IgE mediated autoallergy against thyroid peroxidase--a novel pathomechanism of chronic spontaneous urticaria?

Abstract

Background: Chronic spontaneous urticaria (csU), which is characterized by recurrent episodes of mast cell-driven wheal and flare-type skin reactions, is often associated with elevated total IgE levels and thyroid autoimmunity. We speculate that some csU patients express IgE autoantibodies against thyroid antigens such as thyroid peroxidase (TPO), which could bind to skin mast cells and induce their activation.

Methods: We developed and used a site-directed human IgE capture ELISA to quantify IgE-anti-TPO. We used this assay and investigated csU patients (n = 478) and healthy control subjects (n = 127) for IgE-anti-TPO and then assessed IgE-anti-TPO-positive and -negative csU patients for clinical and serological differences.

Principal findings: CsU patients were found to express more than 2fold higher IgE-anti-TPO serum levels as compared to healthy control subjects (p<0.001). 54% of csU patients had serum levels higher than the cut off ( = 5 IU/ml). By distribution analyses we identified two distinct subpopulations of csU patients: 1) IgE-anti-TPO(low) ( = 39%, IgE-anti-TPO: median 2.17 interquartile range 0.86-5.44, = comparable to healthy controls) and 2) IgE-anti-TPO(high) ( = 61%, IgE-anti-TPO: median 6.67, interquartile range 5.39-8.24). IgE-anti-TPO-positive and -negative csU patients had very similar distributions of age and gender as well as disease activity and duration. IgE-anti-TPO-positive csU patients exhibited significantly higher IgG-anti-TPO levels and lymphocyte counts as well as decreased C4 complement levels.

Conclusion: Our findings show that a sizeable subgroup of csU patients expresses IgE antibodies against thyroid peroxidase. These autoantibodies could cause "autoallergic" mast cell activation, a novel pathomechanism of chronic spontaneous urticaria.

Figure 1. Patients with chronic spontaneous urticaria exhibit elevated levels of IgE-anti-TPO.

Fig. 1a Box-Plot: Healthy persons (n = 127) exhibit in the mean IgE-anti-TPO levels of 2.58 IU/ml±2.46, 1st quartile 0.27– median 1.46– 3rd quartile 4.45 (median 1.46, IQR 0.27–4.45 IU/ml). Highest value among the healthy persons was 7.8 IU/ml. CU patients (n = 478) show elevated mean levels of 5.69 IU/ml±3.17, 1st quartile 3.2– median 5.5– 3rd quartile 7.73, (median 5.50, IQR 3.2–7.7 IU/ml), highest value 18.0 IU/ml. The differences between the two groups are statistical significant (p<0.001). Figure 1b ROC-Curve: Diagnostic accuracy for the distinction of CU patients and healthy controls was analysed by ROC curve including selected pairs of sensitivity and specificity (Table 1), the area under the curve (AUROC = 0.78) and the confidence limits for this curve (CI = 0.74–0.83). The selected specificity of 0.8 and the resulting sensitivity of 0.55 are displayed as dotted line in the graph.

Figure 2. CU Patients can be divided into IgE-anti-TPO^high and IgE-anti-TPO^low subgroups.

Figure 2a Density Estimation: CU patients (full line) and healthy controls (dotted line) were clearly different regarding their IgE-anti-TPO levels. CU patients can be subdivided in two subgroups, one similar to the healthy controls and the other one above the indicated cut off level of 5 IU/ml. Figure 2b Theoretical ROC-Curve: The theoretical ROC-Curve shows the result of the applied method of mixed distribution to identify subgroups within the patients' sample. This analysis was motivated by the hypothesis that only for a subtype of the disease IgE is involved in the pathological pathway. For the resulting normal distribution of the second subpopulation with elevated IgE-anti-TPO (IgE-anti-TPO^high) values the theoretical ROC curve is displayed.