The Proceedings of the American Thoracic Society 2:162-165 (2005)
© 2005 The American Thoracic Society
Asthma Death, CD8+ T Cells, and Viruses
Siobhán M. O'Sullivan
Department of Immunology, Royal Free and University College Hospital Medical School, London, United Kingdom
Correspondence and requests for reprints should be addressed to Siobhán O' Sullivan, Ph.D., Royal Irish Academy, 19 Dawson St, Dublin 2 Ireland. E-mail: sioosu{at}indigo.ie
 |
ABSTRACT
|
|---|
Despite advances in the understanding of the pathophysiology of asthma and the availability of effective treatment, the World Health Organization estimates that asthma accounts for 1 in every 250 deaths worldwide. Viruses are associated with half of all asthma exacerbations. The immune response to viral infection may enhance preexisting airway inflammation via the release of chemokines and cytokines and local recruitment of inflammatory cells. Murine models have provided evidence for a deleterious role for CD8+ T cells in the context of respiratory viral infection. Passive transfer of respiratory syncytial virus–specific cytotoxic T lymphocytes (CTLs) to infected mice results in virus clearance, which is associated with acute and sometimes fatal pulmonary disease. Compared with control subjects, CD8+ cells appear to be preferentially sequestered in the airways of individuals with asthma during acute exacerbations. In addition, an expanded CD8+ T cell population, dominated by activated cytotoxic CD8+ lymphocytes, has been documented in biopsies from patients dying as a result of acute asthma in association with a viral infection. Undoubtedly, CD8+ CTLs are a crucial in cell-mediated immunity in response to respiratory viruses. However, it would appear that an aberrant CD8+ T cell response in the context of a viral infection may place individuals with asthma at risk for fatal asthma.
Key Words: cytotoxic T lymphocytes • fatal asthma • virus
|
ASTHMA MORTALITY
|
|---|
Asthma is often considered a chronic but not a life-threatening disease, a view perhaps born of comments made by the distinguished Sir. William Osler at the beginning of the last century, when he referred to the "asthmatic panting into old age" (1). The World Health Organization (WHO), however, estimate that asthma accounts for 1 in every 250 deaths worldwide (2). The Global Burden of Asthma Report (3), developed for the Global Initiative for Asthma in 2004, compiled WHO country-specific asthma mortality rates in the 5- to 34-year age group (the diagnosis of asthma mortality is firmly established in this group). China, Russia, South Africa, and Mexico record some of the highest asthma case fatalities in the world, with more than 10 out of 100,000 individuals with asthma dying each year as a result of their asthma.
There is no doubt that recent advances in the understanding of the pathophysiology of asthma, the development and use of effective treatment targeting airway inflammation, and improvements in asthma education and self management has resulted in a decrease in asthma mortality. Recent large epidemiologic studies have demonstrated that regular treatment with conventional or low-dose inhaled corticosteroids results in a significant reduction in fatalities due to asthma (4, 5). After the introduction of Pranlukast (leukotriene receptor antagonist) to the Japanese market in 1995, the asthma death rate had decreased in 1999 by 23% (6).
While acknowledging the contribution of effective treatment to decreasing asthma mortality, it is worth noting that the annual rate of asthma-related deaths in the United States increased from 1.3 to 1.9 per 100,000 during the 10-year period from 1980 to 1990 (7). Since 1988, rates of death from asthma in the United States for most ages have stabilized, but at rates more than 50% higher than those of 1979 (8, 9).
|
PATHOLOGY OF ASTHMA DEATH
|
|---|
Much of what we know today about the inflammatory basis of asthma is as a result of insights gained from the histopathologic and immunopathologic examination of bronchi from patients who have died of asthma. The cardinal features of asthma death pathology include loss of the airway epithelium, increased thickening of the reticular membrane, occlusion of the airways by plugs of mucus, and infiltration of inflammatory cells, specifically neutrophils and eosinophils into the airway wall (10, 11). It has been proposed that asthma deaths can be differentiated according to the time between onset of acute attack and the time of death (11). Sur and coworkers observed that eosinophils were more abundant in cases of slow-onset than sudden-onset fatal asthma, whereas neutrophils were mainly associated with sudden-onset fatal asthma. In the view of the this author, the stimulus rather than the time-frame between the attack and death is crucial in determining the pathologic picture in terms of inflammatory cells. In virally induced severe asthma exacerbations, an intense sputum neutrophil influx and degranulation as been documented. In contrast, severe asthma exacerbations due to noninfective causes are characterized by increased eosinophil activation and interleukin (IL)-5 in sputum (12).
|
VIRUSES AS A PRECIPITATING FACTOR IN ASTHMA DEATH
|
|---|
There is surprisingly little data available in relation to precipitating factors in asthma death. The stimuli most often associated in the literature with asthma death are profound emotional upsets, ingestion of nonsteroidal antiinflammatory drugs, air pollution, thermal inversions, and seasonal or perennial exposure to allergens (13, 14).
In the last number of years, a substantial body of evidence has accumulated implicating viruses as an important precipitating factor for asthma exacerbations. Johnston and colleagues reported that 80 to 85% of childhood asthma exacerbations are associated with viral airway infection in children aged 9 to 11 years. Rhinovirus was the most commonly identified virus (15). In adults the incidence of virus in asthma exacerbations seems to be lower than that reported in children. Nicholson and coworkers in a longitudinal study of adults with asthma documented that 44% of asthma exacerbations in adults were associated with a viral infection (16). In adults requiring hospital admission for an acute severe asthma exacerbation in a 1-year period, virus was identified in 29% of the subjects, with rhinovirus and influenza A, the most commonly identified infectious agents (17).
Clearly, viruses are important in precipitating asthma exacerbations, even severe exacerbations, but until quite recently, the role of viruses as a precipitating factor in asthma death has remained ambiguous. This has largely been due to the difficulty in gaining access to individuals with asthma during the terminal event, because slightly fewer than half of all deaths occur in a hospital (18–20) and because of the lack of sensitive methodologies to detect virus in the lower airways.
More recently, using a polymerase chain reaction (PCR)–based method, adenovirus and picornavirus were isolated from respiratory secretions in 10 of 17 patients hospitalized with near-fatal asthma (21). We have previously documented that viruses are present within the lower respiratory tract in asthma death (22). Postmortem lung biopsies were obtained from seven victims of asthma death (AD), seven individuals with asthma who died of a cause unrelated to their asthma (AUC), and seven control subjects with no history or evidence of respiratory disease (C). Application of a virus PCR panel designed to detect common respiratory viruses and atypical bacteria to bronchial tissue revealed the presence of rhinovirus (RV) and respiratory syncytial virus (RSV) in the subjects with asthma, but not in the control subjects (Table 1). There was a similar prevalence of nucleic acid from these viruses among the individuals with asthma who died an asthma death and the individuals with asthma who died of another cause. Moreover, viral load was similar in both groups. We could not find an association of a specific virus or combination of viruses with fatal asthma. Macek and colleagues with the same study design in terms of patient groups, detected virus in postmortem specimens of lower airway secretions in 19 of 20 subjects, and multiple viruses were detected in 14 subjects. In agreement with our study, the prevalence of each virus was similar in the three groups studied and the lower airway secretions did not show a specific pattern of viral nucleic acid (23). Using reverse transcription PCR, Watson and coworkers did not detect RV in archival, wax-embedded lung tissue obtained postmortem from patients who had died from asthma. The authors suggest that this may have been due to viral RNA degradation occurring between the time of death and when the postmortem material was collected and preserved (24).
|
MECHANISMS OF VIRALLY INDUCED ASTHMA EXACERBATIONS
|
|---|
A number of mechanisms have been identified that could contribute to airway obstruction and increased airway responsiveness (AHR) seen in virally induced exacerbations of asthma. Viral infection results in the release of proinflammatory chemokines and cytokines, including IL-6, IL-8, IL-11, and granulocyte colony–stimulating factor (25–27). Once these cytokines and chemokines are released, they induce infiltration and activation of inflammatory cells into the airway. Concentrations of IL-8 and RANTES in respiratory secretions of infants with bronchiolitis correlate with the number of leukocytes in the same secretions, indicating that these chemokines may be responsible for leukocyte infiltration of the airway during RSV infection.
Neutrophils are prominent in the airway and the peripheral blood during acute viral infection (28, 25). Neutrophil counts in the peripheral blood of 35 individuals with atopic asthma inoculated with RV 16, correlated with virally induced changes in AHR (25). Eosinophils are present in airway mucosal biopsy samples from individuals with asthma during experimental RV 16 infection (29). Furthermore, Grünberg and coworkers documented increased sputum eosinophil cationic protein in individuals with asthma after experimental infection with RV 16 (30). Respiratory viruses also induce early, nonspecific T cell recruitment. Lymphopenia occurs in peripheral blood during the acute phase of rhinoviral infection, suggestive of a lymphocytic migration to the lung (31). Fraenkel and colleagues demonstrated a bronchial mucosal lymphocytic infiltrate in association with RV 16 infection. (29). Once present in the airways, T lymphocytes may enhance preexisting inflammation by releasing chemotactic cytokines, thereby attracting mast cells, basophils, and eosinophils. Depletion of CD8+ T cells in RSV-infected mice results in an inhibition of local IL-5 production in the airways, which is critical for recruitment of eosinophils and development of AHR (32).
|
CD8+ T LYMPHOCYTE RESPONSE TO RESPIRATORY VIRUSES
|
|---|
Viral infections characteristically elicit strong CD8+ T-cell lymphocytosis predominated by cytotoxic, IFN-
–secreting cells (33). Evidence points to both a salubrious and deleterious role for CD8 T cells in the context of respiratory viral infection.
Studies in both mouse models and humans have demonstrated that CD8+ cytotoxic T lymphocytes (CTLs) play a crucial role in eradicating virus from the respiratory tract. Influenza virus is initially eliminated via killing of virally infected epithelial cells by MHC class I restricted CD8+ CTLs, which are recruited into the airway and peak at 7 days after infection (34). RSV-specific CTLs are present in peripheral blood of children with acute bronchiolitis, in whom CTL responses are associated with decreased clinical symptoms (35). In children with adenovirus infection, CD8+T cells are increased during the acute phase of the infection comapred with control subjects and return to normal during the convalescent stage (36).
Studies in murine models have provided evidence that RSV-specific CD8+ T cells may play a role in RSV-induced lung pathogenesis. Passive transfer of RSV-specific CTLs to infected mice results in virus clearance, which is associated with acute and sometimes fatal pulmonary disease (37). Interestingly, clearance of virus by influenza-specific CTLs in the lung of influenza-infected mice correlates with resolution of pulmonary pathology (38).
|
ROLE OF CD8+ T LYMPHOCYTES IN VIRALLY INDUCED ASTHMA EXACERBTIONS AND ASTHMA DEATH
|
|---|
Analysis of submucosal cell counts before, during, and after experimental RV 16 infection of a group of individuals with asthma and without asthma revealed a significant increase in the number of CD3+ T lymphocytes during the cold. There was a subsequent decrease in the numbers of CD3+ T lymphocytes observed during the convalescence period. Examination of the CD8+ T subset in bronchial biopises from both individuals with and without asthma revealed similar strong trends. However, due to the small sample size, no firm conclusions could be drawn with respect to differences between the numbers of CD8+ T cells documented in the bronchial mucosa of individuals with asthma versus those without asthma during RV infection (29).
Lee and coworkers documented a high percentage of CD8+ T cells in the bronchoalveolar lavage from patients with asthma compared with control subjects, resulting in a decreased CD4/CD8 ratio (39). In contrast, the CD4/CD8 ratio in the peripheral blood during acute asthma exacerbation was significantly higher than that of control subjects. This would seem to suggest that CD8+ T cells are more sequestered in the airway during an acute asthma attack. No attempt however, was made to document the etiology, viral or otherwise, of the acute asthma exacerbations under observation in this study.
Earlier work from our laboratory has demonstrated that T cells represented the major cell type identified in the inflammatory infiltrate in both the proximal and distal airways in five cases of asthma death. Subset analysis revealed that the majority of T cells both in the proximal and distal airways were CD8+ T cells (40). In a subsequent study, postmortem samples from the peribronchial region of the lung were obtained from asthma death cases, individuals with asthma who died of unrelated causes, and postmortem cases with no history of lung disease. An expanded CD8+ T cell population dominated by activated (CD25+) CD8+ CTLs were observed in the asthma death cases in association with a viral infection (Figure 1) (22). Unfortunately, viral specificity of the CD8+ CTLs was not assessed in this study due to the difficulties in applying major histocompatibility complex class I tetramer technology to tissue.
View larger version (9K):
[in this window]
[in a new window]
|
Figure 1. Left panel: Expression (mean ± SE) of the activation marker CD25 by CD8+ T cells in tissue from AD victims (black bar), was significantly greater than that in the AUC (gray bar) or C groups (white bar); p < 0.01. Right panel: Percentage (mean ± SE) of CD8+ T cells expressing perforin, a marker of cytotoxicity, was significantly higher in the AD group (black bar) as compared with the AUC group (gray bar) and the C group (white bar); p < 0.01.
|
|
It is impossible to determine if the CD8+ CTL infiltrate observed in the asthma death group was as a result of increased recruitment of CD8+ T cells to the airways, or a defect in apoptosis of these cells. One potential mechanism for increased infiltration of CD8+ T cells into the asthmatic lung is BLT-1–mediated LTB4 chemotaxis (41). Tager and colleagues have demonstrated BLT-1–mediated LTB4-induced CD8+ T cell recruitment into the airway in a murine asthma model (42). Interestingly, increased levels of the proinflammatory mediator LTB4 have been documented in endotracheal aspirates from 14 children intubated with RSV bronchiolitis, compared with control subjects (43), and increases in plasma LTB4 levels have been described in children during acute asthmatic episodes (44). As previously mentioned, neutrophils are a prominent feature of the cellular immune response to respiratory viruses and are the predominant cellular source of LTB4.
Apoptosis of expanded virus-specific cytotoxic CD8+ T cells limits tissue damage and reestablishes cellular homeostasis after a viral infection (45). In the aforementioned study (22), expression of the antiapoptotic protein Bcl-2 was lower in both the asthmatic groups in whom viral RNA was detected, irrespective of whether they had died as a result of their asthma. This would suggest that there was an attempt by the immune system to resolve the viral infection, making a defect in apoptosis an unlikely cause of the bronchial CD8+ CLT infiltrate observed.
Coyle and coworkers have demonstrated that a type 2 (Th2) cytokine environment, such as that in the asthmatic lung, can transform CD8+ cytotoxic T cells into noncytotoxic IL-5–producing cells in vivo (46). This IL-4–dependent switch to CD8+ T cells that secrete IL-5 is thought to not only promote eosinophilia but also to lead to impaired viral clearance owing to reductions in IFN- production. CD8+ T cells from RSV-infected infants produce more IL-4 and less IFN- than those from healthy control subjects (47). A low IFN-/IL-4 ratio has also been documented after mitogen stimulation of peripheral blood mononuclear cells from RSV-infected infants (48). A significantly higher percentage of IL-4–producing CD8+ T cells have been found in postmortem bronchial biopsies from asthma death cases compared with control subjects without asthma(22). Together, these studies provide evidence for a viral-induced Th1/Th2 "switch" in vivo, thereby providing a potential mechanism for eosinophil recruitment and impaired viral clearance in individuals with asthma.
Undoubtedly, CD8+ CTLs are a crucial player in cell-mediated immunity in response to respiratory viruses. However, a fine balance clearly exists between the protective and pathologic effects of these cells. It would appear that a dysregulation or aberrant CD8+ T cell responses in the context of a viral infection may place individuals with asthma at risk for fatal asthma.
|
FOOTNOTES
|
|---|
Conflict of Interest Statement: S.M.O. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
(Received in original form February 12, 2005; accepted in final form May 6, 2005)
|
REFERENCES
|
|---|
- Siegel SC. History of asthma deaths from antiquity. J Allergy Clin Immunol 1986;80:458–462.[CrossRef]
- World Health Organisation. Fact Sheet No. 206. Bronchial Asthma. Revised January 2000.
- Masoli M, Fabian D, Holt S, Beasley R. Global Initiative for Asthma (GINA) Program. The global burden of asthma; execuitive summary of the GINA Dissemination Committee report. Allergy 2004;58:469–478.
- Suissa S, Ernst P, Benayoun S, Baltzan M, Cai B. Low-dose inhaled corticosteroids and the prevention of death from asthma. N Engl J Med 2000;343:332–336.[Abstract/Free Full Text]
- Blais L, Ernst P, Bovin JF. Suissa S. Inhaled corticosteroids and the prevention of readmission to hospital for asthma. Am J Respir Crit Care Med 1998;158:126–132.
- Suissa S, Ernst P. Use of anti-inflammatory therapy and asthma mortality in Japan. Eur Respir J 2003;21:101–104.[Abstract/Free Full Text]
- Centres for Disease Control. Asthma: United States 1980–1990. JAMA 1992;268:1995–1996.[Free Full Text]
- Sly RM, O'Donnell R. Stabilization of asthma mortality. Ann Allergy Asthma Immunol 1997;78:347–354.[Medline]
- Sly RM. Continuing decreases in asthma mortality in the United States. Ann Allergy Asthma Immunol 2004;92:313–318.[Medline]
- Azzawi M, Johnston PW, Majumdar S, Kay AB, Jeffrey PK. T lymphocytes and activated eosinophils in airways mucosa in fatal asthma and cystic fibrosis. Am Rev Respir Dis 1992;145:1477–1482.[Medline]
- Sur S, Crotty TB, Kephart GM, Hyma BA, Colby TV, Reed CE, Hunt LW, Gleich GJ. Sudden-onset fatal asthma: a distinct entity with few eosinophils and relatively more neutrophils in the airway submucosa? Am Rev Respir Dis 1993;148:713–719.[Medline]
- Wark PAB, Johnston SL, Moric I, Simpson JL, Hensley MJ, Gibson PG. Neutrophil degranulation and cell lysis is associated with clinical severity in virus-induced asthma. Eur Respir J 2002;19:68–75.
- Benatar SR. Fatal Asthma. N Engl J Med 1984;53:20–25.
- O'Hollaren MT, Yunginger JW, Offord KP, Somers MJ, O'Connell EJ, Ballaerd DJ, Sachs MI. Exposure to aeroallergen as a possible precipitating factor in respiratory arrest in young patients with asthma. N Engl J Med 1991;324:359–363.[Abstract]
- Johnston SL, Pattemore PK, Sanderson G, Smith S, Lampe F, Josephs L, Symington P, O'Toole S, Myint SH, Tyrrell DA, et al. Community study of role of viral infections in exacerbations of asthma in 9–11 year old children. BMJ 1995;310:1225–1229.[Abstract/Free Full Text]
- Nicholson KG, Kent J, Ireland DC. Respiratory viruses and exacerbations of asthma in adults. BMJ 1993;307:982.[Abstract/Free Full Text]
- Teichtahl H, Buckmaster N, Pertnikovs E. The incidence of respiratory tract infection in adults requiring hospitalization for asthma. Chest 1997;112:591–596.[Abstract/Free Full Text]
- Rothwell RP, Rea HH, Sears MR, Beaglehole R, Gillies AJ, Holst PE, O'Donnell TV. Lessons from the national asthma mortality study: deaths in hospital. N Z Med J 1987;100:199–202.[Medline]
- Manning P, Murphy E, Clancy L, Callaghan B. Asthma mortality in the Republic of Ireland 1970–84 and an analysis of hospital deaths in a single year. Ir Med J 1987;80:406–409.[Medline]
- Picard E, Barmeir M, Schwartz S, Villa Y, Goldberg S, Virgilis D, Kerem E. Rate and place of death from asthma among different ethnic groups in Israel: national trends 1980 to 1997. Chest 2002;122:1222–1227.[Abstract/Free Full Text]
- Tan WC, Xiang X, Qiu D, Ng TP, Lam SF, Hegele RG. Epidemiology of respiratory viruses in patients hospitalized with near-fatal asthma, acute exacerbations of asthma, or chronic obstructive pulmonary disease. Am J Med 2003;115:272–277.[CrossRef][Medline]
- O'Sullivan S, Cormican L, Faul JL, Ichinohe S, Johnston SL, Burke CM, Poulter LW. Activated, cytotoxic CD8(+) T lymphocytes contribute to the pathology of asthma death. Am J Respir Crit Care Med 2001;164:560–564.[Abstract/Free Full Text]
- Macek V, Dakhama A, Hogg JC, Green FH, Rubin BK, Hegele RG. PCR detection of viral nucleic acid in fatal asthma: is the lower respiratory tract a reservoir for common viruses? Can Respir J 1999;6:37–43.[Medline]
- Watson MW, Beasley R, Holgate ST, Bardin PG. Rhinovirus is not detectable in peripheral lung tissue after asthma death. Respirology 2003;8:234–238.[CrossRef][Medline]
- Grunberg K, Smits HH, Timmers MC, de Klerk EPA, Dolhain RJEM, Dick EC, Hiemstra PS, Sterk PJ. Experimental rhino-virus 16 infection: effects on cell differentials and soluble markers in sputum in asthmatic subjects. Am J Respir Crit Care Med 1997;156:609–616.[Abstract/Free Full Text]
- Einarsson O, Geba GP, Zhu Z, Landry M, Elias JA. Interleukin-11: stimulation in vivo and in vitro by respiratory viruses and induction of airway hyperresponsiveness. J Clin Invest 1996;4:915–924.
- Jarjour NN, Gern JE, Kelly EAB, Swenson CA, Dick CR, Busse WW. The effect of an experimental rhinovirus 16 infection on bronchial lavage neutrophils. J Allergy Clin Immunol 2000;105:1169–1177.[CrossRef][Medline]
- Trigg CJ, Nicholson KG, Wang JH, Ireland DC, Jordan S, Duddle JM. Bronchial inflammation and the common cold: a comparison of atopic and non-atopic subjects. Clin Exp Allergy 1996;26:665–676.[CrossRef][Medline]
- Fraenkel DJ, Bardin PG, Sanderson G, Lampe F, Johnston SL, Holgate ST. Lower airways inflammation during rhinovirus colds in normal and in asthmatic subjects. Am J Respir Crit Care Med 1995;151:879–886.[Abstract]
- Grünberg K, Kuijpers AP, deKlerk EPA, de Gouw HW, Kroes AC, Dick EC, Sterk PJ. Effects of experimental rhinovirus 16 infection on airway hyperresponsiveness to bradykinin in asthmatic subjects in vivo. Am J Respir Crit Care Med 1997;155:833–838.[Abstract]
- Levandowski RA, Ou DW, Jackson CG. Acute phase decrease of T lymphocyte subsets in rhinovirus infection. J Infect Dis 1986;153:743–748.[Medline]
- Schwarze J, Cieslewicz G, Joetham A, Ikemura T, Hamelmann E, Gelfand EW. CD8 T cells are essential in the development of respiratory syncytial virus-induced lung eosinophilia and airway hyperresponsiveness. J Immunol 1999;162:4207–4211.[Abstract/Free Full Text]
- Lukacher A, Braciale V, Braciale T. In vivo effector function of influenza virus-specific cytotoxic T lymphocyte clones is highly specific. J Exp Med 1984;160:814–826.[Abstract/Free Full Text]
- Allan W, Tabi Z, Cleary A, Doherty PC. Cellular events in the lymph node and lung of mice with influenza. Consequences of depleting CD4+ T cells. J Immunol 1990;144:3980–3986.[Abstract]
- Isaacs D, Bangham CR, McMichael AJ. Cell-mediated cytotoxic response to respiratory syncytial virus in infants with bronchiolitis. Lancet 1987;2:769–771.[Medline]
- Matsubara T, Inoue T, Tashiro N, Katayama K, Matsuoka T, Furukawa S. Activation of peripheral blood CD8+ T cells in adenovirus infection. Pediatr Infect Dis J 2000;19:766–768.[Medline]
- Cannon MJ, Openshaw PJ, Askonas BA. Cytotoxic T cells clear virus but augment lung pathology in mice infected with respiratory syncytial virus. J Exp Med 1988;168:1163–1168.[Abstract/Free Full Text]
- Mackenzie CD, Taylor PM, Askonas BA. Rapid recovery of lung histology correlates with clearance of influenza virus by specific CD8+ cytotoxic T cells. Immunology 1989;67:375–381.[Medline]
- Lee SY, Kim SJ, Kwon SS, Kim YK, Moon HS, Song JS, Park SH. Distribution and cytokine production of CD4 and CD8 T-lymphocyte subsets in patients with acute asthma attacks. Ann Allergy Asthma Immunol 2001;86:659–664.[Medline]
- Faul J, Tormey V, Leonard C, Burke C, Horne S, Poulter L. Lung immunopathology in cases of sudden asthma death. Eur Respir J 1997;10:301–307.[Abstract]
- Goodarzi K, Goodarzi M, Tager AM, Luster AD, von Andrian UH. Leukotriene B4 and BLT1 control cytotoxic effector T cell recruitment to inflamed tissues. Nat Immunol 2003;4:965–973.[CrossRef][Medline]
- Tager AM, Bromley SK, Medoff BD, Islam SA, Bercury SD, Friedrich EB, Carafone AD, Gerszten RE, Luster AD. Leukotriene B4 receptor BLT1 mediates early effector T cell recruitment. Nat Immunol 2003;4:982–990.[CrossRef][Medline]
- Sznajer Y, Westcott JY, Wenzel SE, Mazer B, Tucci M, Toledano BJ. Airway eicosanoids in acute severe respiratory syncytial virus bronchiolitis. J Pediatr 2004;145:115–118.[Medline]
- Sampson AP, Castling DP, Green CP, Price JF. Persistent increase in plasma and urinary leukotrienes after acute asthma. Arch Dis Child 1995;73:221–225.[Abstract/Free Full Text]
- van Lier RA, ten Berge IJ, Gamadia LE. Human CD8(+) T-cell differentiation in response to viruses. Nat Rev Immunol 2003;3:931–939.[CrossRef][Medline]
- Coyle A, Erard F, Bertrand C, Walti S, Pircher H, Le Gros G. Virus-specific CD8+ cells can switch to interleukin-5 production and induce airway eosinophilia. J Exp Med 1995;181:1229–1233.[Abstract/Free Full Text]
- Bendelja K, Gagro A, Bace A, Lokar-Kolbas R, Krsulovic-Hresic V, Drazenovic V, Mlinaric-Galinovic G, Rabatic S. Predominant type-2 response in infants with respiratory syncytial virus (RSV) infection demonstrated by cytokine flow cytometry. Clin Exp Immunol 2000;121:332–338.[CrossRef][Medline]
- Roman M, Calhoun W, Hinton K, Avendano L, Simon V, Escobar A, Gaggero A, Diaz P. Respiratory syncytial virus infection in infants is associated with predominant Th-2-like response. Am J Respir Crit Care Med 1997;156:190–195.[Abstract/Free Full Text]
This article has been cited by other articles:
|
|
|
|
 
K. Takeda, S. W. Dow, N. Miyahara, T. Kodama, T. Koya, C. Taube, A. Joetham, J.-W. Park, A. Dakhama, R. M. Kedl, et al.
Vaccine-Induced CD8+ T Cell-Dependent Suppression of Airway Hyperresponsiveness and Inflammation
J. Immunol.,
July 1, 2009;
183(1):
181 - 190.
[Abstract]
[Full Text]
[PDF]
|
|
|
TOP
ABSTRACT
ASTHMA MORTALITY
