To clarify the essential role of NKT cells in allergy, we investigated the contribution of NKT cells to the pathogenesis of eosinophilic airway inflammation using α‐galactosylceramide (α‐GalCer), a selective ligand for NKT cells. Although continuous administration of α‐GalCer during ovalbumin (OVA) sensitization increased OVA‐specific IgE levels and worsened eosinophil inflammation, a single administration of α‐GalCer at the time of OVA challenge completely prevented eosinophilic infiltration in wild‐type mice. This inhibitory effect of α‐GalCer was associated with a decrease in airway hyperresponsiveness, an increase in IFN‐γ, and decreases in IL‐4, IL‐5 and IL‐13 levels in the bronchoalveolar lavage fluids. Analysis of lung lymphocytes revealed that production of IFN‐γ increased in NK cells, but not in T or NKT cells, following α‐GalCer administration. Induction of vascular cell adhesion molecule‐1 in the lungs of wild‐type mice was also significantly attenuated by treatment with α‐GalCer. These effects of α‐GalCer were abrogated in Jα281^–/– mice, which lack NKT cells, and in wild‐type mice treated with anti‐IFN‐γ Ab. Hence, our data indicate that α‐GalCer suppresses allergen‐induced eosinophilic airway inflammation, possibly by inducing a Th1 bias that results in inhibition of eosinophil adhesion to the lung vessels.See accompanying commentary: http://dx.doi.org/10.1002/eji.200535425

Steroid-insensitive asthma is an infrequent but problematic airway disease that presents with persistent symptoms, airflow limitation, or recurrent exacerbations even when treated with steroid-based therapies. Because of unsatisfactory results obtained from currently available therapies for steroid-insensitive asthma, a better understanding of its pathogenesis and the development of new targeted molecular therapies are warranted. Recent studies indicated that levels of interleukin (IL)-17 are increased and both eosinophils and neutrophils infiltrate the airways of severe asthmatics. IL-17 is a proinflammatory cytokine mainly secreted from helper T (Th) 17 cells and is important for the induction of neutrophil recruitment and migration at sites of inflammation. This review focuses on the pathogenetic role of Th17 cells and their associated cytokines in steroid-insensitive asthma and discusses the prospects of novel therapeutic options targeting the Th17 signaling pathway.

The expression of IL-17F is seen in the airway of asthmatics and its level is correlated with disease severity. Several studies have demonstrated that IL-17F plays a pivotal role in allergic airway inflammation and induces several asthma-related molecules such as CCL20. IL-17F-induced CCL20 may attract Th17 cells into the airway resulting in the recruitment of additional Th17 cells to enhance allergic airway inflammation. We have recently identified, for the first time, that bronchial epithelial cells are its novel cell source in response to IL-33 via ST2-ERK1/2-MSK1 signaling pathway. The receptor for IL-17F is the heterodimeric complex of IL-17RA and IL-17RC, and IL-17F activates many signaling pathways. In a case-control study of 867 unrelated Japanese subjects, a His161 to Arg161 (H161R) substitution in the third exon of the IL-17F gene was associated with asthma. In atopic patients with asthma, prebronchodilator baseline FEV1/FVC values showed a significant association with the H161R variant. Moreover, this variant is a natural antagonist for the wild-type IL-17F. Moreover, IL-17F is involved in airway remodeling and steroid resistance. Hence, IL-17F may play an orchestrating role in the pathogenesis of asthma and may provide a valuable therapeutic target for development of novel strategies.

The incidence of pulmonary nontuberculous mycobacterial (NTM) infection is increasing worldwide, and its clinical outcomes with current chemotherapies are unsatisfactory. The incidence of tuberculosis (TB) is still high in Africa, and the existence of drug-resistant tuberculosis is also an important issue for treatment. To discover and develop new efficacious anti-mycobacterial treatments, it is important to understand the host-defense mechanisms against mycobacterial infection. Nuclear erythroid 2 p45-related factor-2 (NRF2) is known to be a major regulator of various antioxidant response element (ARE)-driven cytoprotective gene expressions, and its protective role has been demonstrated in infections. However, there are not many papers or reviews regarding the role of NRF2 in mycobacterial infectious disease. Therefore, this review focuses on the role of NRF2 in the pathogenesis of Mycobacterium tuberculosis and Mycobacterium avium infection.