Anaphylaxis: Focus on Transcription Factor Activity

Abstract

Anaphylaxis is a severe allergic reaction, rapid in onset, and can lead to fatal consequences if not promptly treated. The incidence of anaphylaxis has risen at an alarming rate in past decades and continues to rise. Therefore, there is a general interest in understanding the molecular mechanism that leads to an exacerbated response. The main effector cells are mast cells, commonly triggered by stimuli that involve the IgE-dependent or IgE-independent pathway. These signaling pathways converge in the release of proinflammatory mediators, such as histamine, tryptases, prostaglandins, etc., in minutes. The action and cell targets of these proinflammatory mediators are linked to the pathophysiologic consequences observed in this severe allergic reaction. While many molecules are involved in cellular regulation, the expression and regulation of transcription factors involved in the synthesis of proinflammatory mediators and secretory granule homeostasis are of special interest, due to their ability to control gene expression and change phenotype, and they may be key in the severity of the entire reaction. In this review, we will describe our current understanding of the pathophysiology of human anaphylaxis, focusing on the transcription factors' contributions to this systemic hypersensitivity reaction. Host mutation in transcription factor expression, or deregulation of their activity in an anaphylaxis context, will be updated. So far, the risk of anaphylaxis is unpredictable thus, increasing our knowledge of the molecular mechanism that leads and regulates mast cell activity will enable us to improve our understanding of how anaphylaxis can be prevented or treated.

Keywords: Mast cells; anaphylaxis; proinflammatory mediators; transcription factors.

Figure 1

GATA, STAT, and MITF family in anaphylaxis. (A) GATA family plays a central role in mast cell activity. GATA2 is key for mast cell activity. FcεRIα, FcεRIβ, and KIT expression is regulated by GATA2, while FcεRIα is also controlled by GATA1 [52,53]. GATA1 regulates Il-4 production in basophils [50]. GATA1 and GATA2 regulate tryptases (including mTMT, mMCP6, and mMCP7). Furthermore, GATA2 regulates histamine and proteases (Cpa3, Mcpt4, Mcpt8, Cma1) synthesis [27,54]. GATA3 defines a Tfh13 population involved in anaphylactic IgE production [59]. (B) STAT family is downstream of key receptors and controls mast cell activity. STAT3 increases IgE-dependent degranulation in a canonical and non-canonical pathways increasing ATP production in mitochondria [74]. STAT5 is downstream of KIT D816V in mastocytosis, it increases cell survival, degranulation, leukotriene synthesis and stabilizes IL-13, IL-4, and TNFα mRNA [92,93]. Thymic stromal lymphopoietin (TSLP) binding to MRGPRX2 increases STAT5 activity [94]. (C) IgE-LysRS-MITF axis in anaphylaxis. MITF is downstream of KIT and IgE signaling [114,118]. MITF and KIT are reciprocally regulated [114,115]. Upon IgE-Ag, LysRS is phosphorylated by the MAP kinase pathway and translocated into the nucleus. LysRS activity in the nucleus dissociated MITF–HINT complex, inducing MITF transcriptional activities [118]. TFE3 is important for IgE–dependent pathway anaphylaxis by regulating FcεRI and KIT receptor expression [120]. TFEB is a master transcription factor for mast cell granule [81,82].

Figure 2

Host factors or mutations related to transcription factors in anaphylaxis. (A) Loss of GATA2 function in human subjects result in lower KIT and FcεRI expression and IgE-dependent degranulation impaired [53]. GATA3 is essential for Tfh13 cell production, which regulates B cells to produce anaphylactic IgE [59]. (B) Loss of STAT3 function in autosomal dominant-hyper IgE syndrome (AD-HIES) shows a decrease in anaphylaxis compared to normal STAT3 activity [77].(C) LysRS P542R induces a conformational change in LysRS allowing translocation into the nucleus, activating MITF, and relative targets genes in the absence of stimuli (quiescent cells). Eventually, the allergen encounter leads to anaphylaxis [141].