Autoreactive IgE in chronic spontaneous urticaria
Chronic spontaneous urticaria (CSU), a common skin disease, is characterized by the recurrence of itchy wheals, angioedema, or both for more than 6 weeks50,51. The signs and symptoms of CSU are caused by skin mast cells and their FcεRI-mediated activation through IgG AAb to IgE or FcεRI and IgE AAb, in autoimmune and autoallergic CSU, respectively52,53.
The first CSU “autoallergen”, TPO, was reported in 1999 by Bar-Sela and colleagues 54. At that time, it was well known that CSU and thyroid autoimmunity often occur together, but it was unclear how the two diseases were linked mechanistically55,56. Since then, several studies confirmed that patients with CSU have anti-TPO IgE at varying rates up to 100%57-64. The reasons for the differing rates of anti-TPO IgE-positive patients across studies are currently unclear, but they likely include differences in patient populations investigated and methods used65,66. Other autoantigens to which CSU patients have autoreactive IgE include double stranded DNA67, eosinophil cationic protein59, eosinophil peroxidase59, FcεRI68, interleukin-24 (IL-24)53,69, thyroglobulin (TG)60,61,68,70, tissue factor (TF)68,70, and transglutaminase 2 (TG2)71 (Table 2 and Figure 2). Most of them have been reported by single studies, and further verification is needed.
As of now, little is known about how the presence and levels of IgE autoantibodies in CSU are linked to demographic and clinical features. A study by Altrichter and coworkers found no difference in disease duration, urticaria activity score (UAS) and dermatology life quality index (DLQI) (all indicators of CSU disease severity) between patients with and without anti-TPO IgE 57. Another study reported elevation of anti-TPO IgE during CSU exacerbation62. Cugno and colleagues showed that anti-TG and anti-TF IgE levels dropped after one week of omalizumab (OMZ) treatment correlating with the reduction in disease activity70. Anti-IL-24 IgE levels are positively linked to disease activity and negatively associated with blood basophil counts69.
IgE AAb contribute to the pathogenesis of CSU via “autoallergic” FcεRI-mediated activation of mast cells in the skin, which results in the release of proinflammatory mediators and the recruitment of inflammatory cells including basophils (Figure 2). Autoantigens recognized by autoreactive IgE, i.e. autoallergens, lead to the crosslinking of FcεRI on mast cells and basophils and their degranulation, as shown for IgE against TPO, IL-24, and dsDNA in vitro and in vivo 58,67,69,72. For dsDNA and TPO, patient basophils with the respective autoreactive IgE showed upregulated CD203c or CD63 expression after stimulation with different concentrations of autoallergen58,67,72. As of now, it is unclear why autoallergens induce IgE responses primarily in the skin. One possible explanation is cross-reactivity to skin-prominent antigens such as, for instance, anti-TPO IgE and eosinophil peroxidase in lesional CSU skin59.
Treatment options for urticaria target either mast cell mediators (e.g. histamine) or activators, such as autoantibodies. Currently, there is only one licensed anti-IgE treatment in CSU, OMZ. Additional IgE-targeted antibodies, i.e. OMZ biosimilars, ligelizumab and UB-221, as well as quilizumab, FB825 and dupilumab, which downregulates IgE production, have been investigated. Dupilumab is a monoclonal antibody that targets the common chain of IL-4 and IL-13 receptors (IL-4Rα)73. These cytokines are responsible, among other central functions, for B cell class switching to IgE. Therefore, dupilumab reduces IgE production, which has been shown to be beneficial in multiple atopic and allergic diseases73,74 and also in CSU75.