PURPOSE OF THE STUDY.
Allergic diseases involve epithelial surfaces, and the epithelial cytokine thymic stromal lymphopoietin (TSLP) has been described as the “master switch” for allergic inflammation. The purpose of this study was to determine how TSLP contributes to allergic disease pathogenesis.
Most studies were performed in mice. Human studies were performed with the use of basophils from patients with eosinophilic esophagitis or from healthy controls.
TSLP-treated mice were evaluated for changes in circulating immune cells and cytokine secretion. The effect of tissue-specific TSLP production was determined by using transgenic mice overexpressing TSLP in the lung, or an atopic dermatitis model. Bone marrow cells were cultured with either TSLP or interleukin (IL)-3, and basophil differentiation was assessed. Characterization of TSLP-induced basophils from mice or humans was performed by the use of gene expression analysis and immune phenotyping.
Mice injected with TSLP had increased numbers of IL-4–secreting basophils in the spleen, as well as increased plasma levels of the proallergic T-helper type 2 (TH2) cytokines IL-4, IL-5, and IL-13. Endogenous overexpression of TSLP in the lungs or skin also promoted peripheral basophilia. This systemic basophilia resulted from TSLP-triggered expansion of bone marrow precursor cells through a mechanism independent of IL-3 signaling. Basophils were present in TSLP-deficient mice, indicating that TSLP was not essential for normal basophil development. In comparison with classical basophils induced by IL-3, TSLP-elicited basophils expressed higher levels of TH2-skewing cytokines and proinflammatory mediators. Furthermore, basophils obtained from patients with eosinophilic esophagitis, a disease associated with aberrant TSLP production, were phenotypically distinct from those found in healthy controls.
Abnormal TSLP production at 1 barrier surface may promote development of allergic inflammation at other sites by increasing the number and altering the function of circulating basophils.
It is well known that patients with 1 allergic disorder are likely to develop others, but the mechanisms for this “atopic march” remain obscure. Here, the authors show an important role for the cytokine TSLP, which has been shown to be highly expressed in animal and human tissues with active allergen-driven inflammation. The ability of TSLP to expand and alter the phenotype of peripheral basophils may promote the development of allergic disease at other barrier surfaces and could explain why patients with atopic dermatitis frequently go on to develop asthma or food allergy. In addition to contributing to our understanding of the biology of allergic diseases, these studies also identify TSLP as a potentially important target for pharmacological blockade in vulnerable patients.
- Copyright © 2012 by the American Academy of Pediatrics