Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 6 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 6 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 7 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 5 uppsatser.

House dust mite (HDM) is an indoor aeroallergen which is commonly associated with the development of allergic rhinitis and allergic asthma. In fact, up to 70% of allergic asthmatic individuals have been shown to demonstrate reactivity towards HDM allergens. The downstream adaptive immune response to HDM is well characterize and is described as being largely T helper cell type 2 (Th2) and partly T helper cell type 17 (Th17) dominated. However, less is known about how resident antigen presenting cells (APCs) and structural cells such as airway epithelial cells recognize and respond to HDM. Unlike other microbial antigens, recognition of HDM is not primarily mediated through pattern recognition, rather by an intrinsic enzymatic or lipid-binding ability or by specific prost-translational modifications such as glycosylation. Various innate immune receptors, such as toll-like receptors (TLRs), C-type lectin receptors (CLRs), and protease-activated receptors (PARs), found on the surface of APCs and airway structural cells, have been demonstrated to be important in response to HDM. Nonetheless, the exact mechanisms by which these receptors or other undescribed receptors or molecules promote adaptive immunity, particularly Th2 immunity, is unclear. Using knock-out mice, we have shown that the kinase RIP2, which functions downstream of the peptidoglycan receptor NOD2, is involved in the early response to HDM likely within AECs and that its activation promotes airway inflammation. In follow-up work, we also demonstrate that early and acute pharmacologic inhibition of this kinase in a HDM asthma model has lasting effects on the reduction of airway inflammation and type 2 immunity associated with the pathology. The third project describes the identification of a novel receptor for HDM, LMAN1. We find that LMAN1 on dendritic cells functions to inhibit inflammatory responses to HDM and that loss of LMAN1 enhances airway inflammation in an asthma model. Altogether, my work has contributed to our understanding of the early events and molecules involved in responding to HDM. Our hope is that these findings will be useful in the discovery and testing of new therapies for treatment of allergic disease.

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 5 uppsatser.

<p>Asthma is a lung disease characterized by wide variations in airflow over short periods of time. Exacerbations of asthma can be accompanied by symptoms of chest tightness, shortness of breath and wheezing; airway inflammation characterized by an influx of eosinophils and/or neutrophils; and the expression of pro-inflammatory cytokines in the airway. There is strong evidence supporting a central role for the T cell in asthma. In atopic asthma, T cells are documented components of the late-phase response to inhaled allergen, driving airway inflammation, mucus hypersecretion, and bronchoconstriction through the release of cytokines and other mediators. T cells have also been shown to produce inflammatory cytokines in response to allergen in nonatopic asthmatics, indicating a potential role in mediating disease in this phenotype. In both atopic and nonatopic asthma, aberrant T cell responses to allergen may drive the infiltration of neutrophils and eosinophils into the airway through the production of pro- inflammatory cytokines, leading to exacerbations of disease. This project has investigated the role of several T cell cytokines in driving disease and acting as biomarkers in asthma: interleukin-5, interleukin-17A, interleukin-23, interleukin- 10, and interferon-γ. We have measured allergen-induced cytokine production by peripheral blood mononuclear cells (PBMCs) and examined its ability to distinguish between different asthma phenotypes: asthma vs normal, atopic vs nonatopic asthma, eosinophilic bronchitis vs noneosinophilic bronchitis, and neutrophilic vs nonneutrophilic bronchitis. Our data shows that allergen-induced peripheral blood mononuclear cell responses to allergen are not good biomarkers of disease in asthma. No differences in PBMC cytokine production are seen in patients with asthma, compared with normal controls, or between patients with different asthmatic phenotypes. It is not possible to determine a patient’s disease state, atopic status, or type of bronchitis by examining their PBMC cytokine responses to allergen.</p> / Master of Science (MSc)