| Popis: |
Immune homeostasis is essential to protect mucosal airway surfaces from unnecessary and damaging inflammation against inhaled harmless environmental antigens, such as allergens. However, in allergic individuals this protective homeostatic response seems to be absent. Innate cells that are part of the mononuclear phagocytic system (MPS) play an important role in these processes. Most of our knowledge on allergic immune responses comes from animal models or from peripheral blood immune responses in humans. Information on tissue-specific responses in humans is scarce, however allergen-specific immune responses are initiated locally and this information is therefore crucial for the development of novel therapies. In this study we performed mass-cytometry proteomics and single cell RNA sequencing on immune cells from nasal biopsies of allergic rhinitis subjects and non-allergic controls, before and three days after repeated nasal challenge with House Dust Mite allergen. Following challenge, patients displayed a clinical nasal response together with enhanced eosinophilia, a cardinal feature of allergic inflammation. Although clinically silent, we observed a distinct, local, innate immune response to allergen in non-allergic individuals, characterized by infiltration of HLA-DRlowCD14+ monocytes expressing anti-microbial genes (S100A8, S100A9, S100A12) as well as transcriptional activation in cDC2, including several inhibitory/tolerogenic genes (NR4A1, IL4I1, ANXA2, TIMP1). The innate response in allergic individuals indicated an inflammatory role for infiltrating HLA-DRhi CD14+ monocytes, CD16+ monocytes, and CD1A+ cDC2 (ALOX15, CD1A, CCL17), in the development/maintenance of an allergic response. Future therapies should address those innate MPS populations, either enhancing or reducing their activity for the treatment of inflammatory airway disease. |
