Beyond immunoglobulin E (IgE): Novel roles of mas-related G protein-coupled receptor X2 (MRGPRX2) and protease-activated receptor 2 (PAR2) as nonhistaminergic pruriceptors in chronic spontaneous urticaria.

Background

Mas-related G protein-coupled receptor X2 (MRGPRX2) and protease-activated receptor 2 (PAR2), are the main markers of nonhistaminergic pruriceptors. Elevated circulating MRGPRX2 levels have been reported in severe chronic spontaneous urticaria (CSU), whereas the role of serum PAR2 remains unclear.

Objective

This study aimed to determine the differences in serum MRGPRX2 and PAR2 levels between patients with CSU and normal healthy controls (NC), and to evaluate their associations with disease severity and utility as biomarkers in CSU.

Methods

The patients were stratified by the urticaria activity score over 7 days (UAS7) into three groups: severe (UAS7 ≥ 28), moderate (16 ≤ UAS7 < 28), and mild (UAS7 < 16). Serum samples from 60 patients with CSU and 30 NCs were screened for MRGPRX2 and PAR2 by using enzyme-linked immunosorbent assay.

Results

The serum MRGPRX2 level was higher in the severe CSU group (0.31 ± 0.12 ng/mL) than in NCs (0.19 ± 0.11 ng/mL) (p < 0.001) and in patients with mild-to-moderate CSU (0.24 ± 0.08 ng/mL) (p = 0.019). Similarly, the serum PAR2 level was also significantly higher in patients with severe CSU (0.38 [0.21-0.53] ng/mL) compared with NCs (0.21 [0.11-0.27] ng/mL) (p < 0.001) and with patients with mild-to-moderate CSU (0.20 [0.15-0.27] ng/mL) (p < 0 .001). Both MRGPRX2 and PAR2 showed positive correlations with UAS7. PAR2 was negatively correlated with the basophil percentage, whereas MRGPRX2 showed no correlation with the basophil percentage. Logistic regression analysis identified serum MRGPRX2 levels ≥ 0.2375 ng/mL (odds ratio 2.498; p = 0.002) and serum PAR2 levels ≥ 0.12 ng/mL (odds ratio 1.901; p = 0.043) as two independent risk factors for CSU. In addition, serum PAR2 levels ≥ 0.271 ng/mL (odds ratio 3.317; p = 0.002) were identified as an independent risk factor for severe CSU.

Conclusion

We suggest that serum MRGPRX2 and PAR2 are both biomarkers of disease severity and independent risk factors for CSU.