Mechanisms of histamine release from mast cells beyond the high affinity IgE receptor in severe chronic spontaneous urticaria

There is growing evidence suggesting that in a subset of patients with severe chronic urticaria (CSU) mast cells are activated via mechanisms that bypass the high affinity IgE receptor. This might explain why some patients do not respond at all to anti-IgE therapy (omalizumab). The present article reviews the pathogenic mechanisms able to lead to histamine release from mast cells described so far in patients with CSU. These include the activation of the coagulation cascade, the activation of the complement system, the activation of the MRGPRX2 receptor, and the platelet activating factor vicious circle. The article suggests some possible interpretations for the clinical events occurring in this specific subset of patients.