Allergic asthma is a complex and chronic inflammatory disorder which is associated with airway hyper-responsiveness and tissue remodelling of the airway structure. Although originally thought to be a Th2-driven inflammatory response to inhaled innocuous allergen, the immune response in asthma is now considered highly heterogeneous. There are now various in vivo systems which have been designed to examine the pathways leading to the development of this chronic immune response and reflect, in part this heterogeneity. Furthermore, the emergence of endogenous immunoregulatory pathways and active pro-resolving mediators hold great potential for future therapeutic intervention. In this review, the key cellular and molecular mediators relating to chronic allergic airway disease are discussed, as well as emerging players in the regulation of chronic allergic inflammation.

Chronic inflammation and asthma

Exposure to ozone, which is a major component of air pollution, induces a form of asthma that occurs in the absence of adaptive immunity. Although ozone-induced asthma is characterized by airway neutrophilia, and not eosinophilia, it is nevertheless associated with airway hyperreactivity (AHR), which is a cardinal feature of asthma. Because AHR induced by allergens requires the presence of natural killer T (NKT) cells, we asked whether ozone-induced AHR had similar requirements. We found that repeated exposure of wild-type (WT) mice to ozone induced severe AHR associated with an increase in airway NKT cells, neutrophils, and macrophages. Surprisingly, NKT cell–deficient (CD1d−/− and Jα18−/−) mice failed to develop ozone-induced AHR. Further, treatment of WT mice with an anti-CD1d mAb blocked NKT cell activation and prevented ozone-induced AHR. Moreover, ozone-induced, but not allergen-induced, AHR was associated with NKT cells producing interleukin (IL)-17, and failed to occur in IL-17−/− mice nor in WT mice treated with anti–IL-17 mAb. Thus, ozone exposure induces AHR that requires the presence of NKT cells and IL-17 production. Because NKT cells are required for the development of two very disparate forms of AHR (ozone- and allergen-induced), our results strongly suggest that NKT cells mediate a unifying pathogenic mechanism for several distinct forms of asthma, and represent a unique target for effective asthma therapy.

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Ozone exposure in a mouse model induces airway hyperreactivity that requires the presence of natural killer T cells and IL-17

Asthma is a common, disabling inflammatory respiratory disease that has increased in frequency and severity in developed nations. We review studies of murine allergic airway disease (MAAD) and human asthma that evaluate the importance of Th2 cytokines, Th2 response-promoting cytokines, IL-17, and proinflammatory and anti-inflammatory cytokines in MAAD and human asthma. We discuss murine studies that directly stimulate airways with specific cytokines or delete, inactivate, neutralize, or block specific cytokines or their receptors, as well as controversial issues including the roles of IL-5, IL-17, and IL-13Rα2 in MAAD and IL-4Rα expression by specific cell types. Studies of human asthmatic cytokine gene and protein expression, linkage of cytokine polymorphisms to asthma, cytokine responses to allergen stimulation, and clinical responses to cytokine antagonists are discussed as well. Results of these analyses establish the importance of specific cytokines in MAAD and human asthma and have therapeutic implications.

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Importance of cytokines in murine allergic airway disease and human asthma.

Rhinovirus-induced modulation of gene expression in bronchial epithelial cells from subjects with asthma

New insights into the pathogenesis of Behçet's disease.

Many studies have shown the implication of CD14 and toll-like receptors (TLRs) 2, 4 and 9 in the pathogenesis of asthma or atopy. To evaluate the association of CD14 and TLRs gene polymorphisms with asthma or atopy, 210 asthmatic children, 224 controls and 80 families were enrolled in this study. Six single nucleotide polymorphisms TLR2 (+2408 G-->A), TLR4 (+1196 C-->T), TLR4 (+896 A-->G), TLR9 (-1237 T-->C), TLR9 (-1486 T-->C) and CD14 (-159 C-->T) were genotyped using polymerase chain reaction followed by restriction fragment length polymorphism in the case-control and family study. The -1237C allele in TLR9 gene polymorphisms was associated with increased risk of asthma [odds ratio 1.53, 95% confidence interval (1.03-2.27)], although no statistically significant differences in allele or genotype frequencies of four other TLRs polymorphisms were evident between the asthmatic and control groups. The CD14 -159 C allele was found to be significantly higher in the asthmatic group when compared with controls (P=0.0006<0.05). Transmission disequilibrium test of 80 asthmatic families showed significant transmission of the -159 C allele in the CD14 gene to asthma-affected offspring. It was concluded that TLR9 and CD14 gene polymorphisms may contribute to an inherited predisposition to asthma in Tunisian children.

Toll-like receptors and CD14 genes polymorphisms and susceptibility to asthma in Tunisian children.

To determine whether there was a specific inflammatory process in severe asthmatics, the phenotypic characteristics of induced sputum immune cells were analysed among patients with severe asthma. Twenty-two induced sputa (10 severe asthmatics) were studied. Flow cytometric analysis was performed using immune cells of the sputum and monoclonal antibodies to CD3, CD4, CD8, CD56, CD25, and TCRgammadelta. The number of NKT (CD3(+) CD56(+)) cells was significantly higher in the sputum of severe asthmatics compared with mild asthmatic and healthy control groups (P < .05). CD8(+)CD56(+) cells were the predominant subtype of the increased NKT cells in severe asthmatics. CD3(+)CD56(+)Valpha24(+), TCRgammadelta(+) CD56(+), and CD4(+)CD25(+) T cells were significantly increased in severe asthmatic patients. These results suggest that the immunopathogenesis of severe asthmatics vary between severe and mild asthmatics, and that CD8(+)CD56(+) NKT cells may play an important role in the immunopathogenesis of severe asthma.

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NKT Cells in the Induced Sputum of Severe Asthmatics

Tumor necrosis factor gene polymorphisms in Tunisian patients with Behcet's disease.

Association between RANTES polymorphisms and asthma severity among Tunisian children.

Several lines of evidence point to a relevant role of IL-18 in the process of asthma. Some studies suggest that the polymorphism in the gene of IL-18 can be involved in many inflammatory and atopic diseases such as asthma. The aim of our study is to estimate the frequency of the IL-18-607 C/A (rs 1946518) promoter polymorphism in Tunisian children with asthma. We investigated whether the presence of this polymorphism -607 C/A was associated with asthma or atopy and whether this polymorphism influenced the severity of asthma in affected children. We examined also the relationship between the IL-18 gene polymorphism and the serum total IgE level. The IL-18/-607 C/A polymorphism was analysed by polymerase chain reaction and restriction fragment-length polymorphism (PCR-RFLP) analysis. A total of 105 asthma patients and 112 controls as part of the whole children population were studied in a case-control study. Among the 105 children with asthma, 40 were also studied for linkage analyses with their respective parents. We noted that the A allele was associated with statistically significant increases in the risk of asthma in the case-control study (odd ratio (OR) = 1.55, 95% confidence interval (CI) 1.03-2.33. Moreover, the A allele was also associated with atopic asthma (P = 0.008), but not with asthma severity. The transmission disequilibrium test (TDT) analysis in this family study did not suggest a preferential transmission of the IL-18/ -607 C/A polymorphism to affected children. There is no correlation between the IgE level and the IL-18 -607 C/A promoter polymorphism. Our data indicate that IL-18 -607 C/A promoter polymorphism is associated with susceptibility to developing asthma in Tunisian population.

Hanene Chelbi

Papers

Toll-like receptors and CD14 genes polymorphisms and susceptibility to asthma in Tunisian children.

NKT Cells in the Induced Sputum of Severe Asthmatics

Tumor necrosis factor gene polymorphisms in Tunisian patients with Behcet's disease.

Association between RANTES polymorphisms and asthma severity among Tunisian children.

Promoter polymorphism of the IL-18 gene is associated with atopic asthma in Tunisian children.