Transferring allergies in the womb

doi:10.1126/science.abe8283

GSTDTAP > 气候变化

DOI	10.1126/science.abe8283
	Transferring allergies in the womb
	Marc E. Rothenberg
	2020-11-20
发表期刊	Science
出版年	2020
英文摘要	Allergic diseases, which affect 10 to 30% of the global population, have a high degree of heritability contributed by a combination of parental factors ([ 1 ][1]). In addition to genetics, such parental factors include the amount of maternal immunoglobulin E (IgE), the antibody type that binds to allergens, which directly correlates with the risk of allergy in offspring ([ 2 ][2]). On page 941 of this issue, Msallam et al . ([ 3 ][3]) delve into the relationship of maternal IgE and fetal mast cells in mice and humans, demonstrating that IgE crosses the placenta and binds to fetal mast cells, and relate this to the subsequent development of allergic responses in offspring. Mast cells reside in various tissues near mucosal interfaces, blood vessels, and nerve fibers. They serve as cellular guards, sensing a variety of chemical, pathogenic, and biophysical triggers, and subsequently release pleiotropic molecules that contribute to diverse responses ranging from protective immunity to exacerbation of inflammation. Mast cells are traditionally considered the primary cells responsible for allergies because they express the high-affinity IgE receptor Fc"R1. Upon cross-linking with IgE, Fc"R1 induces cellular activation, including degranulation and release of preformed and de novo immune mediators such as histamine, leukotrienes, proteases, and cytokines. The formation of IgE and its specificity for distinct antigens (allergens) is an essential pathogenic process in diseases such as atopic eczema, food allergies, asthma, and hay fever. During embryonic development, mouse mast cells and macrophages develop from the yolk sac at an earlier stage than other leukocytes ([ 4 ][4]). Why mast cells are present so early in development may be related to their role in organ development, but their functional competence has been unclear. Msallam et al. show that mouse fetal mast cells are functional and that mast cells, particularly those readily detectable and abundant in fetal skin, become loaded with surface-bound maternal IgE. These IgE+ mast cells could respond to and degranulate upon exposure to an experimental allergen recognized by the IgE intravenously given to the mother, and this occurred even before birth. Furthermore, pups born to allergic mothers developed allergic responses, including airway hyperreactivity, upon their first postnatal exposure to the experimental allergen originally given to the mother (see the figure). ![Figure][5] Fetal allergic responses Maternal immunoglobulin E (IgE) is transported across the placenta by the neonatal Fc receptor (FcRN). Fetal mast cells bear the IgE receptor (Fc ε R1) and bind maternal IgE. In mice, these IgE-loaded fetal mast cells are functionally competent, degranulate upon exposure to allergen, and persist in neonates, in whom they may mediate allergic disease in early life. GRAPHIC: KELLIE HOLOSKI/ SCIENCE Fetal IgE has not been deeply studied, and whether it is produced by the fetus or derived from the mother (similar to most IgG in the fetus) is not agreed upon. However, emerging studies have provided evidence that human IgE in umbilical cord blood is maternally derived ([ 5 ][6]). Thus, the findings by Msallam et al. fit well with these data. The authors also identify the neonatal Fc receptor (FcRN) as the key IgE transporter, expressed by fetal endothelial cells and syncytiotrophoblast cells in the placenta. Previously, FcRN was shown to transfer IgG across the placenta ([ 6 ][7]). Although fetal mast cells are capable of mediating classical allergic responses, it is important to note that the models used by Msallam et al . rely on artificial experimental systems that involve unnaturally high doses of passive IgE administration and allergen sensitization schemes that are likely stronger than those that occur naturally in humans ([ 7 ][8]). Additionally, the presence of allergen-specific IgE and the ability of allergens to degranulate mast cells are not sufficient for the development of allergies, as many individuals elicit these responses in the absence of clinical symptoms. Indeed, the development of allergic diseases involves other key immunocytes, including basophils, eosinophils, innate lymphoid cells, T helper type 2 cells, and regulatory T cells. Even when focusing on mast cells, their activation status is influenced by a variety of inhibitory signals including expression of the inhibitory receptor CD200R ([ 8 ][9]), which was present on fetal mast cells ([ 3 ][3]). Furthermore, IgG can neutralize antigens and directly inhibit mast cells ([ 9 ][10]); the roles of CD200R and IgG were not assessed by Msallam et al . Additionally, the degree of allergic inflammation seen in newborn mice could be considered modest: Lung eosinophils increased by a factor of ~2, whereas a factor of >10 increase in eosinophils is typically seen in human asthma and experimental asthma models in adult mice. Msallam et al. found that human fetal lung and skin mast cells were IgE+ and appeared to be functionally mature. Notably, by 14 weeks of gestation, human fetal mast cells were already present in the skin at numbers comparable to those of adults. IgE may not only equip these mast cells to respond to allergens, but also promote their functional maturation and activation potential, creating a skin environment with primed mast cells, perhaps contributing to the “sensitive” skin of newborns. Indeed, a variety of unexplained newborn rashes, including infant atopic eczema, may be influenced by in utero–conditioned mast cells. Conversely, it is interesting to speculate that IgE-loaded mast cells may equip newborns with early-life protection against threatening infections. A substantial body of evidence supports the idea that the development of allergic disease involves an “allergic march,” which starts in the infant skin and subsequently develops into food allergy and then respiratory allergy ([ 10 ][11]). Msallam et al. demonstrated that loading of fetal mast cells with maternal IgE is transient, gone by 6 weeks of age in mice; this time period is a critical window for long-term immune polarization, as exemplified by the recent recognition that early-life exposure to allergens is protective for the development of food hypersensitivity ([ 11 ][12]). An immediate implication of the results is the occurrence of vertical transmission of anaphylaxis. However, this is not a phenomenon readily observed in humans because infants rarely have anaphylaxis and mothers seldom pass specific allergies (e.g., to penicillin or peanut) to their offspring ([ 11 ][12], [ 12 ][13]). Perhaps this is due to the short lifespan of the surface-bound IgE, estimated to be 70 days ([ 13 ][14]), meaning that maternal IgE would be gone by the time most infants begin to develop acute allergic reactions when solid foods are introduced. Instead, mothers pass on the tendency to develop allergies but not specific antigen sensitization. Although this has been attributed to the transfer of genetic variants in allergy susceptibility genes and commensal microbiota, the findings of Msallam et al. raise the possibility that in utero events, most notably the priming of mast cells with surface IgE, may contribute to a variety of subsequent immune responses, perhaps by promoting the continuation of the type 2 immune polarization that is characteristic of neonates ([ 14 ][15]). 1. [↵][16]1. N. P. Azouz, 2. M. E. Rothenberg , J. Clin. Invest. 129, 1419 (2019). [OpenUrl][17] 2. [↵][18]1. C. A. Liu et al ., J. Allergy Clin. Immunol. 112, 899 (2003). [OpenUrl][19][CrossRef][20][PubMed][21][Web of Science][22] 3. [↵][23]1. R. Msallam et al ., Science 370, 941 (2020). [OpenUrl][24][Abstract/FREE Full Text][25] 4. [↵][26]1. R. Gentek et al ., Immunity 48, 1160 (2018). [OpenUrl][27][CrossRef][28][PubMed][29] 5. [↵][30]1. K. 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领域	气候变化 ; 资源环境
URL	查看原文
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/304387
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Marc E. Rothenberg. Transferring allergies in the womb[J]. Science,2020.
APA	Marc E. Rothenberg.(2020).Transferring allergies in the womb.Science.
MLA	Marc E. Rothenberg."Transferring allergies in the womb".Science (2020).