptoms, in those with detectable IgE in nasal secretions ( P < 0.01). A similar association was found between clinical scores and serum IgE concentrations 150 IU/ml, but the relationship with systemic atopy, as assessed by skin-prick tests to common allergens, was less marked. A more detailed study of twelve of the infected volunteers failed to explain these findings on the basis of mast ceil mediator release, as concentrations of leukotriene B₄, the sulphidopeptide leukotriene C₄, and histamine, were not appreciably elevated in the nasal secretions following virus inoculation. Similarly, there was no evidence that circulating coronavirus specific IgE was produced. Thus, this study suggests that atopy may be related to the severity of cold symptoms produced by coronavirus 229E, although the exact connection has yet to be determined.     

Relationship between IgE and specific aeroallergen sensitivity in Alaskan native children.

BACKGROUND: The relationship between atopic disease and serum IgE levels varies among populations and geographic regions. The close association of atopy with IgE may not occur in subarctic populations as it does in developed countries in temperate climates. OBJECTIVE: To evaluate the relationship between total and specific IgE concentrations and clinical atopy in 5- to 8-year-old Alaskan native children. METHODS: Medical record reviews, interviews, physical examinations, serum IgE measurements, and radioallergosorbent testing (RAST) were performed. RESULTS: The IgE geometric mean was 122.1 IU/mL. Fifty-eight percent of patients had IgE levels greater than 70 IU/mL, and 17% had levels greater than 1,000 IU/mL; 14% had RAST values greater than 0.35 kU/L. Both IgE levels greater than 70 IU/mL and greater than 1,000 IU/mL were associated with RAST values greater than 0.35 IU/L (P = .004) and early wheezing (P = .005) but not with current wheezing, asthma, eczema, or a history of allergies. A RAST value greater than 3.51 kU/L was associated with eczema (P = .04) but not with allergies or wheezing. Children with current wheezing were more likely to have allergies (P = .03) but not eczema, an IgE level greater than 70 IU/mL, or a positive RAST value. Children hospitalized with respiratory syncytial virus (RSV) were not more likely than controls to have current wheezing. CONCLUSIONS: Elevated serum IgE concentrations, including levels greater than 1,000 IU/mL, are common among Alaskan native children; positive RAST reactions to aeroallergens are not. The IgE levels do not relate to wheezing, eczema, a history of allergies, or past hospitalization for RSV infection but likely reflect infections other than RSV and environmental factors in subarctic indigenous populations.     

RANTES may be predictive of later recurrent wheezing after respiratory syncytial virus bronchiolitis in infants.

BACKGROUND: In vitro studies have shown that RANTES is strongly induced by respiratory syncytial virus (RSV) infection in cultures of upper airway epithelial cells. RANTES is known as a chemoattractant and activator for eosinophils. OBJECTIVES: We performed this study to investigate whether RANTES is increased in the airway during naturally acquired RSV bronchiolitis. RANTES levels were then evaluated in relation to the severity of illness and later development of recurrent wheezing. METHODS: We measured RANTES in nasal secretions of 30 patients with acute RSV bronchiolitis. Eosinophil cationic protein (ECP) was determined to evaluate the activation of eosinophils. The severity of illness was determined by the initial PaO2 values and the duration of wheezing. At a 1-year followup, all infants were re-evaluated if they had experienced subsequent wheezing, and we investigated if RANTES levels could predict the later development of recurrent wheezing. RESULTS: Both RANTES and ECP in RSV bronchiolitis were significantly higher than in controls. There was a significant correlation between the levels of RANTES and ECP. RANTES was not significantly higher in patients with severe symptoms than in patients with mild symptoms. RANTES in infants who had experienced subsequent wheezing was significantly higher than in infants who had not. CONCLUSIONS: Our results showed that RANTES is increased in nasal secretion during acute RSV bronchiolitis and suggest that high levels of RANTES may be predictive of later development of recurrent wheezing.     

Serum concentrations of interferon-γ and intercellular adhesion molecule-1 eight years after an early respiratory syncytial virus infection

BACKGROUND: Respiratory syncytial virus (RSV) infection may influence the development of recurrent wheezing and atopy, but the mechanisms are unclear. OBJECTIVE: The purpose was to evaluate serum concentrations of soluble intercellular adhesion molecule-1 (sICAM-1), CD14, IgE, IL-5 and IFN-gamma in children 6-10 years after an RSV infection and their correlation with subsequent asthma and atopy. METHODS: Fifty-one subjects admitted to hospital for RSV infection during the first year of life and controls matched for birth date and sex underwent clinical examinations including lung function, skin prick and blood tests. RESULTS: The RSV subjects had significantly higher serum concentrations of IFN-gamma and sICAM-1 than the controls (for IFN-gamma 224.9 pg/mL (standard deviation (SD) 271.3) vs. 187.1 pg/mL (372.9), difference 37.8 pg/mL, 95% confidence interval (CI) -90.3 to 166.0, P = 0.05; for sICAM-1 170.2 ng/mL (SD 63) vs. 147.8 ng/mL (SD 57), difference 22.4 ng/mL, 95% CI -1.4 to 46.1, P = 0.04). The RSV subjects with asthma had significantly higher concentrations of IFN-gamma than the controls with asthma, and the RSV subjects with wheezing during the previous 12 months had significantly higher concentrations of both IFN-gamma and sICAM-1 than the controls with wheezing. CONCLUSIONS: Children hospitalized for RSV infection in infancy still differ in IFN-gamma and sICAM-1 production 6-10 years after the infection. The data suggest that the pathomechanism of asthma and wheezing after an early RSV infection may be different from that of children without an early RSV infection.     

Innate immune responses in respiratory syncytial virus infections

Respiratory syncytial virus (RSV) is the most important viral respiratory pathogen of early life. Studies of the immune response in general (and the innate response in particular) to this agent are of interest for a number of reasons. First, severe forms of illness may be a result of enhanced immunologic responsiveness to viral constituents at the time of infection. Secondly, the immune response to RSV may consist principally of innate immune responses at the time of maximum severity of illness. Third, RSV infection in infancy may be linked via immune mechanisms to the development of childhood wheezing. Finally there are no meaningfully effective forms of therapy for RSV infection, and elucidation of the immune response may suggest new therapeutic approaches. This review will summarize our current knowledge of innate immune responses to RSV infection. Specifically we will review early interactions of the virus with surfactant proteins and Toll-like receptors, chemokine release from infected cells, cytokine release from activated inflammatory cells, activation of neuroimmune pathways, generation of dendritic cells, the release of soluble mediators of airway obstruction, and genetic polymorphisms associated with RSV-related illness.     

Development of antibody-dependent cell-mediated cytotoxicity in the respiratory tract after natural infection with respiratory syncytial virus.

Antibody-dependent cell-mediated cytotoxicity (ADCC) was measured in nasopharyngeal secretions collected from 42 infants and young children at various intervals after primary or secondary infection with respiratory syncytial virus. ADCC was determined by specific immune release of 51Cr from respiratory syncytial virus-infected HEp-2 cell culture monolayers, with lymphocytes from adult volunteers as effector cells. Specific ADCC responses in nasopharyngeal secretions after primary infection were observed as early as 3 days after the onset of clinical symptoms, and peak activity was observed 14 to 29 days after the onset of illness. ADCC responses after reinfection were significantly greater in both the acute and convalescent phases (P less than 0.05) than were ADCC responses after primary infection. ADCC in secretions was mediated primarily by the immunoglobulin G isotype of respiratory syncytial virus antibody.     

Rapid recovery in mice after combined nasal/oral immunization with killed respiratory syncytial virus

Based on the concept of a common mucosal immune system, the murine gastrointestinal tract was inoculated (oral) with three doses (5, 20, and 40 micrograms) of UV-inactivated respiratory syncytial virus (RSV) in order to elicit a virus-specific immune response in the respiratory tract. Only the 40 micrograms dose induced significant (P less than 0.01) anti-RSV-IgG rises in serum and lung wash compared to controls. To improve the immune response, mice were immunized intranasally under light anesthesia with the same 40 micrograms dosage regimen of killed RSV so that each dose passed through the nose and was swallowed. This combined nasal/oral immunization stimulated anti-RSV-IgG in serum, lung wash and nasal wash (P less than 0.001) and anti-RSV-IgA in lung and nasal wash (P less than 0.001) that were comparable to levels after infection with live RSV. Three days after challenge with live RSV, mice given combined nasal/oral immunization showed suppressed nasal virus shedding (P = 0.025). Nasal virus shedding correlated inversely with concentrations of anti-RSV-Ig in nasal secretions but did not correlate with concentrations in serum.     

Eosinophil activation and cysteinyl leukotriene production in infants with respiratory syncytial virus bronchiolitis

BACKGROUND: It has been suggested that acute infantile bronchiolitis associated with respiratory syncytial virus (RSV) may share some pathogenic features with atopic asthma in that virus-specific IgE is produced and cysteinyl leukotrienes (cLTs) and eosinophil cationic protein (ECP) have been detected in airway secretions. ECP is a specific marker of eosinophil activation although leukotrienes can be released from a variety of cells including mast cells, eosinophils and monocytes. OBJECTIVE: To test the association between eosinophil activation and cysteinyl leukotriene production in the upper airway secretions of infants with RSV positive (RSV+ve) bronchiolitis. METHODS: Nasal lavage samples were performed in 78 infants (0.0-11.5 months) admitted to hospital with RSV+ve bronchiolitis soon after admission (0-48 h). Leukotriene C4 (LTC4) was assayed by enzyme immunoassay (EIA) and eosinophil cationic protein (ECP) by fluoroimmunoassay (FIA). RESULTS: LTC4 was detectable in 51 and ECP in 57 of 78 samples with a significant positive relationship between LTC4 and ECP (r=0.557, P<0.001). CONCLUSION: In the majority of our subjects with RSV+ve bronchiolitis ECP and LTC4 were detectable in upper airway secretions and were significantly associated with each other. In this clinical setting much of the detected LTC4 within upper airway secretions is likely to originate from the eosinophil, an observation that may have implications for clinical management and for delineation of the underlying mechanisms associated with this illness.     

Increased production of IFN-gamma and cysteinyl leukotrienes in virus-induced wheezing

BACKGROUND: An imbalance of production of T-helper lymphocyte cytokines, favoring overproduction of IL-4, is believed to be important in the pathogenesis of allergic asthma. However, less is known about the cytokine response in virus-induced wheezing, which is a major cause of morbidity in asthma. OBJECTIVE: We undertook this study to determine the magnitude of IFN-gamma, IL-4 and IL-10, and leukotriene (LT) responses in infants and children with virus-induced wheezing. METHODS: We measured the concentrations of IFN-gamma, IL-4 and IL-10, and cysteinyl LTs in respiratory secretions of 82 infants and young children during acute episodes of virus-induced wheezing. Control subjects were 47 infants and children with uncomplicated upper respiratory infections and 18 normal healthy infants. RESULTS: Ratios of IFN-gamma to IL-4 were higher (due to increased quantities of IFN-gamma) in subjects with wheezing than in those with upper respiratory infection alone (P =. 003). Quantities of LTs were also increased in wheezing subjects in comparison with those with upper respiratory infections (P =.009). There was a significant correlation between measured concentrations of IFN-gamma and LTs (correlation coefficient =.451, P =.007). Quantities of IL-4 were slightly suppressed in the wheezing groups. CONCLUSIONS: An imbalance favoring overproduction of IFN-gamma appears to be associated temporarily with virus-induced wheezing. A possible mechanism is the enhanced release of LTs from eosinophils or mast cells after sensitization by IFN-gamma.     

Larval exoantigens from ascarid nematodes are potent inducers of histamine release from human blood basophils

Histamine release (HR) from washed human blood cells after challenge with the excretory-secretory antigens (ES) of the parasitic nematodes Toxocara canis and Ascaris suum was studied, employing a recently developed microfibre-based assay combined with hyperosmolar release media for maximal sensitivity. Blood samples were obtained from 30 patients suspected of parasite infection and 11 healthy volunteers serving as controls. Specific antibodies of IgE, IgG1 and IgG4 subclasses were determined by ELISA. Virtually no HR could be provoked by ES in the 11 controls. In contrast, HR was seen in 16 patients after challenge with T. canis ES and in 11 patients with A. suum ES. In the majority of these, HR was detectable after challenge with ES protein concentrations of less than 1 ng/ml, and the maximal HR obtained with ES was greater than that seen with optimal concentrations of anti-IgE. The HR after ES antigen challenge correlated with the amount of specific IgE in patient plasma, and coincided with the presence of specific IgG1 and IgG4.     

Relation between frequency of asthma and IgE antibody levels against Dermatophagoides farinae and total serum IgE levels in schoolchildren

The relation between the frequency of wheezing illness and IgE antibody levels against Dermatophagoides farinae (Df) and total IgE levels was examined in 457 randomly selected schoolchildren. From the response to the ATS-DLD-78-C respiratory symptoms questionnaire, 14 subjects (3.1%) were found to have asthma syndrome (recurrent episodes of attacks of shortness of breath with wheezing) and 17 subjects (3.7%), wheezing syndrome (only wheezing). The percentage of the asthma syndrome increased with increasing levels of Df-specific IgE, and there was an intimate correlation between the percentage of asthma syndrome and Df-specific IgE levels (r = 0.97; p less than 0.001), whereas such association was not found between the two (r = -0.19; p greater than 0.5). Similar relations were found between the frequencies of the specific syndromes and total IgE levels. There was a significant correlation between total IgE levels and Df-specific IgE levels in the total population (r = 0.7; p less than 0.001). These results suggest that allergic reaction greatly contributes to the development of asthma in children.     

Rhinovirus illnesses during infancy predict subsequent childhood wheezing

BACKGROUND: The contribution of viral respiratory infections during infancy to the development of subsequent wheezing and/or allergic diseases in early childhood is not established. OBJECTIVE: To evaluate these relationships prospectively from birth to 3 years of age in 285 children genetically at high risk for developing allergic respiratory diseases. METHODS: By using nasal lavage, the relationship of timing, severity, and etiology of viral respiratory infections during infancy to wheezing in the 3rd year of life was evaluated. In addition, genetic and environmental factors that could modify risk of infections and wheezing prevalence were analyzed. RESULTS: Risk factors for 3rd year wheezing were passive smoke exposure (odds ratio [OR]=2.1), older siblings (OR=2.5), allergic sensitization to foods at age 1 year (OR=2.0), any moderate to severe respiratory illness without wheezing during infancy (OR=3.6), and at least 1 wheezing illness with respiratory syncytial virus (RSV; OR=3.0), rhinovirus (OR=10) and/or non-rhinovirus/RSV pathogens (OR=3.9) during infancy. When viral etiology was considered, 1st-year wheezing illnesses caused by rhinovirus infection were the strongest predictor of subsequent 3rd year wheezing (OR=6.6; P < .0001). Moreover, 63% of infants who wheezed during rhinovirus seasons continued to wheeze in the 3rd year of life, compared with only 20% of all other infants (OR=6.6; P < .0001). CONCLUSION: In this population of children at increased risk of developing allergies and asthma, the most significant risk factor for the development of preschool childhood wheezing is the occurrence of symptomatic rhinovirus illnesses during infancy that are clinically and prognostically informative based on their seasonal nature.     

Severe respiratory syncytial virus infection in early life is associated with increased type 2 cytokine production in Gambian children

BACKGROUND: Severe respiratory syncytial virus (RSV) infection in early childhood has been associated with subsequent wheezing and atopy. The aim of this study was to test if severe RSV infection in early life was associated with an increase in type 2 cytokine production and atopy in Gambian children 5 years later. METHODS: A cohort of children with severe RSV infection during the first year of life ('cases', n = 66) and without ('controls', n = 122) was followed-up at 5 years of age. Immediate hypersensitivity to common allergens, airway reactivity, serum IgE concentration and the production of IFN-gamma, IL-5 and IL-13 by lymphocytes activated in vitro with RSV F-G or control antigens was determined. RESULTS: After adjustment for confounders, cases produced significantly higher concentrations of IL-13 in response to RSV F-G and of IL-5 and IL-13 in response to tuberculin. Cases were more likely to have presented with a wheezy lower respiratory tract infection in the first 3 years of life (adjusted odds ratio = 9.9; 95% CI 1.6-61.0), but not thereafter. Cases and controls had similar skin response to allergens, airway reactivity and serum IgE concentrations. CONCLUSION: Severe RSV infection in early life is associated with a higher production of type 2 cytokines in Gambian children at 5 years of age. However this does not appear to result in increased risk of atopy or clinical allergy at that age.     

The mechanism of basophil histamine release in patients with periodontal disease.

Histamine release from washed peripheral blood basophils of thirty-three subjects with varying degrees of periodontal disease was studied. Dental plaque, serum and basophil leucocytes were collected from individual patients. There was no histamine release when autologous, washed sonicated plaque was added to leucocytes. However, the incubation of autologous plaque with serum at 37 degrees C for 30 min generated a factor which induced histamine release from basophils. This serum factor was stable to heat (56 degrees C, 30 min), eluted from a Sephadex G-100 column at a volume corresponding to a molecular weight of approximately 16,000 daltons and its action was inhibited by antibody to C5. This factor, therefore, is probably C5a. There was a variation in the degree of histamine release seen with the leucocytes of different donors. This variability was a property of the basophil rather than a function of the serum. Basophils from patients with gingival indices of 0.5 to 1.0 had significantly more histamine release than basophils from patients with gingival indices of less than 0.5 or greater than 1.5 (P less than 0.001). These experiments demonstrate that dental plaque activates serum to form C5a which in turn releases histamine from basophils. However, these experiments do not indicate a role for IgE in this reaction since the direct interaction of plaque with basophils did not cause histamine release. The release of mediators from mast cells could play an important role in the induction of the inflammatory response in periodontal disease.     

Hyperreactivity of mediator-releasing cells from patients with allergic bronchopulmonary aspergillosis as evidenced by basophil histamine release

Histamine release was performed on 28 patients with allergic bronchopulmonary aspergillosis (ABPA) in various stages and on 14 patients with mold-sensitive asthma, by using Aspergillus antigens, other mold antigens, and anti-IgE. Total serum IgE, IgE and IgG antibodies to Aspergillus fumigatus (Af), and end point cutaneous titration for Af were determined for each patient. There was greater histamine release to Aspergillus mix (p = 0.0000) and anti-IgE (p = 0.047) in patients with ABPA than in patients with mold-sensitive asthma. Patients with stages IV and V ABPA had greater histamine release to Aspergillus mix than patients with stage I, II, or III ABPA (p = 0.0014). There was greater histamine release to other molds in ABPA patients than in mold-sensitive asthmatics. There was no correlation between histamine release to Aspergillus mix and total serum IgE, IgE or IgG antibodies to Af, ratio of IgE and IgG antibodies to Af to total IgE, or cutaneous end point titration for Af in ABPA patients or mold-sensitive asthmatics. Peripheral basophils from ABPA patients demonstrated marked hyperreactivity as evidenced by histamine release to Aspergillus antigens, other molds, and anti-IgE. This hyperreactivity is the first cellular difference recognized in ABPA patients when compared to mold-sensitive asthma patients. If this hyperreactivity is manifested by mediator release from other cells such as pulmonary mast cells, which would be in close contact with growing Af, a possible mechanism for pulmonary response in ABPA would be suggested.     

Relationship between atopic status and nasal interleukin 10 and 11 levels in infants with respiratory syncytial virus bronchiolitis.

BACKGROUND: Interleukin 10 (IL-10) and IL-11 are known to have anti-inflammatory activities, and they have been implicated in the pathogenesis of respiratory syncytial virus (RSV) infection. OBJECTIVES: To determine IL-10, IL-11, and myeloperoxidase levels in nasal secretions of infants with acute RSV bronchiolitis and to investigate whether there are any differences in these levels in patients with vs without atopy. METHODS: We measured IL-10, IL-11, and myeloperoxidase levels in nasal secretions of 44 infants (20 were atopic) with acute RSV bronchiolitis. The nasal secretion samples were obtained from patients at hospital admission and were stored immediately at -70 degrees C until analysis. Atopy was defined as having at least 1 positive skin prick test reaction to common allergens, a history of atopic dermatitis, or a high serum IgE level compared with age-matched controls. RESULTS: Levels of IL-10, IL-11, and myeloperoxidase increased significantly in samples from infants with acute RSV bronchiolitis. Levels of IL-10 and IL-11 were significantly lower in patients with vs without atopy (P < .05). Myeloperoxidase levels showed no significant difference in patients with vs without atopy (P = .18). Patients with severe symptoms tended to have lower IL-10 levels (P = .09), but no relationship was shown between symptom severity and IL-11 levels. Nasal myeloperoxidase levels were significantly higher in patients with severe symptoms (P < .05). CONCLUSIONS: Production of IL-10 and IL-11 was significantly lower in patients with vs without atopy during acute RSV bronchiolitis. The airway inflammation induced by RSV infection may be different in patients with vs without atopy, and this is associated with lower induction of these immunoregulatory cytokines in children with atopy.     

Basophil releasability in human hydatidosis.

We studied immunoglobulin E (IgE)- and non-IgE-mediated releasability in basophils from 31 patients with hydatidosis. Histamine release to non-IgE-dependent stimuli did not differ significantly between normal individuals and patients with hydatidosis. On the contrary, an increased histamine liberation was obtained by challenging basophils from hydatid patients with anti-human IgE. It is concluded that Echinococcus granulosus infection induces an enhanced sensitivity of basophils to IgE-dependent stimuli.