The expression of the mast cell receptor Mas-related G protein–coupled receptor X2 (MRGPRX2) appears to be increased in indolent systemic mastocytosis (SM) lesions; however, it has not been associated with symptom severity, according to a recently published study in Frontiers in Immunology

There is currently no curative treatment for indolent SM; available therapies such as nonselective tyrosine kinase inhibitors and cytoreductive therapies are not effective in all patients and can cause severe adverse effects. Therefore, there is a great interest in new therapeutic targets that could help improve the quality of life of patients with indolent SM.

MRGPRX2 is a multiligand receptor involved in immunoglobulin E (IgE)-independent mast cell activation that is known to respond to many triggers, such as quinolone antibiotics and insect venom. It has been reported to be overexpressed in maculopapular cutaneous mastocytosis; nonetheless, its role in indolent SM remains unclear. 

“IgE-independent MC activation could lead to clinically relevant reactions, particularly associated with drug intolerance, via the Mas-related G protein–coupled receptor X2 (MRGPRX2) on MCs,” the authors wrote. 

Read more about SM etiology

The authors used immunohistochemistry techniques to assess MRGPRX2 expression in lesional and nonlesional skin in 22 patients with indolent SM, and compared the results with those of a healthy control group. Levels of cortistatin and major basic protein (MBP), both known MRGPRX2 ligands, were also assessed. 

Immunohistochemistry revealed that MRGPRX2 expression was significantly higher in lesional skin than in nonlesional skin in patients with indolent SM. MRGPRX2 was almost undetectable in the cell membranes of healthy controls. Both cortistatin and major basic protein were higher in lesional skin in SM patients. However, differences in cortistatin did not reach statistical significance. 

The authors also aimed to correlate MRGPRX2 expression with clinical features such as evidence of anaphylaxis and/or osteopenia/osteoporosis and the severity of mastocytosis in the skin, among others. However, no correlation was found between MRGPRX2 and the aforementioned variables, suggesting that MRGPRX2 expression might not be linked to symptom severity. 

“Whether other factors, such as a combination of different MRGPRX2 agonists, synergy with the FcεRI-dependent pathway, or MRGPRX2 genetic alterations, are being involved in [mast cell] activation in patients with [indolent SM] is yet unknown,” the authors concluded. 


Pyatilova P, Ashry T, Luo Y, et al. The number of MRGPRX2-expressing cells is increased in skin lesions of patients with indolent systemic mastocytosis, but is not linked to symptom severity. Front Immunol. 2022;13:930945. doi:10.3389/fimmu.2022.930945