One in five patients with chronic spontaneous urticaria has IgE to tissue transglutaminase 2

To the Editor, Chronic spontaneous urticaria (CSU) is a mast cell-mediated inflammatory skin disease characterized by itchy wheals and angioedema that occur for longer than 6 weeks. IgE antibodies to various autoantigens, for example, thyroperoxidase (TPO) and interleukin 24 (IL-24), are held to drive the occurrence of signs and symptoms in type I autoimmune CSU, also known as autoallergic CSU (aaCSU).1, 2 Expression of tissue transglutaminase 2 (TG2), the autoantigen in celiac disease, was demonstrated to be increased in lesional skin mast cells of CSU patients.3 Furthermore, serum TG2 activity has been proposed as a potential biomarker of CSU severity and response to treatment with omalizumab.4 Here, we assessed the levels of IgE directed against TG2 (IgE-anti-TG2) in CSU patients and the correlation of IgE-anti-TG2 with clinical and serological features of CSU. We used a human IgE capture ELISA to quantify IgE-anti-TG2 levels in 160 CSU patients and 54 healthy control subjects. We compared CSU patients with high and low serum levels of IgE-anti-TG2 for differences in clinical features and laboratory markers (Table 1). The methodology including statistical tests is described in File S1. Overall, CSU patients had significantly higher IgE-anti-TG2 serum levels as compared to healthy control subjects (Figure 1). Using a cut-off value of 77.7 AU, as determined by the 95th percentile of respective levels in sera of control subjects, 33 of 160 CSU patients (20.6%) had elevated IgE-anti-TG2 levels (median: 144.6 AU), whereas 79.4% had normal levels (median 7.0 AU, Figure 1). Elevated IgE-anti-TG2 levels were not linked to any demographic, clinical and laboratory features of CSU including the presence of additional, previously described aaCSU-related autoreactive IgE, that is, IgE-anti-TPO and IgE-anti-IL-24 (Table 1 and Table S1). TG2 and TG3 belong to a family of structurally and functionally related enzymes involved in post-translational modifications of proteins. TG2 along with TG3 are major autoantigens in celiac disease and dermatitis herpetiformis and are associated with the production of TG-targeting IgA autoantibodies.5 Furthermore, TG3 is an autoallergen actively involved in skin inflammation in patients with atopic dermatitis, with higher levels of IgE-anti-TG3 as compared to healthy controls that correlate with disease activity.6 The rate of CSU patients with elevated levels of IgE-anti-TG2, that is, 21%, is lower than the rates previously reported for IgE-anti-IL-24 (80%)2 and IgE-anti-TPO (54%–61%).1 Future studies should assess the levels of IgE and IgG autoantibodies to all three antigens in the same patient population, ideally in a multicenter approach. Interestingly, the presence of IgE-anti-TG2 was not linked to elevated levels of IgE-anti-IL-24 or IgE-anti-TPO, suggesting that different subpopulations of autoallergic CSU patients exhibit distinct profiles of autoallergens targeted by their IgE. Functional assays have to be performed to confirm that TG2 and IgE-anti-TG2 can activate and degranulate human skin mast cells. Recently, mast cells have been shown to release TG2, leading to enhanced IgE production in B cells by up-regulating CD40L expression.3, 4 This suggests autocrine activation of mast cells by TG2-IgE-anti-TG2 crosslinking of FcεRI. Furthermore, further research should assess CSU patients' levels of IgE-anti-TG3, which were shown to be increased in patients. Additional studies are needed to compare levels of IgE-anti-TG2 in different responders to omalizumab (fast, slow, non-responders) both at baseline and during follow-up. Finally, CSU patients are shown to have an increased risk of celiac disease and vice versa, and further studies should clarify whether the presence of IgE-anti-TG2 is associated with this risk. In summary, a distinct and sizeable subpopulation of CSU patients shows increased IgE-anti-TG2 levels. The role of IgE-anti-TG2 and TG2 in the pathogenesis of CSU pathogenesis as well as their clinical relevance should be evaluated in further studies. Conceived and designed the experiments: Huichun Su, Scheffel Jörg, Xu Yao, and Sabine Altrichter; Performed the experiments: Huichun Su; Analyzed the data: Pavel Kolkhir, Huichun, Su; Wrote the paper: Huichun Su, Sabine Altrichter, Pavel Kolkhir, Marcus Maurer. Data for IgE anti-TPO, IgG anti-TPO, and IgE anti-IL-24: Yi-Kui Xiang; Statistical analysis: Pavel Kolkhir, Huichun Su. Natural Science Foundation of Fujian Province (2019 J01060945), Intramural funds of Fujian Medical University Union Hospital (2021XH026). Huichun Su: No conflicts of interest regarding any aspects of this study. Pavel Kolkhir: No conflicts of interest regarding any aspects of this study. Jörg Scheffel: No conflicts of interest regarding any aspects of this study. Yi-Kui Xiang: No conflicts of interest regarding any aspects of this study. Xu Yao: No conflicts of interest regarding any aspects of this study. MM is or recently was a speaker and/or advisor for and/or has received research funding from Allakos, Aralez, Genentech, GSK, Menarini, Merckle Recordati, Moxie, Novartis, Sanofi, MSD, and Uriach. SA is or recently was a speaker and/or advisor for and/or has received research funding from AstraZeneca, Allakos, CSL Behring, Sanofi, Takeda, ThermoFisher, Moxie, and Novartis. Open Access funding enabled and organized by Projekt DEAL. Data S1. Table S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.