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.