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PurposeGroup 2 innate lymphoid cells (ILC2s) have been implicated in the pathogenesis of allergic disease. However, the effect of allergen-specific immunotherapy (AIT) on ILCs remains to be clarified. The aim of this study was to evaluate the levels of ILC subsets in allergic rhinitis (AR) patients in response to house dust mite (HDM)-specific immunotherapy.MethodsWe enrolled 37 AR patients undergoing AIT (16 responders and 11 non-responders) for 2 years, 35 HDM AR patients and 28 healthy subjects. Peripheral blood mononuclear cells (PBMCs) were analyzed by flow cytometry to identify ILC subsets. Stimulation of ILC2s with recombinant allergen-specific protein was used to determine ILC2's activation (CD69 expression).ResultsResponder AIT patients and healthy subjects had a decreased frequency of circulating ILC2s compared to non-responder AIT and AR patients. Conversely, ILC1s from responder AIT patients and healthy subjects showed increased frequency compared to non-responder AIT and AR patients. The frequency of ILC3s natural cytotoxicity receptor (NCR)+ and NCR− in responder AIT patients was significantly lower compared to AR patients and healthy subjects. The ILC1: ILC2 proportion in responder AIT patients was similar to that of healthy subjects. PBMCs from patients who were responders to AIT had a significantly lower expression of the activation marker CD69 on ILC2s in response to allergen re-stimulation compared to AR patients, but no difference compared to non-responder AIT patients and healthy subjects.ConclusionsWe propose that AIT might affect ILC responses. The activation of ILC2s was reduced in AR patients treated with AIT. Our results indicate that a relative ILC1/ILC2 skewed response is a possible key to successful AIT.

Whereas the biology of IgG, IgA, and IgE has been extensively studied in allergic diseases, the regulation and function of IgD remain poorly investigated. IgG4 is a blocking antibody, which prevents the cross-linking of receptor-bound IgE. IgD is unable to recruit complement protein which is similar to mucosal IgA. 1 IgD was shown to increase Th2 cell polarization in germinal centers, boosting Th2 cytokine production. 2 IgD-activated basophils also enhance IgG1 and IgE production by allergen-specific B cells. Interestingly, IgD could interfere with IgE-mediated basophil degranulation supporting its role in the development of allergen immune tolerance. 2 Of note, beekeepers with tolerance to bee venom developed higher serum IgDspecific phospholipase A2 (PLA2) levels and lower total IgD levels compared with healthy controls. 2 Moreover, milk-and egg-allergic children treated with oral immunotherapy showed increased serum allergen-specific IgD responses compared with placebo controls. 2 Allergen-specific immunotherapy (AIT) is the only treatment which induces long-term clinical tolerance.

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