原標(biāo)題：非IgE介導(dǎo)的過(guò)敏反應(yīng)
　　速發(fā)型過(guò)敏反應(yīng)的定義是一種嚴(yán)重的、危及生命的、迅速發(fā)展的、廣泛或全身性的超敏反應(yīng)。典型的臨床癥狀包括支氣管收縮、血管擴(kuò)張、低血容量，可導(dǎo)致呼吸功能不全、休克和死亡。當(dāng)反應(yīng)是由免疫機(jī)制(IgE、IgG和補(bǔ)體相關(guān)的免疫復(fù)合物)介導(dǎo)時(shí)，被稱為過(guò)敏反應(yīng)。根據(jù)IgE的參與情況，反應(yīng)又可分為IgE介導(dǎo)反應(yīng)和非IgE介導(dǎo)反應(yīng)。典型的臨床癥狀包括支氣管收縮、血管擴(kuò)張和低血容量(單獨(dú)或聯(lián)合使用)，可導(dǎo)致呼吸功能不全、休克和死亡。兒童過(guò)敏反應(yīng)的最主要原因是食物，而成人過(guò)敏反應(yīng)的主要原因是藥物，特別是抗生素、神經(jīng)肌肉阻斷劑(NMBA)、非甾體類抗炎藥(NSAID)、造影劑和生物制劑。由IgE抗體介導(dǎo)的過(guò)敏反應(yīng)的典型例子是花生誘導(dǎo)的食物過(guò)敏反應(yīng)，它可被稱為IgE介導(dǎo)的過(guò)敏反應(yīng)。這種過(guò)敏反應(yīng)通常被認(rèn)為是由于T細(xì)胞識(shí)別抗原并啟動(dòng)Th2型反應(yīng)后，B細(xì)胞產(chǎn)生IgE抗體。
　　IgE介導(dǎo)通路由過(guò)敏原啟動(dòng)，當(dāng)過(guò)敏原與特異性IgE抗體結(jié)合時(shí)，導(dǎo)致肥大細(xì)胞(MC)和嗜堿性細(xì)胞上的高親和性IgE受體(FcεRI)發(fā)生交聯(lián)并啟動(dòng)信號(hào)級(jí)聯(lián)，釋放包括組胺在內(nèi)的介質(zhì)，以及預(yù)形成的細(xì)胞因子和蛋白酶，以及合成和分泌額外的細(xì)胞因子和脂質(zhì)介質(zhì)，如血小板激活因子(PAF)、白三烯和前列腺素。典型的過(guò)敏反應(yīng)途徑是適應(yīng)性免疫的一個(gè)例子。對(duì)過(guò)敏原過(guò)敏反應(yīng)的臨床診斷是基于這種IgE范式的。當(dāng)使用免疫調(diào)節(jié)治療(如免疫療法或抗IgE)時(shí)，對(duì)特定過(guò)敏原的IgE水平高與疾病嚴(yán)重或持續(xù)時(shí)間長(zhǎng)有關(guān)，也與治療失敗有關(guān)。然而，有相當(dāng)一部分經(jīng)歷過(guò)過(guò)敏反應(yīng)的患者并沒(méi)有出現(xiàn)IgE依賴性免疫激活的任何證據(jù)。在這些患者中，沒(méi)有跡象表明IgE介導(dǎo)的MC或嗜堿性粒細(xì)胞激活，如皮膚試驗(yàn)陽(yáng)性結(jié)果、存在過(guò)敏原特異性IgE或組胺升高。在一些患者中，根本沒(méi)有MC激活的證據(jù)，例如，他們有正常的胰蛋白酶。所有這些數(shù)據(jù)表明存在其他潛在的機(jī)制。
　　事實(shí)上，在缺乏IgE的情況下，小鼠模型仍可發(fā)生過(guò)敏反應(yīng)，獨(dú)立于IgE的MC/嗜堿性粒細(xì)胞和非MC/嗜堿性粒細(xì)胞通路在小鼠模型中均有描述，肥大細(xì)胞通常被認(rèn)為是驅(qū)動(dòng)過(guò)敏反應(yīng)的最重要的細(xì)胞類型。根據(jù)它們分泌顆粒中不同蛋白酶的表達(dá)情況，可將它們分為兩類。在人類中，類胰蛋白酶和糜酶表達(dá)的MC存在于結(jié)締組織(即皮膚)中，并含有各種蛋白酶，如類胰蛋白酶、糜酶、羧肽酶和組織蛋白酶。相比起來(lái)，表達(dá)胰蛋白酶的MC存在于肺和腸道中，并且只表達(dá)類胰蛋白酶。所有MC均可通過(guò)高親和力IgE受體(FcεRI)交聯(lián)激活；然而，盡管這似乎是與過(guò)敏和過(guò)敏性疾病相關(guān)的體征和癥狀的主要原因，但它可能在內(nèi)源性刺激激活促進(jìn)血管止血、疼痛、瘙癢和宿主防御過(guò)程中，在MC的生理激活中并沒(méi)有發(fā)揮主要作用，特別是表達(dá)類胰蛋白酶和糜酶的MC(也被稱為MCTC)。在后一種機(jī)制中，胰蛋白酶和糜酶表達(dá)的MC對(duì)補(bǔ)體的補(bǔ)體成分片段(補(bǔ)體片段3a [C3a]和補(bǔ)體片段5a [C5a])和48/80(一種能模擬體外對(duì)MC補(bǔ)體活性的化合物)做出反應(yīng)，但內(nèi)源性和/或天然的外源性配體仍然未知。其他機(jī)制包括通過(guò)大量G蛋白偶聯(lián)受體(GPCRs)激活，G蛋白偶聯(lián)受體是最大的膜受體蛋白群，也是藥物治療最常見(jiàn)的靶點(diǎn)，MC在其表面表達(dá)許多G蛋白偶聯(lián)受體。在這些受體中，其中一個(gè)特別有趣的是與質(zhì)粒相關(guān)的G蛋白偶聯(lián)受體X2 (MRGPRX2，以前稱為MrgX2)，它在MC的質(zhì)膜和細(xì)胞內(nèi)位點(diǎn)選擇性表達(dá)，并被抗菌宿主防御肽、神經(jīng)肽、主要堿性蛋白、嗜酸性過(guò)氧化物酶、以及許多FDA批準(zhǔn)的肽類藥物激活。這種導(dǎo)致人類過(guò)敏反應(yīng)的替代機(jī)制的存在并不是確定的，即使一些臨床觀察可能指向這個(gè)方向。例如，在人類的罕見(jiàn)臨床觀察表明，過(guò)敏反應(yīng)不僅發(fā)生于IgE/肥大細(xì)胞/嗜堿性細(xì)胞軸，而且還發(fā)生于通過(guò)各種機(jī)制激活的中性粒細(xì)胞、血小板、內(nèi)皮細(xì)胞，如補(bǔ)體激活、神經(jīng)肽釋放、IC形成、細(xì)胞毒性和IgG依賴性反應(yīng)，以及尚不完全清楚的與嘌呤代謝有關(guān)的機(jī)制。
　　同樣，抗IgE在非IgE介導(dǎo)的疾病中的有效性表明，IgE可能涉及經(jīng)典的IgE/過(guò)敏原機(jī)制之外的機(jī)制，這些可供選擇的途徑,以及非IgE介導(dǎo)經(jīng)典模式中激活肥大細(xì)胞和嗜堿性細(xì)胞的分子可能決定過(guò)敏反應(yīng)的嚴(yán)重程度，可以幫助我們理解為什么過(guò)敏反應(yīng)的嚴(yán)重程度差別很大，盡管IgE通路的激活程度相似。
　　在這篇文章中，我們將回顧在沒(méi)有特異性IgE/過(guò)敏原激活的情況下可能導(dǎo)致過(guò)敏反應(yīng)的途徑，以及那些完全獨(dú)立于MC和嗜堿性粒細(xì)胞的途徑。


延伸閱讀
JACI
Non–IgE-mediated anaphylaxis
https://doi.org/10.1016/j.jaci.2021.02.012

Abstract:
Anaphylaxis is defined as a severe, life-threatening, rapidly evolving, generalized or systemic hypersensitivity reaction.Typical clinical signs include bronchoconstriction, vasodilatation, and hypovolemia, which can lead to respiratory insufficiency, shock, and death.3 The term allergic anaphylaxis is used when the reaction is mediated by an immunologic mechanism (IgE, IgG, and immune complex [IC] complement-related). Based on the involvement of IgE is the reaction then subclassified into IgE-mediated and not IgE-mediated reaction.

Typical clinical signs include bronchoconstriction, vasodilatation, and hypovolemia (alone or in combination), which can lead to respiratory insufficiency, shock, and death. The most prominent cause of anaphylaxis in children is food, whereas in adults it is drugs, especially antibiotics, neuromuscular-blocking agents (NMBAs), nonsteroidal anti-inflammatory drugs (NSAIDs), contrast medium, and biologics.

The classical example of an anaphylactic reaction mediated by IgE antibodies is peanut-induced food anaphylaxis, and it may be referred to as IgE-mediated allergic anaphylaxis. Such anaphylaxis is classically considered to be due to the production of IgE antibodies from B cells after T cells have recognized the antigen and initiated a TH2-type response. 

The IgE-mediated pathway is initiated by an allergen that, when bound to specific IgE antibodies, generates a cross-linking of the high-affinity IgE receptor (FcεRI) on mast cells (MCs) and basophils and initiates a signaling cascade that produces the release of mediators, including histamine, as well as preformed cytokines and proteases, and the synthesis and secretion of additional cytokines as well as lipid mediators, such as platelet-activating factor (PAF), leukotrienes, and prostaglandins. The classical anaphylaxis pathway is an example of adaptive immunity. The clinical diagnosis of anaphylaxis to an allergen is based on this IgE paradigm. Higher levels of IgE to a specific allergen are associated with more severe/persistent disease and treatment failure when using immunomodulatory treatments such as immunotherapy or anti-IgE.

However, a considerable percentage of patients who experience anaphylaxis do not present with any evidence of IgE-dependent immune activation. In these patients, there are no signs of IgE-mediated activation of MCs or basophils as suggested by a positive skin test result, presence of allergen-specific IgE, or elevated histamine. In some patients, there is no evidence of MC activation at all; for example, they have normal tryptase. All together these data suggest the existence of other potential mechanisms.

Indeed, in the absence of IgE, anaphylaxis can still develop in mouse models.

IgE-independent MC/basophil, as well as non-MC/basophil, pathways have been described in mouse models (Fig 1).

MCs are generally considered the most important cell type in driving anaphylactic reactions. They are classified into 2 types on the basis of expression of different proteases in their secretory granules.14 In humans, tryptase and chymase-expressing MCs are found in connective tissue (ie, the skin) and contain various proteases such as tryptase, chymase, carboxypeptidase, and cathepsin. In contrast, tryptase-expressing MCs are found in the lung and gut and express only tryptase.14 All MCs can be activated through the cross-linking of high-affinity IgE receptors (FcεRI); however, even if this appears to be the major contributor to the signs and symptoms associated with hypersensitive and allergic diseases, it likely does not play a major role in the physiological activation of MCs, especially tryptase and chymase-expressing MCs (also known as MCTC), during endogenous stimuli activation to promote vascular hemostasis, pain, itch, and host defense.

In the latter mechanism, tryptase and chymase-expressing MCs respond to complement component fragments of the complement (complement fragment 3a [C3a] and complement fragment 5a [C5a]) and 48/80 (a compound that can mimic in vitro complement activity on MCs), but the endogenous and/or natural exogenous ligands remain unknown (Fig 2). Other mechanisms involve activation through numerous G protein–coupled receptors (GPCRs), the largest group of membrane receptor proteins, and the most common targets of drug therapy and MCs express many of them on their surfaces. 

Among these receptors, the one of particular interest is Mas-related G protein–coupled receptor X2 (MRGPRX2, formerly known as MrgX2), which is expressed selectively in MCs in their plasma membrane and intracellular sites and is activated by antimicrobial host defense peptides, neuropeptides, major basic proteins, eosinophil peroxidase, and many US Food and Drug Administration–approved peptidergic drugs.14

The existence of such alternative mechanism to cause anaphylaxis in humans is not definitive, even if some clinical observation may point toward that direction.

For example, rare clinical observations in humans suggest that anaphylaxis arises not only following the IgE/mast cell/basophil axis but also from neutrophils, platelets, endothelial cells activated via various mechanisms such as complement activation, neuropeptide release, IC formation, cytotoxicity, and IgG-dependent reactions, and the involvement of purinergic metabolism with mechanisms not yet fully understood. 

Similarly, the effectiveness of anti-IgE in non–IgE-mediated diseases may indicate that IgE may be implicated beyond the classical IgE/allergen mechanism.15 These alternative pathways, as well as those molecules that activate MCs and basophils in a non–IgE-mediated classic fashion, may contribute to the intensity of anaphylactic reactions and may help us to understand why the severity of the anaphylaxis varies widely, despite similar degrees of activation of the IgE pathway.

In this article, we will review pathways that may lead to anaphylaxis in the absence of specific IgE/allergen activation, as well as those independent of MCs and basophils   altogether. 

Author:
Antonella Cianferoni
2021-5-11  Review
　　創(chuàng)建過(guò)敏性疾病的科研、科普知識(shí)交流平臺(tái)，為過(guò)敏患者提供專業(yè)診斷、治療、預(yù)防的共享平臺(tái)。