Progress in Defining the Role of RSV in Allergy and Asthma: From Clinical Observations to Animal Models

Respiratory syncytial virus (RSV), an RNA virus in the family Paramyxoviridae, causes respiratory disease in humans. A closely related bovine RSV is responsible for a remarkably similar disease syndrome in young cattle. Severe RSV disease is characterized by bronchiolitis. The impact of RSV on human health is demonstrated annually when infants are admitted to the hospital in large numbers. Nearly every child will have been infected with RSV by the age of 3 years. While the disease is most severe in young infants and elderly people, it can re-infect adults causing mild upper respiratory tract disease throughout life. In addition, there is growing evidence that RSV infection may also predispose some children to the development of asthma. This is based on the observation that children who wheeze with RSV-induced bronchiolitis are more likely to develop into allergic asthmatics. Recent studies describe attempts to create an RSV induced asthma model in mice and other species; these have shown some degree of success. Such reports of case studies and animal models have suggested a wide range of factors possibly contributing to RSV induced asthma, these include timing of RSV infection with respect to allergen exposure, prior allergic sensitization, environmental conditions, exposure to endotoxin, and the genetic background of the person or animal. Herein, we primarily focus on the influence of RSV infection and inhalation of extraneous substances (such as allergens or endotoxin) on development of allergic asthma

Uterine Mast Cells and Immunoglobulin-E Antibody Responses During Clearance of \u3ci\u3eTritrichomonas foetus\u3c/i\u3e

We showed earlier that Tritrichomonas foetus–specific bovine immunoglobulin (Ig)G1 and IgA antibodies in uterine and vaginal secretions are correlated with clearance of this sexually transmitted infection. Eosinophils have been noted in previous studies of bovine trichomoniasis but the role of mast cells and IgE responses have not been reported. The hypothesis that IgE and mast cell degranulation play a role in clearance was tested in 25 virgin heifers inseminated experimentally and infected intravaginally with T. foetus strain D1 at estrus and cultured weekly. Groups were euthanatized at 3, 6, 9, or 12 weeks, when tissues were fixed and secretions were collected for culture and antibody analysis. Immunohistochemistry using a monoclonal antibody to a soluble lipophosphoglycan (LPG)–containing surface antigen (TF1.17) demonstrated antigen uptake by uterine epithelial cells. Lymphoid nodules were detected below antigen-positive epithelium. Little IgG2 antibody was detected but IgG1, IgA, IgM, and IgE T. foetus–specific antibodies increased in uterine secretions at weeks 6 and 9 after infection. This was inversely proportional to subepithelial mast cells numbers and most animals cleared the infection by the sampling time after the lowest mast cell count. Furthermore, soluble antigen was found in uterine epithelium above inductive sites (lymphoid nodules). Cross-linking of IgE on mast cells by antigen and perhaps LPG triggering appears to have resulted in degranulation. Released cytokines may account for production of predominantly Th2 (IgG1 and IgE) and IgA antibody responses, which are related to clearance of the infection

Phenotypic Characterization of Chicken Thymic Stromal Elements

Phenotypic profiles of the thymic stromal components provide an excellent approach to elucidating the nature of the microenvironment of this organ. To address this issue in chickens, we have produced an extensive panel of 18 mAb to the thymic stroma. These mAb have been extensively characterized with respect to their phenotypic specificities and reveal that the stromal cells are equally as complex as the T cells whose maturation they direct. They further demonstrate that, in comparison to the mammalian thymus, there is a remarkable degree of conservation in thymic architecture between phylogenetically diverse species. Eleven mAb reacted with thymic epithelial cells: MUI-73 was panepithelium, MUI-54 stained all cortical and medullary epithelium but only a minority of the subcapsule, MUI-52 was specific for isolated stellate cortical epithelial cells, MUI-62, -69, and -71 were specific for the medulla (including Hassall’s corpusclelike structures), MUI-51, -53, -70, and -75 reacted only with the type-I epithelium, or discrete regions therein, lining the subcapsular and perivascular regions and MUI-58 demonstrated the antigenic similarity between the subcapsule and the medulla. Seven other mAb identified distinct isolated stromal cells throughout the cortex and medulla. Large thymocyte-rich regions, which often spanned from the outer cortex to medulla, lacked epithelial cells. These mAb should prove invaluable for determining the functional significance of thymic stromal-cell subsets to thymopoiesis

Tissue Tropism in Host Transcriptional Response to Members of the Bovine Respiratory Disease Complex.

Bovine respiratory disease (BRD) is the most common infectious disease of beef and dairy cattle and is characterized by a complex infectious etiology that includes a variety of viral and bacterial pathogens. We examined the global changes in mRNA abundance in healthy lung and lung lesions and in the lymphoid tissues bronchial lymph node, retropharyngeal lymph node, nasopharyngeal lymph node and pharyngeal tonsil collected at the peak of clinical disease from beef cattle experimentally challenged with either bovine respiratory syncytial virus, infectious bovine rhinotracheitis, bovine viral diarrhea virus, Mannheimia haemolytica or Mycoplasma bovis. We identified signatures of tissue-specific transcriptional responses indicative of tropism in the coordination of host's immune tissue responses to infection by viral or bacterial infections. Furthermore, our study shows that this tissue tropism in host transcriptional response to BRD pathogens results in the activation of different networks of response genes. The differential crosstalk among genes expressed in lymphoid tissues was predicted to be orchestrated by specific immune genes that act as 'key players' within expression networks. The results of this study serve as a basis for the development of innovative therapeutic strategies and for the selection of cattle with enhanced resistance to BRD

Second-hand Smoke Increases Nitric Oxide and Alters the IgE Response in a Murine Model of Allergic Aspergillosis

This study was performed to determine the effects of environmental tobacco smoke (ETS) on nitric oxide (NO) and immunoglobulin (Ig) production in a murine model of allergic bronchopulmonary aspergillosis (ABPA). Adult BALB/c mice were exposed to aged and diluted sidestream cigarette smoke from day 0 through day 43 to simulate “second-hand smoke”. During exposure, mice were sensitized to soluble Aspergillus fumigatus (Af) antigen intranasally between day 14 and 24. All Af sensitized mice in ambient air (Af + AIR) made elevated levels of IgE, IgG1, IgM, IgG2a and IgA. Af sensitized mice housed in ETS (Af + ETS) made similar levels of immunoglobulins except for IgE that was significantly reduced in the serum and bronchoalveolar lavage (BAL). However, immunohistochemical evaluation of the lung revealed a marked accumulation of IgE positive cells in the lung parenchyma of these Af + ETS mice. LPS stimulation of BAL cells revealed elevated levels of NO in the Af + AIR group, which was further enhanced in the Af+ETS group. In vitro restimulation of the BAL cells on day 45 showed a TH0 response with elevated levels of IL3, 4, 5, 10 and IFN-γ. However, by day 28 the response shifted such that TH2 cytokines increased while IFN-γ decreased. The Af + ETS group showed markedly reduced levels in all cytokines tested, including the inflammatory cytokine IL6, when compared to the Af+AIR group. These results demonstrate that ETS affects ABPA by further enhancing the NO production and reduces the TH2 and the inflammatory cytokines while altering the pattern of IgE responses

Gender Differences in the Allergic Response of Mice Neonatally Exposed to Environmental Tobacco Smoke

Exposure to environmental tobacco smoke (ETS) has been shown to increase allergic sensitization and reactivity and there has been some suggestion that the influence of ETS on the allergic response is dissimilar in males and females. It is to be determined whether gender differences exist in the IgE response to ovalbumin (OVA) sensitization following ETS exposure from the neonatal period through adulthood. To address this thesis, we examined gender differences in OVA sensitization of BALB/c mice housed from birth through adulthood under smoking and nonsmoking conditions. At 6 weeks of age (day 0) all mice were injected i.p. with OVA in aluminum hydroxide adjuvant followed by three 20 min exposures to 1% aerosolized OVA between day 14 and 80. There were significantly (p<0.05) more total and OVA specific IgE and IgG1 in the serum of females compared to males. Moreover, these sex responses, along with eosinophilia, were further enhanced in mice exposed to ETS. There were also significantly more IgE positive cells in the lungs of female, but not male, mice exposed to ETS compared with ambient air (p<0.05). There was also an elevation of Th2 cytokines (IL4, IL5, IL10, and IL13) after re-stimulation of lung homogenates following ETS exposure. These data demonstrate that female animals are significantly more susceptible than males to the influence of ETS on the allergic response

Second-Hand Smoke Increases Bronchial Hyperreactivity and Eosinophilia in a Murine Model of Allergic Aspergillosis

Involuntary inhalation of tobacco smoke has been shown to aggravate the allergic response. Antibodies to fungal antigens such as Aspergillus fumigatus (Af) cause an allergic lung disease in humans. This study was carried out to determine the effect of environmental tobacco smoke (ETS) on a murine model of allergic bronchopulmonary aspergillosis (ABPA). BALB/c mice were exposed to aged and diluted sidestream cigarette smoke to simulate 'second-hand smoke'. The concentration was consistent with that achieved in enclosed public areas or households where multiple people smoke. During exposure, mice were sensitized to Af antigen intranasally. Mice that were sensitized to Af antigen and exposed to ETS developed significantly greater airway hyperreactivity than did mice similarly sensitized to Af but housed in ambient air. The effective concentration of aerosolized acetylcholine needed to double pulmonary flow resistance was significantly lower in Af + ETS mice compared to the Af + AIR mice. Immunological data that supports this exacerbation of airway hyperresponsiveness being mediated by an enhanced type 1 hypersensitivity response include: eosinophilia in peripheral blood and lung sections. All Af sensitized mice produced elevated levels of IL4, IL5 and IL10 but no IFN-γ indicating a polarized Th2 response. Thus, ETS can cause exacerbation of asthma in ABPA as demonstrated by functional airway hyperresponsiveness and elevated levels of blood eosinophilia