Infection and Immunology

The chemokine eotaxin (CCL11) is elevated in biological fluids in patients with asthma, and correlates with eosinophilia, but its role as a chemoattractant in asthma is not well defined. Dent and coworkers collected sputum from healthy subjects and from subjects with mild, stable-moderate, unstable-moderate, and severe asthma, and measured eotaxin levels and eosinophil chemotactic activity. Eotaxin was significantly increased in sputum from subjects with moderate and severe asthma, but not in those with mild asthma. Chemotactic activity was significantly increased in all subjects with asthma compared with healthy control subjects. However, a high-affinity neutralizing antibody to eotaxin inhibited chemotactic activity only in sputum from subjects with moderate and severe asthma. The authors concluded that the contribution of eotaxin to eosinophil chemotaxis in the airway increases with increasing asthma severity.

Bruder and colleagues established a model to study the role of CD4⁺ T cells, as well as their regulation and immune mechanisms, in producing pulmonary inflammation. In this model, a self-antigen expressed in the lung of mice bearing a major histocompatibility complex-class-II–restricted T-cell receptor specific for the antigen was studied. These transgenic mice developed progressive interstitial pneumonitis characterized by massive lymphocytic and plasmacytic infiltration of alveolar septa, a picture resembling some interstitial lung diseases. Pulmonary inflammation reached a plateau in older mice with prominent formation of lymphoid follicles, reduced interstitial inflammation, and the induction of regulatory T cells at the site of inflammation. This model has the potential to increase our understanding of the evolution of a pulmonary inflammatory response induced by activated CD4⁺ cells with the subsequent induction of regulatory T cells.

Ali and colleagues studied the effects of T-cell peptide epitopes derived from the major cat antigen Fel d-1 when given to cat-allergic subjects with asthma by inhalation. In a previous set of experiments, they showed that intradermal injection of peptides resulted in an isolated late airway response in cat-allergic subjects with asthma, with tolerance to subsequent doses of peptide, demonstrating that late airway responses could be obtained via a mechanism involving T cells alone, without the necessity of a prior early IgE-mediated/mast cell response. In this article, the authors demonstrated that inhalation of T-cell peptides also produced an isolated late airway response, but that this response was accompanied by airway inflammation (sputum eosinophilia), without induction of tolerance to a subsequent airway challenge with peptides. Therefore, these investigators have defined a unique set of human models to study T-cell–dependent late reactions, both with and without tolerance.

Fajardo and coworkers characterized the pattern of proteins increased in mice lungs and bronchoalveolar lavage fluid in animals sensitized and challenged with ovalbumin by proteomic analysis. Among the proteins elevated were glycolytic enzymes, glucose-regulated protein 78kD, prolyl-4-hydroxylase, peroxiredoxin 1, arginase, cathepsin S, and Ym2, a protein with unknown function. This article not only helps to define the pattern of proteins that respond to allergic inflammatory reactions in the lung but also points out an underappreciated relationship between allergic inflammation and the induction of hypoxia-related gene products.

Histone acetylation status is believed to be important in the regulation of inflammatory gene expression and its inhibition by glucocorticoids. Cosío and colleagues showed that alveolar macrophages from patients with asthma, but not peripheral blood mononuclear cells, have increased histone acetylase and decreased histone deacetylase activity when compared with control subjects. The authors suggested that one of the mechanisms of the increased inflammatory response seen in asthma is reduced histone deacetylase and increased histone acetylase activity at the site of the disease. Blood granulocytes (mainly neutrophils) had low histone deacetylase activity, offering a potential explanation for the limited ability of glucocorticoids to regulate neutrophil-mediated inflammatory responses.

To study the kinetics of memory of T lymphocytes in response to allergen, Aronica and coworkers generated T-cell receptor–transgenic CD4⁺ vector cells in vitro and transfected these into naive recipient mice, which were then allowed to resume a quiescent state. Inhalation of protein antigen activated these antigen-specific Th2 donor cells, resulting in pulmonary inflammatory and airway hyperreactivity. The susceptibility to pulmonary inflammation was correlated with the size of the input of Th2 cells, but inflammation in this model was not affected by Th1 cells. The reactivation of these antigen-experienced cells by inhaled antigen did not change the cytokine balance of recipient-derived T cells recruited to the lung. These data suggest that quiescent memory Th2 cells can create susceptibility to allergic pulmonary inflammation in a manner refractory to inhibition by Th1 cells or endogenous inhibitory mechanisms.

To assess the mechanisms involved in allergic-induced hyperreactivity and airway remodeling, Leigh and coworkers studied wild-type and IL-4–, IL-5–, and IL-13–deficient (^–/–) mice sensitized and studied 4 weeks after chronic allergen exposure. The study showed that wild-type mice developed sustained airway hyperreactivity and airway remodeling after chronic antigenic allergen exposure. However, both IL-4^–/– and IL-13^–/– mice were protected from development of sustained airway hyperreactivity and aspects of airway remodeling. This was not the case for IL-5^–/– mice, which developed sustained airway hyperreactivity and airway remodeling similar to that seen in wild-type mice. These results indicate that IL-4 and IL-13, but not IL-5, are critical for the development of sustained hyperreactivity and airway remodeling after allergen exposure.

In 36 patients with mild-to-moderate asthma and allergy to house dust, de Kluijver and coworkers did a three-arm double-blind trial. Patients inhaled a low dose of house dust mite allergen over 10 working days (Days 1 to 5 and Days 8 to 12), and were then randomized to experimental infection with rhinovirus or placebo (Days 15 and 16). Exposure to allergen produced decreases in FEV₁ and the provocative dose of histamine causing a decrease in FEV₁, and increases in exhaled nitric oxide and sputum eosinophils. Infection with rhinovirus 16 produced a decrease in FEV₁, and increases in sputum interleukin-8, sputum neutrophils, and neutrophil elastase. Successive allergen exposure and rhinovirus infection did not have any synergistic or additive effect on any clinical or inflammatory outcome. The authors conclude that inhalation of a low dose of allergen and experimental infection with rhinovirus 16 induces distinct inflammatory profiles, and that a preceding allergen exposure does not influence the severity of rhinovirus-induced exacerbations of asthma. An editorial commentary by Johnston accompanies this article.

In 100 patients admitted to hospital with an acute exacerbation of asthma, Lieberman and coworkers studied the role of four atypical pathogens. Serologic evidence of acute infection with Mycoplasma pneumoniae was found in 18% of the patients and in 3% of the control group; 56% of this subgroup had evidence of acute infection with a second pathogen (usually a virus). Acute infections with Chlamydia pneumoniae were present in 8% of the patients and in 6% of the control group, and acute infections with Legionella spp. were present in 5% of the patients and in 3% of the control group; evidence of infection with Coxiella burnettii was not found in either group. The authors conclude that infection with M. pneumoniae is associated with hospitalization for an acute exacerbation of asthma.

Viruses cause most exacerbations of asthma and rhinovirus is the most common. Because decreased generation of interferon- may be associated with severity of colds and delayed elimination of viruses, Brooks and coworkers examined whether the generation of interferon- is associated with the severity of asthma. Peripheral blood mononuclear cells from 19 patients with atopic asthma were incubated with rhinovirus 16 for 6 days and the production of interferon- and interleukin-5 was measured. The production of interferon- was correlated with the dose of methacholine provoking a 20% decrease in FEV₁ (r = 0.50) and the ratio of interferon- to interleukin-5 was correlated with FEV₁ (r = 0.53). Asthma severity was not correlated with the production of interleukin-5. The authors conclude that a deficient Th1 response, but not Th2 response, to rhinovirus is associated with the severity of asthma and that impaired antiviral responses are associated with asthma severity.

Citations 1-12 of 12 total displayed.

CD4 T Lymphocyte–mediated Lung Disease: Steady State between Pathological and Tolerogenic Immune Reactions

Dunja Bruder, Astrid M. Westendorf, Robert Geffers, Achim D. Gruber, Marcus Gereke, Richard I. Enelow, and Jan Buer
Am. J. Respir. Crit. Care Med. 170: 1145 -1152. First published online as doi:10.1164/rccm.200404-464OC [Abstract] [Full text]  

Increased Levels of Hypoxia-sensitive Proteins in Allergic Airway Inflammation

Ignacio Fajardo, Linda Svensson, Anders Bucht, and Gunnar Pejler
Am. J. Respir. Crit. Care Med. 170: 477 -484. First published online as doi:10.1164/rccm.200402-178OC [Abstract] [Full text]  

Higher Prostaglandin E2 Production by Dendritic Cells from Subjects with Asthma Compared with Normal Subjects

Julie A. Long, Mirjana Fogel-Petrovic, Darryl A. Knight, Philip J. Thompson, and John W. Upham
Am. J. Respir. Crit. Care Med. 170: 485 -491. First published online as doi:10.1164/rccm.200311-1595OC [Abstract] [Full text]  

Histone Acetylase and Deacetylase Activity in Alveolar Macrophages and Blood Mononocytes in Asthma

Borja G. Cosío, Buphinder Mann, Kazuhiro Ito, Elen Jazrawi, Peter J. Barnes, K. Fan Chung, and Ian M. Adcock
Am. J. Respir. Crit. Care Med. 170: 141 -147. First published online as doi:10.1164/rccm.200305-659OC [Abstract] [Full text]  

Contribution of Eotaxin-1 to Eosinophil Chemotactic Activity of Moderate and Severe Asthmatic Sputum

Gordon Dent, Chrystalleni Hadjicharalambous, Takahiro Yoshikawa, Rachel L. C. Handy, John Powell, Ian K. Anderson, Renaud Louis, Donna E. Davies, and Ratko Djukanovic
Am. J. Respir. Crit. Care Med. 169: 1110 -1117. First published online as doi:10.1164/rccm.200306-855OC [Abstract] [Full text]  

Type 2 Cytokines in the Pathogenesis of Sustained Airway Dysfunction and Airway Remodeling in Mice

Richard Leigh, Russ Ellis, Jennifer N. Wattie, Jeremy A. Hirota, Klaus I. Matthaei, Paul S. Foster, Paul M. O'Byrne, and Mark D. Inman
Am. J. Respir. Crit. Care Med. 169: 860 -867. First published online as doi:10.1164/rccm.200305-706OC [Abstract] [Full text]  

Recall Helper T Cell Response: T Helper 1 Cell–resistant Allergic Susceptibility without Biasing Uncommitted CD4 T Cells

Mark A. Aronica, Susan McCarthy, Shadi Swaidani, Daphne Mitchell, Mehmet Goral, James R. Sheller, and Mark Boothby
Am. J. Respir. Crit. Care Med. 169: 587 -595. First published online as doi:10.1164/rccm.200301-100OC [Abstract] [Full text]  

Late Asthmatic Reactions Induced by Inhalation of Allergen-derived T Cell Peptides

F. Runa Ali, William L. G. Oldfield, Noritaka Higashi, Mark Larché, and A. Barry Kay
Am. J. Respir. Crit. Care Med. 169: 20 -26. First published online as doi:10.1164/rccm.200305-690OC [Abstract] [Full text]  

Experimental Models of Rhinovirus-induced Exacerbations of Asthma: Where to Now?

Sebastian L. Johnston
Am. J. Respir. Crit. Care Med. 168: 1145-1146. [Full text]  

Are Rhinovirus-induced Airway Responses in Asthma Aggravated by Chronic Allergen Exposure?

Josephine de Kluijver, Christine E. Evertse, Jacob K. Sont, Jasmijn A. Schrumpf, Christel J. G. van Zeijl-van der Ham, Claire R. Dick, Klaus F. Rabe, Pieter S. Hiemstra, and Peter J. Sterk
Am. J. Respir. Crit. Care Med. 168: 1174 -1180. First published online as doi:10.1164/rccm.200212-1520OC [Abstract] [Full text]  

Rhinovirus-induced Interferon- and Airway Responsiveness in Asthma

G. Daniel Brooks, Kim A. Buchta, Cheri A. Swenson, James E. Gern, and William W. Busse
Am. J. Respir. Crit. Care Med. 168: 1091 -1094. First published online as doi:10.1164/rccm.200306-737OC [Abstract] [Full text]  

Atypical Pathogen Infection in Adults with Acute Exacerbation of Bronchial Asthma

David Lieberman, Devora Lieberman, Shmuel Printz, Miriam Ben-Yaakov, Zilia Lazarovich, Bella Ohana, Maureen G. Friedman, Bella Dvoskin, Maija Leinonen, and Ida Boldur
Am. J. Respir. Crit. Care Med. 167: 406 -410. First published online as doi:10.1164/rccm.200209-996OC [Abstract] [Full text]