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 , unpublished data).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.