Autoreactive IgE in Atopic dermatitis
Atopic dermatitis (AD) is a common chronic relapsing inflammatory skin
disease characterized by pruritic (itchy), red and dry skin lesions with
an impaired skin barrier function. AD is associated with the development
of food allergies, allergic asthma, allergic rhinitis, and anaphylaxis
(“atopic march”)76. In patients with AD, an
increased risk of co-morbid autoimmune diseases was
found77,78. The first evidence of autoreactive
responses to human dander was
reported about 80 years ago79,80. Several research
groups have demonstrated the presence of IgE AAb in
AD81-94. At least 140 autoantigens recognized by IgE
AAb in AD patients have been identified95, including
epidermal antigens82,96. A review of 8 studies on the
prevalence of IgE AAb described a range from 23% (40/174) to 91%
(11/12) in patients with eczema and 0 to 12% in
controls97. The evaluation of studies with a sample
size greater than 100 showed a range of 23-28% in eczema
patients97. A recent study including 672 subjects
found a prevalence of 16.4% in patients with AD and atopic
comorbidities, 9.6% in patients with solely AD, 9.6% in atopic
controls without AD, and 2.7% in non-atopic subjects (Kortekaas Krohnet al. , unpublished data).
The levels of IgE AAb in AD patients are correlated with disease
severity82,87,89,92,98-100. Therefore, it is held that
their presence is clinically relevant, but their precise
pathophysiological contribution still requires further investigations.
Allergen-mediated or autoallergen-mediated FcεRI-crosslinking on mast
cells, basophils, Langerhans cells and probably eosinophils in AD skin
may contribute to the pathogenic activation of these cells along with
IgE-independent pathways101 (Figure 3). Of note,
FcεRI-bearing mast cells and eosinophils are potent producers of IL-13,
one of the key cytokine in AD pathogenesis (Figure 3).
In AD, the exact role of IgE AAb (i.e. cause, consequence, or
epiphenomenon) in the disease pathophysiology is still
debated102. It is believed that pruritus, a key
feature of chronic skin inflammation in AD, incites scratching, which
leads to skin damage and the release of alarmins and
self-antigens102. These autoantigens may then be
processed by antigen presenting cells and presented to lymphocytes
resulting in the production of IgG and/or IgE AAb by plasma
cells103. IgE-mediated autoimmunity in AD may also be
caused by molecular mimicry due to cross-reactive peptides between
environmental antigens or skin microbiome and
self-antigens89,104-106. In addition, skin residing
CD8+ cytotoxic T cells with intermediate affinity to
self-peptides may contribute to skin damage, and unconventional γδ T
cells may also accumulate in the skin107,108. Finally,
an extraordinary unspecific activation of the T and B cells might also
underlie the response due to the conditions of an ongoing inflammation.
So far, it is unclear whether the presence of IgE AAb in AD is linked to
a distinct endotype or an epiphenomenon secondary to the chronic
inflammation of the skin109. Once present, they
contribute to the ongoing inflammation in a “circulus vitiosus”type fashion and may predict further development of type-2 comorbid
diseases, such as food allergies, allergic asthma, rhinoconjunctivitis/
hay fever, which is an important topic for future investigation.
As is the case for all diseases that come with autoreactive IgE, no
commercial diagnostic test is currently available for the detection of
IgE AAb in AD, which hampers their evaluation and further research on
clinical relevance. Also, published differences on the prevalence might
be due to the diverse diagnostic test methods used by the different
research groups as described in CSU (Table 2).
Anti-IgE treatment has not been approved for the treatment of AD, due to
low efficacy data in early pilot studies110. Radiet al. recently reviewed the promising therapeutic targets for
AD. Some of them, such as alarmins, IL-4, IL-13, IL-5 and kinase
inhibitors, may directly or indirectly impact levels of autoreactive IgE
and their effects on FcεRI-bearing cells111.