Basophils activation of patients with chronic spontaneous urticaria in response to C5a despite failure to respond to IgE-mediated stimuli

Abstract

Urticaria is characterized by the occurrence of wheals and flares in response to vasoactive mediators, such as histamine. Various studies have suggested the involvement of basophils in the pathogenesis of chronic spontaneous urticaria (CSU). However, histamine release from peripheral basophils in response to stimuli acting on the high affinity IgE receptor (FcϵRI) is impaired in many patients with CSU (non/low responders). We previously demonstrated that tissue factor (TF)s expressed on vascular endothelial cells in response to a combination of various stimuli, such as that of histamine and lipopolysaccharide (LPS), activates the extrinsic coagulation pathway and produces anaphylatoxin, complement 5a (C5a), which then activates basophils and mast cells via the C5a receptor (C5aR). We have revealed that histamine release was induced in response to C5a and formyl-l-methionyl-l-leucyl-l-phenylalanine (fMLP), regardless of the response to anti-IgE antibody, the reduced numbers of basophils and severity of urticaria. Moreover, we found that spontaneous release of histamine ex vivo from basophils of patients with CSU is higher than that from healthy individuals. These results suggest that basophils and the complement system, which could be activated by coagulation factors, may play a critical role in the pathogenesis of CSU, especially in cases refractory to treatment involving the IgE/FcϵRI pathway.

Basophils in pruritic skin diseases

“…Basophils of CSU patients exhibited significantly higher amounts of CD63, than those of healthy controls. CD203c expression however was unchanged (88). In contrast, another study revealed no difference of activation marker levels in CSU patients in comparison with healthy subjects.…”

“…In contrast, another study revealed no difference of activation marker levels in CSU patients in comparison with healthy subjects. However, histamine release was reported to be higher in patients with CSU than in controls ( 89 ). In CSU patients in remission, basophils were more activated, as determined through the presence of CD63 and CD203c, than in healthy control ( 90 ).…”

Basophil Characteristics as a Marker of the Pathogenesis of Chronic Spontaneous Urticaria in Relation to the Coagulation and Complement Systems

“…Several basophil characteristics and their behavior in CSU patients are summarized in Table 1 . In a group of patients, the concentration of histamine in the plasma of patients with CSU was significantly higher than that of healthy controls ( Table 1 ) [ 31 ]. Moreover, spontaneous histamine release from basophils without stimulation in patients with CSU was increased, compared to that in healthy donors ( Table 1 ) [ 31 , 32 ].…”

“…In a group of patients, the concentration of histamine in the plasma of patients with CSU was significantly higher than that of healthy controls ( Table 1 ) [ 31 ]. Moreover, spontaneous histamine release from basophils without stimulation in patients with CSU was increased, compared to that in healthy donors ( Table 1 ) [ 31 , 32 ]. Nevertheless, the degree of spontaneous release of histamine was not correlated with total amount of histamine in the whole blood of patients with CSU [ 31 ], suggesting that the percent release of histamine from individual basophils of patients with CSU is higher than that of healthy control.…”

“…Moreover, spontaneous histamine release from basophils without stimulation in patients with CSU was increased, compared to that in healthy donors ( Table 1 ) [ 31 , 32 ]. Nevertheless, the degree of spontaneous release of histamine was not correlated with total amount of histamine in the whole blood of patients with CSU [ 31 ], suggesting that the percent release of histamine from individual basophils of patients with CSU is higher than that of healthy control. Levels of IgE antibodies in serum are also increased in patients with CSU ( Table 1 ) [ 32 , 33 ].…”