This would not be accompanied by the typical signs of degranulation like rash and pruritus, but a closer look at mast cell, and MRGPRX2, involvement in these delayed and long-lived side effects might be justified

This would not be accompanied by the typical signs of degranulation like rash and pruritus, but a closer look at mast cell, and MRGPRX2, involvement in these delayed and long-lived side effects might be justified. Discussion A question that is raised repeatedly in the literature is whether MRGPRX2 activation is capable of triggering anaphylaxis. for several drugs shown to have MRGPRX2 agonist activity. Surprisingly, the analysis shows that mild-to-moderate events are far more common than currently appreciated. A comparison with plasma drug levels suggests that MRGPRX2 mediates many of these mild-to-moderate events. For some of these drugs, then, MRGPRX2 activation may be considered a regular and predictable feature after administration of high doses. MRGPRX2-Mediated Mast Cell Activation A pressing issue in the field is how to determine whether mast cell activation is mediated by IgE or MRGPRX2 when a patient has suffered an allergic-type event due to a drug that is an MRGPRX2 agonist. These drugs also may be immunogenic, so simply exhibiting MRGPRX2 agonism does not rule out IgE. Technically, distinguishing between these is not yet possible because there are no biomarkers that reliably identify or exclude one or the other mechanism, such as a mediator only released after stimulation of one but not the other receptor. However, specific measurements can be made that support the involvement of each pathway. MRGPRX2 Involvement MRGPRX2 should be suspected if an event is observed at concentrations high enough to activate the receptor, and resolves when the concentration drops below this. As described in detail in th next section, the drug concentrations needed to activate MRGPRX2 are very high and GW 441756 only achieved transiently for most drugs. Many allergic-type reactions also are very transient and only occur at very high drug concentrations. In contrast, there is a widespread assumption that IgE-mediated mast cell activation occurs even at very low concentrations of an antigen C for example, food allergies only require miniscule amounts of food- though this is not proven for every allergy. Another factor is that mediator release after IgE-driven mast cell activation persists for much longer than after antibody-independent mast cell stimulation (20), so events that are short-lived are less likely to be IgE-driven, especially if they only occur at high drug concentrations and disappear when plasma or tissue concentrations drop below EC50 values for MRGPRX2. EC50 values for MRGPRX2 can be used to determine whether plasma or tissue drug concentrations are high enough to activate the receptor. However, several additional factors should be considered when evaluating these. First, Klf2 plasma concentration measurements may not reflect concentrations in some tissues; specific examples are discussed in the fluoroquinolones and neuromuscular blocking drug sections. Second, EC50 values must be taken in context, as caveats exist. The values were calculated for the most common MRGPRX2 variant, but dozens of others with slightly different amino acid compositions, due to natural variations in the coding DNA, have been identified (21, 22). These sometimes have altered properties; most of the ones characterized are loss-of-function, but ones with enhanced signaling have also been reported (23, 24). It is quite possible that alleles that respond to much lower drug concentrations are expressed by some patients, and if so, EC50 values for those variants should be used instead. Also, MRGPRX2 expression levels vary tremendously between subjects (25), and those GW 441756 with abnormally high expression may also respond to low drug concentrations, even when the canonical receptor variant is expressed. Another consideration is that EC50 values usually are calculated in cell lines, not in primary cells. Finally, concurrent illnesses may either enhance or reduce mast cell responsiveness, or how tissues respond to mast cell mediators. An GW 441756 example is provided below in the vancomycin section, in which bacterial infections appear to dramatically reduce systemic mast cell responses. On the other hand, patients with chronic spontaneous urticaria appear to have much stronger responses to MRGPRX2 agonists (26). This is an emerging topic and more research needs to be performed, but it is clear that comorbidities can have a profound influence on allergic-type reactions. IgE Involvement IgE-mediated GW 441756 mast cell activation should be suspected when events occur at GW 441756 low drug concentrations, when the events are of.

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