Innate lymphocytes-ILC2-might be the drivers of T2-high nonatopic asthma in children

Background: Asthma in children is usually considered a T2-high (T2H) atopic disease, yet the T2H non-atopic and T2-low (T2L) endotypes, seen in adults, have not been well defined in children. Aim: To investigate the expression of innate lymphoid cells-2 (ILC2), IL-4 and IL-5 in the different endotypes of childhood asthma. Methods: In bronchial biopsies of 109 children (61 with, 48 without asthma) undergoing a clinical indicated bronchoscopy, we quantified by immunohistochemistry eosinophils (eos), ILC2, IL-4 and IL-5+ cells and remodelling hallmarks such as thickening of the basement membrane (BM) and epithelial shedding. Results: 45 (73%) children were T2H (eos>23cell/mm2), 16 (27%) T2L. Among T2H children, 23 (51%) were atopic (T2H-A) and 22 (49%) non-atopic (T2H-nA). Eos were similar in T2H-A and T2H-nA [158±127 vs 150±180cell/mm2]. IL-5 was similarly increased in T2H-A and T2H-nA [414±165 and 434±178 vs T2L 268±93 and controls 281±158 cell/mm2;p=0.04] and was related to eos (r=0.51;p=0.005). IL-4 was significantly higher in T2H-A than in T2H-nA [220±164 vs 73±42cell/mm2;p=0.04] and related to IgE (r=0.32;p=0.04) and eos (r=0.59;p=0.004). ILC2 cells were increased in T2H-nA and almost absent in the other groups [41±18 vs T2H-A 9±13, T2L and CTR 5±7cell/mm2;p<0.05]. All asthma endotypes (T2H-A, T2H-nA and T2L) showed significant BM thickening and epithelial shedding despite lack of eos in the T2L. Conclusion: In asthmatic children all endotypes, T2-high atopic, T2-high nonatopic and T2-low, are well represented. The exclusive presence of ILC2 in the T2-high non-atopic asthma, points to this cell as an important driver for this endotype.