TSLP, asthma heterogeneity, and human nuocytes

It seems that the variable presentation of asthma is even more variable than imagined. Just listing some of the known pathological variables in asthma, there is eosinophilic, atopic, IL-13 dominant, IL-5 dominant, treatment-refractory, and now, TSLP-associated asthma, the majority of which characterize the disease in its more severe forms. Shikotra and colleagues report findings in this month’s issue (J Allergy Clin Immunol 2012;129:104-111.e9) of upregulation of the innate Th2 cytokine TSLP in asthmatic epithelium, but also predominant expression of IL-13 protein in non-epithelial CD45+ cells found in the airway mucosa and the lamina propria.

Shikotra et al. demonstrate increased TSLP production in the airway mucosa with mild, moderate and severe asthma. TSLP expression was also found in the lamina propria of subjects with severe asthma. The authors note that increased TSLP production was inversely correlated to FEV1/FVC ratio. Increased TSLP production is associated with increased IL-13 and IL-4 production, but only in a subset of asthma subjects. Shikotra et al. comment that their results suggest that there are Th2-high- and -low- asthma phenotypes.

Interestingly, the authors find that the dominant sources of TSLP are from airway epithelial cells and both mast cells and lineage-negative CD45+ cells within the airway epithelium and the lamina propria. These findings support a previous hypothesis of a TSLP-mast cell pathway in the development of asthma. Additionally, the authors suggest that the CD45+ non-epithelial cells within the airway epithelium and lamina propria, may represent the human equivalent of nuocytes, innate Th2 immune cells characterized by high IL-13 production. Since nuocyte-associated IL-13 would be expected to increase TSLP production in both mast cells and epithelial cells, Shikotra et al. further suggest that this observation implies both TSLP-mast cell and TSLP-nuocyte pathways.

In the final summary, Shikotra et al. note that TSLP is a possible therapeutic target, but caution that like other anti-cytokine drugs, anti-TSLP will most likely be effective in asthma subjects with high TSLP and Th2 cytokine profiles.