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• W2022050088 abstract "It is well established, that viral infections may trigger urticaria or allergic asthma; however, as viral infections induce T helper 1 polarized responses, which lead to the inhibition of T helper 2 cell development, the opposite would be plausible. We wanted to investigate how viral infections may mediate allergic symptoms in a mouse model; therefore, we infected BALB/C mice with influenza A virus intranasally. Histologic analyses of lung sections and bronchoalveolar lavages were performed. In addition, cells from the mediastinal lymph nodes were restimulated in vitro to analyze which types of cytokines were induced by the flu infection. Furthermore, flu-specific antibody titers were determined and local anaphylaxis was measured after rechallenge with flu antigen. We found that airways inflammation consisted predominately of macrophages and lymphocytes, whereas only a few eosinophils were observed. interferon-γ but no interleukin-4 and little interleukin-5 could be detected in the culture supernatants from in vitro restimulated T cells from the draining lymph nodes. The antibody response was characterized by high levels of virus-specific IgG2a, IgG2b, and IgG1 and, surprisingly, low levels of virus-specific IgE antibodies. Interestingly, flu-infected mice developed active and passive cutaneous anaphylaxis after rechallenge with flu-antigen. As the passive cutaneous anaphylaxis reaction persisted over 48 h and was significantly lower after passive transfer of the serum, which was IgE depleted, local anaphylaxis seemed to be mediated predominately by specific IgE antibodies. Taken together, our results demonstrate that mice infected with flu virus develop virus-specific mast cell degranulation in the skin. Our results may also have implications for the pathogenesis of urticaria or other atopic disorders in humans. It is well established, that viral infections may trigger urticaria or allergic asthma; however, as viral infections induce T helper 1 polarized responses, which lead to the inhibition of T helper 2 cell development, the opposite would be plausible. We wanted to investigate how viral infections may mediate allergic symptoms in a mouse model; therefore, we infected BALB/C mice with influenza A virus intranasally. Histologic analyses of lung sections and bronchoalveolar lavages were performed. In addition, cells from the mediastinal lymph nodes were restimulated in vitro to analyze which types of cytokines were induced by the flu infection. Furthermore, flu-specific antibody titers were determined and local anaphylaxis was measured after rechallenge with flu antigen. We found that airways inflammation consisted predominately of macrophages and lymphocytes, whereas only a few eosinophils were observed. interferon-γ but no interleukin-4 and little interleukin-5 could be detected in the culture supernatants from in vitro restimulated T cells from the draining lymph nodes. The antibody response was characterized by high levels of virus-specific IgG2a, IgG2b, and IgG1 and, surprisingly, low levels of virus-specific IgE antibodies. Interestingly, flu-infected mice developed active and passive cutaneous anaphylaxis after rechallenge with flu-antigen. As the passive cutaneous anaphylaxis reaction persisted over 48 h and was significantly lower after passive transfer of the serum, which was IgE depleted, local anaphylaxis seemed to be mediated predominately by specific IgE antibodies. Taken together, our results demonstrate that mice infected with flu virus develop virus-specific mast cell degranulation in the skin. Our results may also have implications for the pathogenesis of urticaria or other atopic disorders in humans. bronchoalveolar lavage egg infectious dose 50% influenza A virus antigen optical density Atopic disorders are the result of T helper (Th) 2-dominated immune responses towards antigens leading to eosinophilia and the production of allergen-specific IgE antibodies, which induce mast cell degranulation following challenge with the relevant allergens (Parronchi et al., 2000Parronchi P. Brugnolo F. Sampognaro S. Maggi E. Genetic and environmental factors contributing to the onset of allergic disorders.Int Arch Allergy Immunol. 2000; 121: 2-9Crossref PubMed Scopus (34) Google Scholar). In contrast, viral infections generally induce strong Th1-dominated immune responses with large amounts of interferon (IFN)-γ produced. IFN-γ in turn has been shown to be a strong inhibitory factor for the development of allergen-specific Th2 cells (Gajewski et al., 1988Gajewski T.F. Goldwasser E. Fitch F.W. Anti-proliferative effect of IFN-gamma in immune regulation. II. IFN-gamma inhibits the proliferation of murine bone marrow cells stimulated with IL-3, IL-4, or granulocyte-macrophage colony-stimulating factor.J Immunol. 1988; 141: 2635-2642PubMed Google Scholar). For this reason it has been proposed that viral infections should inhibit the development of atopic disorders (Erb, 1999Erb K.J. Atopic disorders. a default pathway in the absence of infection?.Immunol Today. 1999; 20: 317-322Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar;Herz et al., 2000Herz U. Lacy P. Renz H. Erb K. The influence of infections on the development and severity of allergic disorders.Curr Opin Immunol. 2000; 12: 632-640Crossref PubMed Scopus (78) Google Scholar). Interestingly, the opposite seems to be true as viral infections are clinically associated with the development of acute urticaria or the exacerbation of asthma and atopic dermatitis (Mortureux et al., 1998Mortureux P. Leaute-Labreze C. Legrain-Lifermann V. Lamireau T. Sarlangue J. Taieb A. Acute urticaria in infancy and early childhood: a prospective study.Arch Dermatol. 1998; 134: 319-323Crossref PubMed Scopus (159) Google Scholar;Sakurai et al., 2000Sakurai M. Oba M. Matsumoto K. Tokura Y. Furukawa F. Takigawa M. Acute infectious urticaria. Clinical and laboratory analysis in nineteen patients.J Dermatol. 2000; 27: 87-93Crossref PubMed Scopus (23) Google Scholar;Lester and Schneider, 2000Lester M.R. Schneider L.C. Atopic diseases and upper respiratory infections.Curr Opin Pediatr. 2000; 12: 511-519https://doi.org/10.1097/00008480-200010000-00018Crossref PubMed Scopus (5) Google Scholar;Gern and Busse, 2000Gern J.E. Busse W.W. The role of viral infections in the natural history of asthma.J Allergy Clin Immunol. 2000; 106: 201-212Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar). How can infections that induce strong Th1 immune responses exacerbate allergic disease? Several mechanisms have been proposed addressing this very interesting question in respect to virus infections of the respiratory tract. For example, epithelial injury may sensitize cholinergic afferent fibers and diminish β-adrenergic fibers leading to acute bronchial hyper-responsiveness (Corne and Holgate, 1997Corne J.M. Holgate S.T. Mechanisms of virus induced exacerbations of asthma.Thorax. 1997; 52: 380-389Crossref PubMed Scopus (77) Google Scholar). Furthermore, the inflammatory Th1 response in the lung (induced by the virus), through the induction of proinflammatory cytokines and chemokines such as IFN-γ, interleukin (IL)-8, and RANTES, may exacerbate the allergic disorder by increasing an influx of inflammatory cells into the lung (van Schaik et al., 1999van Schaik S.M. Tristram D.A. Nagpal I.S. Hintz K.M. Welliver R.C. Increased production of IFN-gamma and cysteinyl leukotrienes in virus-induced wheezing.J Allergy Clin Immunol. 1999; 103: 630-636Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar;Lacy et al., 1999Lacy P. Mahmudi-Azer S. Bablitz B. Hagen S.C. Velazquez J.R. Man S.F. Moqbel R. Rapid mobilization of intracellularly stored RANTES in response to interferon-gamma in human eosinophils.Blood. 1999; 94: 23-32PubMed Google Scholar;Olszewska-Pazdrak et al., 1998Olszewska-Pazdrak B. Casola A. Saito T. et al.Cell-specific expression of RANTES, MCP-1, and MIP-1alpha by lower airway epithelial cells and eosinophils infected with respiratory syncytial virus.J Virol. 1998; 72: 4756-4764Crossref PubMed Google Scholar;Herz et al., 2000Herz U. Lacy P. Renz H. Erb K. The influence of infections on the development and severity of allergic disorders.Curr Opin Immunol. 2000; 12: 632-640Crossref PubMed Scopus (78) Google Scholar;Johnston et al., 1998Johnston S.L. Papi A. Bates P.J. Mastronarde J.G. Monick M.M. Hunninghake G.W. Low grade rhinovirus infection induces a prolonged release of IL-8 in pulmonary epithelium.J Immunol. 1998; 160: 6172-6181PubMed Google Scholar;Harrison et al., 1999Harrison A.M. Bonville C.A. Rosenberg H.F. Domachowske J.B. Respiratory syncytical virus-induced chemokine expression in the lower airways. eosinophil recruitment and degranulation.Am J Respir Crit Care Med. 1999; 159: 1918-1924Crossref PubMed Scopus (208) Google Scholar). Taken together, the clinical observations and experimental data clearly suggest that viral infections, which induce Th1 responses, can under certain conditions exacerbate atopic disorders (Herz et al., 2000Herz U. Lacy P. Renz H. Erb K. The influence of infections on the development and severity of allergic disorders.Curr Opin Immunol. 2000; 12: 632-640Crossref PubMed Scopus (78) Google Scholar); however, in some patients viral infections seem to induce allergic reactions directly. The most prominent example is the induction of acute urticaria shortly after viral infections, especially in children (Mortureux et al., 1998Mortureux P. Leaute-Labreze C. Legrain-Lifermann V. Lamireau T. Sarlangue J. Taieb A. Acute urticaria in infancy and early childhood: a prospective study.Arch Dermatol. 1998; 134: 319-323Crossref PubMed Scopus (159) Google Scholar). How can this occur? A possible explanation is, that viral infections not only induce a Th1 but also a minor Th2 response leading to the production of virus-specific IgE antibodies. Bound to mast cells, virus-specific IgE could directly induce mast cell degranulation when encountering viral antigen, thereby causing urticaria; however, it is still unclear if and to what extent viruses can directly induce Th2 responses in humans, and if the small amounts of virus-specific IgE detected in some patients after infection (Gern and Busse, 2000Gern J.E. Busse W.W. The role of viral infections in the natural history of asthma.J Allergy Clin Immunol. 2000; 106: 201-212Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar), can lead to the degranulation of mast cells. To address this question, we infected mice with influenza A virus and analyzed in detail the resulting Th1- and Th2-type responses. We show here, that the immune response against influenza A virus was strongly dominated by Th1 responses and virus-specific antibodies of the IgG1, IgG2a, and IgG2b subtypes; however, infected mice also produced virus-specific IgE antibodies and showed local anaphylaxis after rechallenge with the influenza A virus antigen (Flu-Ag). The HKx31 (H3N2) influenza A virus was grown in the allantoic fluid of 10 d old embryonated eggs. Female BALB/C and C57/BL6 mice were purchased from Charles River (Sulzfeld, Germany) and were maintained under conventional conditions in an isolation facility. At the onset of the experiments, all animals were between 6 and 8 wk of age. Mice were anesthetized by intraperitoneal (i.p) inoculation with Avertin (2,2,2,-tribromoethanol) and infected intranasally with 30 µl of phosphate-buffered saline (PBS) containing 2 × 105 EID50 (egg infectious dose 50%) of the HKx31 influenza A virus. All experiments were performed according to the guidelines for the care and use of experimental animals prepared and published by the Society for Laboratory Animal Sciences (GV-SOLAS, Biberach an der Riss, Germany), 1988. BALB/C mice were anesthetized by i.p. injection of ketamine and xylazaine (Sigma Deisenhofen, Germany), and 50 µg ovalbumin grade V (Sigma) in 50 µl PBS was administered intranasally a total of six times at 1 wk intervals as described (Nelde et al., 2001Nelde A. Teufel M. Hahn C. Duschl A. Sebald W. Brocker E.B. Grunewald S.M. The impact of the route and frequency of antigen exposure on the IgE response in allergy.Int Arch Allergy Immunol. 2001; 124: 461-469Crossref PubMed Scopus (47) Google Scholar). Subsequently, mice were rechallenged intranasally 1 d after the last ovalbumin sensitization and 24 h later mice were killed and the resulting immune response analyzed. Lung tissues were fixed in 10% phosphate-buffered formalin for at least 24 h and embedded in paraffin wax. Sections (2–3 µm) were cut and stained with hematoxylin and eosin. The stained sections were visualized by light microscopy. At different time points after infection with influenza A virus, or after the final intranasal application of ovalbumin, mice were killed, the trachea cannulated, and BAL performed by flushing lung and airways three times with 1 ml PBS. BAL cells were counted, and spun on to glass slides using a cytospin, followed by staining with Dif-Quik (Dade, Marburg, Germany). Total cell counts and number of macrophages, lymphocytes, eosinophils, and neutrophils were determined microscopically using standard cytologic criteria. Single-cell suspensions from the mediastinal lymph nodes (MLN) were prepared by teasing the MLN through a steel mesh and discarding the cell debris. Culture medium was IMDM (Sigma, St Louis, MO) supplemented with 10 mM HEPES, 2 mM L-glutamine, 1% nonessential amino acids, 1 mM sodium pyruvate, 50 µg gentamycin per ml, 50 µM 2-mercaptoethanol, and 10% fetal bovine serum. Total MLN cells (2 × 106 cells per ml) were left in medium alone or stimulated in microwells coated with either a monoclonal antibody to CD3 (145–2C11; 25 µg per ml) in the presence of 50 U per ml recombinant human IL-2 (Novartis, Basel, Switzerland) purified Flu-Ag (40 µg per ml) (SPAFAS, North Franklin, CT) or ovalbumin (100 µg per ml; Sigma). Supernatants were harvested 48 h later (in some experiments supernatants were also collected at 24 and 72 h). For the detection of IFN-γ, IL-4, and IL-5 in the cell culture supernatants, sandwich ELISA with the following monoclonal antibodies, recognizing two different epitopes of the respective lymphokines, were used: biotinylated rat anti-mouse IFN-γ (AN-18.17.24) and unconjugated rat anti-mouse IFN-γ (R4–6A2); biotinylated rat anti-mouse IL-5 (TRFK4) and unconjugated rat anti-mouse IL-5 (TRFK5); biotinylated rat anti-mouse IL-4 (BVD6–24G2) and unconjugated rat anti-mouse IL-4 (BVD4–1D11; all antibodies were purchased from Pharmingen, San Diego, CA). The assays were performed in polyvinyl chloride microtiter plates (Dynatech, Denkendorf, Germany) according to instructions from the monoclonal antibody manufacturer. The binding reactions were visualized with a conjugate of biotin–streptavidin–alkaline phosphatase (Dako, Denmark) and the phosphatase substrate 104 from Sigma. Absorbance was read at 414 nm in an ELISA microplate reader (Anthos Hill, Salzburg, Austria). For quantification of the cytokines in the culture supernatants, titrations were performed with murine recombinant IFN-γ, recombinant IL-4, and recombinant IL-5 (Pharmingen). IgE and IgG specific for influenza A virus or ovalbumin were measured by ELISA. For the detection of IgG1, IgG2a, and IgG2b the plates were coated with 10 µg Flu-Ag per ml coating buffer (100 mM NaCO3 pH 8.5). For the detection of flu-specific IgE 100 µg Flu-Ag per ml coating buffer was used. For the detection of ovalbumin-specific IgG1 and IgE the plates were coated with 100 µg per ml of ovalbumin (Sigma) in coating buffer. Plates were blocked with 10% bovine serum albumin in PBS containing 0.05% Tween 20 (Sigma), and 100 µl of serial serum dilutions in PBS containing 0.05% Tween 20 and 1% bovine serum albumin were applied overnight at 4°C. Antibody binding was analyzed using biotinylated monoclonal antibodies against mouse IgG1, IgG2a, IgG2b, or IgE as described above (monoclonal antibodies purchased from Pharmingen). Serum titers are expressed as the reciprocal value of the serum dilutions, which were 2-fold over background optical density (OD414) of age-matched noninfected mice (for the virus-specific IgG the OD was measured at a serum dilution of 1/100 and for virus-specific IgE a 1/4 serum dilution) Mice were infected with flu virus for 3 wk, killed, and serum collected. To deplete the IgE, pooled serum (10 mice) was incubated on anti-IgE-coated microtiter plates. The plates were coated (100 µl per well) with 2 mg per ml anti-IgE monoclonal antibody (Pharmingen) in coating-buffer (100 mM NaCO3 pH 8.5) o.n. Plates were blocked with 10% bovine serum albumin in PBS containing 0.05% Tween 20 (Sigma). After washing, 100 µl of serum was added to the wells. After 30 min the serum was transferred to a new anti-IgE coated well. This was repeated until total IgE was reduced from 550 ng per ml before to 20 ng per ml after the depletion of IgE. Total IgG1 serum levels were not significantly altered (258 µg per ml serum before 380 µg per ml after depletion of IgE). The ELISA for the detection of serum IgE and IgG1 were performed as previously described (Erb et al., 1999Erb K.J. Kirman J. Delahunt B. Moll H. Le Gros G. Infection of mice with Mycobacterium bovis-BCG induces both Th1 and Th2 immune responses in the absence of interferon-gamma signalling.Eur Cytokine Netw. 1999; 10: 147-154PubMed Google Scholar). Active cutaneous anaphylaxis was tested 3 wk after influenza infection. BALB/C and C57/BL6 mice were injected i.v. with 200 µl 0.5% Evans Blue in PBS (Sigma). Subsequently the skin of the belly was shaved and 50 µl PBS containing 500 µg per ml influenza antigen or PBS alone was injected intradermally into two premarked sites on the skin. After 15 min, mice were killed and the skin was stripped off. Positive reactions towards virus antigen resulted in mast cell degranulation and fluid extravasation, which led to the formation of a blue patch around the injection site. The intensity of bluing as an indicator for the intensity of mast cell degranulation was scored by two independent observers (0 = no bluing, 1 = slight bluing, 2 = strong bluing;Grunewald et al., 1998Grunewald S.M. Werthmann A. Schnarr B. et al.An antagonistic IL-4 mutant prevents type I allergy in the mouse. Inhibition of the IL-4/IL13 receptor system completely abrogates humoral immune response to allergen and development of allergic symptoms in vivo.J Immunol. 1998; 160: 4004-4009PubMed Google Scholar). For detection of passive cutaneous anaphylaxis serum of noninfected control mice or flu-infected mice was collected 3 wk after infection and pooled. A part of the influenza serum was depleted from IgE antibodies as described above. Subsequently, groups of noninfected mice were injected intradermally with 50 µl of the various serum pools at a 1:5 dilution into premarked sites on the shaved belly. Cutaneous anaphylaxis was measured in the sites of previous serum injection 2, 24, and 48 h as described above. Statistical significance was analyzed by the Mann–Whitney U test. Values of p < 0.05 were considered statistically significant. BALB/C mice were infected with flu virus intranasally and the resulting inflammation in the lung tissue was analyzed histologically. For this purpose, lung sections were prepared before and 7, 14, and 21 d after infection and were stained with hematoxylin and eosin. The results revealed, that mice infected with flu virus for 1 wk showed massive perivascular infiltrates and interstitial edema in comparison with noninfected mice. After 3 wk the interstitial edema has cleared but the perivascular infiltrate could still be detected (data not shown). To analyze the cellular composition of the inflammatory infiltrates in more detail BAL were performed and the amount of the different cell types present in the BAL determined. In agreement with the histologic examinations Figure 1 shows, that total cell counts in the lavage fluids were highest 1 wk after infection and then gradually decreased over the next 2 wk. In comparison with uninfected controls the infected mice show a strong increase in total number of lymphocytes, macrophages, and neutrophils present in the lung. Very few eosinophils could also be detected 1 wk after infection (Figure 1) but not 3 and 5 d after infection (data not shown). To study the cytokine profile of T lymphocytes in the lung, single cell suspensions of the MLN were prepared at different time points after flu virus infection and left in medium alone or restimulated with Flu-Ag or anti-CD3/IL-2 in vitro. MLN cells from uninfected mice were also included as controls. The supernatants were collected 48 h later and the presence of IFN-γ, IL-5, and IL-4 determined by ELISA. Figure 2 shows that T cells from the MLN produce the most IFN-γ after 1 wk of infection, both after antigen-specific and polyclonal anti-CD3/IL-2 restimulation. Antigen-specific IFN-γ production could also be detected 2 and 3 wk after infection. Similar results were obtained, when analyzing the amounts of IFN-γ present in the supernatants 24 h and 72 h after the different stimulations (data not shown). Furthermore, only low levels of IL-4 (after 24 h) and IL-5 (after 72 h) could be detected after anti-CD3/IL-2 stimulation, with no difference between the amounts of IL-4 and IL-5 being produced by the MLN cells from infected vs uninfected mice. No IL-4 could be detected after stimulation with Flu-Ag in any of the cultures (data not shown); however, low levels of antigen-specific IL-5 production could be detected in the supernatants of the MLN from 2 wk infected mice 72 h after restimulation with Flu-Ag (data not shown). Taken together, these results suggest that beside a strong Th1 dominated immune response only small numbers of Th2 cells were generated during the flu infection in the lung. To investigate, whether the B cell response against flu virus in the lung is also strongly biased towards Th1, we determined flu-virus specific antibody titers in the serum. As expected, the Th1-associated virus-specific IgG2a and IgG2b titers showed a strong increase during the flu infection (Figure 3). The same was true for the virus-specific IgG1, which is associated with Th2 responses. Surprisingly, virus-specific IgE antibodies could also be detected. They were induced to 100–1000-fold lower levels than the IgG subtypes but showed a clear kinetic peak 2 wk after infection (Figure 3). These results clearly suggest, that the humoral immune response against influenza A virus is also Th1 dominated but has a clear Th2 component. Next we felt it to be important to investigate how strong the minor Th2 responses against flu virus is in comparison with an antigen known to induce strong Th2 responses. For this reason BALB/C mice were immunized intranasally with ovalbumin (see Materials and Methods). One day after the last intranasal ovalbumin application mice were killed and the Th2 response against ovalbumin was analyzed and compared with the maximal Th2 responses detected in flu-infected mice. Eosinophil numbers after ovalbumin sensitization in the BAL were 7-fold higher than the maximum amounts of eosinophils detected in the BAL after a flu infection [7.5 × 104 per ml ± 6.3 (n = 7) vs 1.04 × 104 per ml ± 0.4 (n = 6)]. The levels of ovalbumin-specific IL-5 secretion by MLN stimulated with ovalbumin for 48 h was also 10-fold higher than the maximum amount of flu-specific IL-5 production measured 72 h after restimulation of MLN cells from 2 wk flu-infected mice [250 pg per ml ± 210 (n = 6) vs 23 pg per ml ± 11 (n = 4)]. Interestingly, flu-antigen induced IFN-γ secretion by the MLN from infected mice could easily be detected (see Figure 2), whereas no IFN-γ could be detected in the supernatants of the MLN from ovalbumin-treated mice 48 h after in vitro stimulation with ovalbumin (n = 6). Furthermore, ovalbumin specific IgG1 and IgE serum levels were also at least 8-fold higher than the maximum flu specific IgG1 and IgE titers detected when using a similar ELISA design (data not shown). Although it is difficult to directly compare the immune response in the lung initiated against flu virus (strong anti-infectious response) with the response initiated after consecutive intranasal applications of ovalbumin, it is clear that the Th2 response against flu virus is a relative weak Th2 response in comparison with the Th2 response initiated after the intranasal application of ovalbumin. In addition, the immune response against ovalbumin is clearly biased towards Th2, whereas the response against flu virus is dominated by flu-specific Th1 responses. Next we asked whether the virus-specific antibodies could elicit allergic symptoms in mice following virus antigen challenge. Therefore, we investigated whether mice that had been infected for 3 wk developed active cutaneous anaphylaxis after the application of Flu-Ag. For this purpose, mice were first injected i.v. with Evans Blue dye and then with Flu-Ag and PBS intradermally into two separate premarked sites in the skin. After 15 min, mast cell degranulation induced the extravasation of fluid, which led to the formation of a blue patch around the injection site of virus antigen only in infected mice (Figure 4a). The lack of this blue patch formation in noninfected mice indicates the lack of mast cell degranulation after virus antigen challenge. Figure 4b shows mean bluing intensities in groups of noninfected vs infected mice at the site of Flu-Ag. After intradermal Flu-Ag injection, mice that had been infected with flu virus showed a much stronger mast cell degranulation than noninfected control animals. As in mice, both IgE and IgG1 antibodies have been shown to induce cutaneous anaphylaxis (Oshiba et al., 1996Oshiba A. Hamelmann E. Takeda K. Bradley K.L. Loader J.E. Larsen G.L. Gelfand E.W. Passive transfer of immediate hypersensitivity and airway hyperresponsiveness by allergen-specific immunoglobulin (Ig) E and IgG1 in mice.J Clin Invest. 1996; 97: 1398-1408Crossref PubMed Scopus (220) Google Scholar), we investigated if the allergic reactivity after Flu-Ag rechallenge in infected mice was mediated by virus-specific IgE antibodies or only by virus-specific IgG1 antibodies. Furthermore, we wanted to exclude that virus-induced alterations of mast cell reactivity may be responsible for the local anaphylaxis reaction in infected mice. Therefore, we passively transferred serum of infected mice into noninfected mice and checked for passive cutaneous anaphylaxis. For this purpose, groups of noninfected mice were injected intradermally with 50 µl serum from mice, which had been infected with flu virus for 3 wk. Two, 24, and 48 h later local anaphylaxis was measured at the sites of the previous serum injections as described above. Figure 5 shows, that the intradermal virus antigen challenge induced similar mast cell degranulation in mice, which had been injected 2, 24, and 48 h earlier with the serum from 3 wk infected mice. In contrast, the passive cutaneous anaphylaxis reaction was significantly lower in mice that were treated with IgE depleted serum from flu-infected mice or with sera of noninfected mice. Taken together, the persisting local anaphylaxis reaction 48 h after serum injection (Lehrer, 1977Lehrer S.B. Role of mouse IgG and IgE homocytotropic antibodies in passive cutaneous anaphylaxis.Immunology. 1977; 32: 507-511PubMed Google Scholar) and the strong reduction of mast cell degranulation after IgE depletion indicates that virus-specific IgE antibodies were mediating allergic skin reactivity. Next we investigated, if C57/BL6 mice infected with flu virus also developed active cutaneous anaphylaxis after the application of Flu-Ag. For this purpose, mice were treated as described above and cutaneous reactivity scored as described in the legend to Figure 4. As expected we found, that noninfected C57/BL6 mice showed no bluing in the skin after intradermal challenge with flu-antigen (average bluing intensity of 0; n = 2). In contrast, 3 wk infected mice showed a clear bluing in the skin after the intradermal application of flu-antigen [average bluing intensity of 1.2 ± 0.75 (n = 8)]. This shows that C57/BL6 mice also develop active cutaneous anaphylaxis after flu infection and indicates, that this is a general phenomenon in mice and not only limited to the BALB/C strain. The results presented in this study clearly indicate that the immune response against influenza A virus in BALB/C mice is strongly polarized towards Th1 but also has a minor Th2 component. This can be seen by the large amounts of IFN-γ, the absence of IL-4, and the low levels of IL-5 secreted by the MLN cells after in vitro restimulation with Flu-Ag or anti-CD3. The small numbers of eosinophils detected in the lung after infection together with the low titers of flu-specific IgE in the serum of infected mice further supports this view. Interestingly, we could show that mice infected with flu virus developed virus-specific IgE antibodies and active cutaneous anaphylaxis after intradermal injection with Flu-Ag. Passive cutaneous anaphylaxis could also be demonstrated, suggesting that the detected virus-specific immunoglobulins and not virus-induced alterations of mast cell reactivity were mediating this effect. The passive cutaneous anaphylaxis reaction is a well established method to demonstrate antibody-mediated mast cell degranulation in the skin (Ovary and Warner, 1972Ovary Z. Warner N.L. Electrophoretic and antigenic analysis of mouse and guinea pig anaphylactic antibodies.J Immunol. 1972; 108: 1055-1062PubMed Google Scholar;Lehrer, 1977Lehrer S.B. Role of mouse IgG and IgE homocytotropic antibodies in passive cutaneous anaphylaxis.Immunology. 1977; 32: 507-511PubMed Google Scholar). It had been shown that after passive transfer of serum both IgE and IgG1 can bind on to mouse mast cells; however, IgG1 antibodies are rapidly cleared from mast cell r" @default.
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• W2022050088 date "2002-04-01" @default.
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• W2022050088 title "Infection with Influenza A Virus Leads to Flu Antigen-Induced Cutaneous Anaphylaxis in Mice" @default.
• W2022050088 cites W1573976459 @default.
• W2022050088 cites W1730417280 @default.
• W2022050088 cites W1795974800 @default.
• W2022050088 cites W1951587871 @default.
• W2022050088 cites W1965854458 @default.
• W2022050088 cites W1966052464 @default.
• W2022050088 cites W1970672159 @default.
• W2022050088 cites W1986511666 @default.
• W2022050088 cites W2007949618 @default.
• W2022050088 cites W2017904926 @default.
• W2022050088 cites W2019661325 @default.
• W2022050088 cites W2021266310 @default.
• W2022050088 cites W2029245561 @default.
• W2022050088 cites W2034467419 @default.
• W2022050088 cites W2040567367 @default.
• W2022050088 cites W2046910834 @default.
• W2022050088 cites W2051335044 @default.
• W2022050088 cites W2054371333 @default.
• W2022050088 cites W2062799408 @default.
• W2022050088 cites W2068347246 @default.
• W2022050088 cites W2069688692 @default.
• W2022050088 cites W2071502595 @default.
• W2022050088 cites W2083036575 @default.
• W2022050088 cites W2087082234 @default.
• W2022050088 cites W2092561305 @default.
• W2022050088 cites W2097648595 @default.
• W2022050088 cites W2104683446 @default.
• W2022050088 cites W2112802424 @default.
• W2022050088 cites W2114394188 @default.
• W2022050088 cites W2121948355 @default.
• W2022050088 cites W2125888328 @default.
• W2022050088 cites W2138244577 @default.
• W2022050088 cites W2297975249 @default.
• W2022050088 cites W2336979047 @default.
• W2022050088 cites W4321429341 @default.
• W2022050088 doi "https://doi.org/10.1046/j.1523-1747.2002.01732.x" @default.
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