Allergic and non-allergic asthma: Translational research in immunology

Sammanfattning: Asthma is a chronic heterogeneous respiratory disease affecting more than 300 million people globally. The different phenotypes, including allergic and nonallergic asthma, are driven by different underlying mechanisms illustrating the complexity of the disease. Allergic asthmatics often exhibit elevated levels of type 2 (T2) cytokines including interleukin (IL)-4, IL-5 and IL-13 which typically coincide with increased numbers of blood and airway eosinophils. This group generally responds well to treatments. However, more research is needed to develop personalized treatments targeting inflammatory drivers in asthmatics that are unresponsive to currently available treatments, which is more common in non-allergic asthmatics. Type 2 innate lymphoid cells (ILC2s) are a major source of T2 cytokines and are implicated in both allergic and non-allergic eosinophilic asthma. ILC2s can respond to the cytokine IL-33 that functions as an alarm signal upon tissue damage or cell injury. We identified bone marrow ILC2s to be IL-33-responsive cell types contributing to IL-5-dependent eosinophilic inflammation induced by the protease allergen papain (Paper I). In the second study (Paper II), we concluded that bone marrow ILC2s might have a critical role at the onset of bone marrow eosinophilia in response to the allergen house dust mite. We also identified IL-33-responsive eosinophils and T helper cells in this study. Targeting ILC2s therapeutically via the IL-33/ST2 axis might be promising in eosinophilic diseases such as asthma. In addition, different pathways are required for pro-inflammatory properties of ILC2s that can be modulated. We demonstrated that airway exposure of IL-33 induced mechanistic target of rapamycin complex 1 (mTORC1) activity in bone marrow ILC2s and that the mTORC1 pathway was crucial for IL-5 production in experiments using the mTORC1 inhibitor rapamycin (Paper III). Other drivers in inflammatory diseases are microRNAs (miRNAs). These short non-coding RNAs exert immune-modulatory effects and can act pro-inflammatory and anti-inflammatory. We identified distinct miRNAs in lung and bone marrow that might drive responses caused by IL-33 (Paper IV). There is a need for new stable biomarkers and identification of disease drivers in non-allergic asthma which can be either T2 low or T2 high. We identified unique proteomic profiles in bronchial lavage supernatants from allergic and non-allergic asthmatics (Paper V). Proteins distinguishing the two asthma groups, were for example shown to be involved in ciliogenesis, mucociliary clearance and complement activation. With the ultimate goal of identifying new therapeutic targets, these studies increase our understanding of different inflammatory mechanisms contributing to the ongoing inflammation that might cause airway disease.