Abstracts Category : Other

Innate mechanisms in upper airway inflammation with focus on epithelium and neutrophils

by Julia Arebro

Mucosal inflammation is a key feature in allergic rhinitis (AR) and chronic rhinosinusitis withnasal polyps (CRSwNP). The traditional idea of the epithelium as a simple barrier andneutrophils as a homogenous cell population, already terminally differentiated, has lately beenreconsidered. Recent findings have identified advanced immunological properties of bothepithelial cells (ECs) and neutrophil subsets. Toll-like receptors (TLRs) and activin receptorlike kinases (ALKs) constitute important receptors of the ECs in recognizing stimuli leading toinflammatory and biological processes through altered gene expression. The new neutrophilclassification, in four various subsets, is based on their expression of FcRIII (CD16) andL-selectin (CD62L). The various subsets appear to have diverse roles during inflammatoryconditions.The overall aim of this thesis is to investigate the role of the epithelial and neutrophil cells inupper airway innate immunity.Papers I-III explored the role of nasal epithelial cells (NECs) in antigen presentation as well asTLRs and ALKs on ECs in AR and CRSwNP. Major histocompatibility complex class II(MHC class II) as well as co-stimulatory molecules were found on NECs from mice andhumans and were upregulated on OVA-sensitized mice. NECs from sensitized mice could takeup, process and present antigens in a class II dependent manner for the activation of antigenspecific CD4+ T cells. NECs from AR patients were able to activate autologous T cells againstthe major birch allergen protein, Bet v 1, and induce an IL-13 release. Normally, TLR9 can befound in NECs, but was found to be almost absent in NECs from the mucosa close to the polypsof CRSwNP patients. The TLR9 expression could be reconstituted by stimulation with itsligand, CpG, both in vitro and in vivo. Stimulation also resulted in a downregulation ofVEGFR2, a receptor of angiogenesis, and cytokines. Investigation of polyp ECs revealed anupregulation of ALK1-6. Upon ligand stimulation, a downregulation of factors affecting cellproliferation (Ki67) and inflammation (ICAM-1 and IL-8) was seen. This was even morepronounced when microbial infection was mimicked.In Papers IV and V, neutrophil subsets were described for the first time in the nasal mucosaand a local shift to the activated subset became evident in AR and CRSwNP. In AR, theactivated subset CD16high CD62Ldim was shown to have T cell priming capacities and an abilityto enhance eosinophil migration. Neutrophils from CRSwNP patients displayed anupregulation of CD11b, most clearly emphasized on the cells of the activated subset. Thecorresponding adhesion molecule ICAM-1 was upregulated on the epithelium of polyps.In summary, epithelial and neutrophil cells in the nasal mucosa of patients with AR andCRSwNP exhibit an alerted receptor pattern with a deranged immunological response.Functional data including T cell activation, migration, adhesion and cytokine release clearlyindicate a role for TLRs, ALKs and