1 | INTRODUCTION
Atopic dermatitis (AD) is a disease characterized by lesions involving eczema with pruritus, which are repeatedly exacerbated and ameliorated.1 Immunologically, AD is characterized by overexpression of T helper 2 (Th2) cytokines including interleukin (IL)-4 and IL-13. Therefore, many AD patients have a predisposition toward allergy, i.e., a condition that readily produces allergen-specific IgE antibodies that are activated and produced by Th2 cytokines.2
Basophils, which have AD-associated features including secretion of Th2 cytokines and histamine release after activation, are the least populated granulocyte in the human body. Therefore, studies on the mechanisms of basophil functions are limited.3However, some reports have described that basophils play an important role for maintenance of type 2 inflammation in AD.4
In AD model mice, basophils and group 2 innate lymphoid cells (ILC2) were the first cells to infiltrate the skin lesions.5Basophil-derived IL-4 was necessary for the promotion of ILC2-mediated inflammation in these model mice.5 The TSLP-dendritic cell-T cell pathway caused basophils to release IL-4 and induce Th2 polarization in mice.6 Elimination of basophils from the skin lesions caused reductions in the numbers of infiltrating eosinophils and neutrophils in mouse models.7Basophils were also suggested to play an important role in the development of IgE-mediated chronic allergic inflammation as an initiator rather than an effector.7
In contrast, studies on basophils in AD patients are limited. Basophils were found in the skin lesions in more than half of AD patients.8 Regarding basophil response markers, two compartments have been identified: CD203c compartment and CD63 compartment.9 Upregulation of CD63, but not CD203c, on basophils reflects histamine release.10, 11In most AD patients, CD203c expression on basophils without stimulation was similar to that in healthy controls (HCs); however there was some variation, with the basophils in certain AD patients showing high levels of CD203c expression.8 Basal CD63 expression on basophils without stimulation was similar between AD patients and HCs.12 However, studies focusing on the properties of circulating basophils in AD patients, including basophils under anti-IgE and anti-FcεRI stimulation, are limited.
Histamine released by basophils is an important inflammatory mediator.13 However, histamine release by basophils in AD patients with and without stimulation remains controversial. Without any stimulation, basophils in AD patients showed high spontaneous histamine release compared with HC basophils.14,15,16 Some reports documented that histamine release by basophils under anti-IgE stimulation was increased in patients with severe AD.13,15 In contrast, other reports described that histamine release was at a similar level to that in HCs16 or decreased.17
The high-affinity IgE receptor (FcεRI) is expressed on mast cells and basophils, and cross-linkage of FcεRI by allergens and specific IgE induces cell activation.14 Expression of FcεRI on mast cells was upregulated by IL-4.18 Preincubation with anti-FcεRI antibody caused histamine degranulation in response to various stimulations in human cultured basophils.16Basophils in AD patients expressed more FcεRI than those in HCs and there was a positive correlation between FcεRI and total serum IgE.19 In addition, omalizumab, a humanized anti-IgE monoclonal antibody, caused downregulation of FcεRI expression and responsiveness to anti-IgE stimulation.20 It has been proposed that FcεRI is controlled by total serum IgE.20,21 However, the relationship between FcεRI and IgE expression on peripheral blood basophils in AD patients is not completely understood.
High total serum IgE concentration in AD patients was shown to have a positive correlation with scoring of atopic dermatitis (SCORAD).22 Another study showed a correlation between total serum IgE concentration and disease severity in severe AD patients.23 Total serum IgE level and peripheral eosinophils were correlated with the eczema area and severity index (EASI) score.24 Thus, increased total serum IgE is observed in AD patients depending on the disease severity. However, it remains unclear whether this increase in serum IgE is directly involved in the disease exacerbation and pathogenesis of AD. In fact, a systematic review documented that the recommendations for omalizumab use in clinical practice for AD are limited.25 In contrast, elevated serum IgE in AD patients was considered to cause activation of basophils in peripheral blood.26Furthermore, some reports mentioned that high serum IgE caused low expression of CD63, a response marker on basophils,27while other reports mentioned that high serum IgE caused high expression of CD203c on basophils.28
Based on these backgrounds, we focused on the status of peripheral blood basophils in AD patients using CD203c and CD63 as response markers. The relationship between AD severity and basophil responsiveness was examined. To clarify the basophil characteristics in AD patients, surface-bound IgE and FcεRI were also examined and these surface expressions were compared with disease severity and serum IgE. In this study, we found some unique functional and conditional characteristics of basophil status in AD patients.