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.