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.

AUTHOR CONTRIBUTIONS

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.

FUNDING INFORMATION

Natural Science Foundation of Fujian Province (2019J01310), Intramural funds of Fujian Medical University Union Hospital (2021XH026).

CONFLICT OF INTEREST STATEMENT

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.