Mariana C G Miranda-Waldetario, Maria A Curotto de Lafaille
Immune tolerance to foods develops in the intestine upon food ingestion and is essential to prevent IgE-mediated food allergy and gut inflammation. In homeostasis, the intestine is a tolerogenic environment that favors the formation of food-specific Foxp3+ regulatory T cells. A tolerogenic intestinal environment depends on colonization by diverse microbiota and exposure to solid foods at a critical period in early life. These early immune responses lead to the induction of antigen-specific Foxp3+ regulatory T cells in draining mesenteric lymph nodes. These peripherally induced regulatory cells circulate and seed the lamina propria of the gut, exerting suppressive function systemically and locally in the intestine. Successful establishment of a tolerogenic intestinal environment in early life sets the stage for oral tolerance to new antigens in adult life.
摄入食物后,肠道会产生对食物的免疫耐受,这对预防 IgE 介导的食物过敏和肠道炎症至关重要。在平衡状态下,肠道是一个产生耐受性的环境,有利于食物特异性 Foxp3+ 调节性 T 细胞的形成。耐受性肠道环境取决于多种微生物群的定植以及在生命早期的关键时期接触固体食物。这些早期免疫反应会在引流的肠系膜淋巴结中诱导抗原特异性 Foxp3+ 调节性 T 细胞。这些外周诱导的调节性细胞在肠道固有层循环和播种,在全身和肠道局部发挥抑制功能。早期肠道耐受环境的成功建立为成年后对新抗原的口服耐受奠定了基础。
{"title":"Oral tolerance to dietary antigens and Foxp3<sup>+</sup> regulatory T cells.","authors":"Mariana C G Miranda-Waldetario, Maria A Curotto de Lafaille","doi":"10.1111/imr.13370","DOIUrl":"https://doi.org/10.1111/imr.13370","url":null,"abstract":"<p><p>Immune tolerance to foods develops in the intestine upon food ingestion and is essential to prevent IgE-mediated food allergy and gut inflammation. In homeostasis, the intestine is a tolerogenic environment that favors the formation of food-specific Foxp3<sup>+</sup> regulatory T cells. A tolerogenic intestinal environment depends on colonization by diverse microbiota and exposure to solid foods at a critical period in early life. These early immune responses lead to the induction of antigen-specific Foxp3<sup>+</sup> regulatory T cells in draining mesenteric lymph nodes. These peripherally induced regulatory cells circulate and seed the lamina propria of the gut, exerting suppressive function systemically and locally in the intestine. Successful establishment of a tolerogenic intestinal environment in early life sets the stage for oral tolerance to new antigens in adult life.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141756010","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Food allergies occur due to a lack of tolerance to the proteins found in foods. While IgE- and non-IgE-mediated food allergies have different clinical manifestations, epidemiology, pathophysiology, and management, they share dysregulated T cell responses. Recent studies have shed light on the contributions of different T cell subsets to the development and persistence of different food allergic diseases. This review discusses the role of T cells in both IgE- and non-IgE-mediated food allergies and considers the potential future investigations in this context.
食物过敏的发生是由于对食物中的蛋白质缺乏耐受性。虽然IgE介导的食物过敏和非IgE介导的食物过敏在临床表现、流行病学、病理生理学和治疗方法上各不相同,但它们都存在T细胞反应失调的问题。最近的研究揭示了不同的 T 细胞亚群对不同食物过敏性疾病的发生和持续存在的作用。本综述讨论了 T 细胞在 IgE 和非 IgE 介导的食物过敏中的作用,并探讨了在此背景下未来可能开展的研究。
{"title":"Contribution of T cell subsets to different food allergic diseases.","authors":"Lisa Hung, Brianna Zientara, M Cecilia Berin","doi":"10.1111/imr.13368","DOIUrl":"https://doi.org/10.1111/imr.13368","url":null,"abstract":"<p><p>Food allergies occur due to a lack of tolerance to the proteins found in foods. While IgE- and non-IgE-mediated food allergies have different clinical manifestations, epidemiology, pathophysiology, and management, they share dysregulated T cell responses. Recent studies have shed light on the contributions of different T cell subsets to the development and persistence of different food allergic diseases. This review discusses the role of T cells in both IgE- and non-IgE-mediated food allergies and considers the potential future investigations in this context.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141756009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Emily R Siniscalco, Adam Williams, Stephanie C Eisenbarth
The increasing prevalence of food allergy and related pathologies in recent years has underscored the need to understand the factors affecting adverse reactions to food. Food allergy is caused when food-specific IgE triggers the release of histamine from mast cells. However, other food-specific antibody isotypes exist as well, including IgG and IgA. IgA is the main antibody isotype in the gut and mediates noninflammatory reactions to toxins, commensal bacteria, and food antigens. It has also been thought to induce tolerance to food, thus antagonizing the role of food-specific IgE. However, this has remained unclear as food-specific IgA generation is poorly understood. Particularly, the location of IgA induction, the role of T cell help, and the fates of food-specific B cells remain elusive. In this review, we outline what is known about food-specific IgA induction and highlight areas requiring further study. We also explore how knowledge of food-specific IgA induction can be informed by and subsequently contribute to our overall knowledge of gut immunity.
近年来,食物过敏和相关病症的发病率不断上升,这凸显了了解影响食物不良反应因素的必要性。食物特异性 IgE 触发肥大细胞释放组胺,从而引起食物过敏。不过,也存在其他食物特异性抗体异型,包括 IgG 和 IgA。IgA 是肠道中的主要抗体同工型,可介导对毒素、共生细菌和食物抗原的非炎症反应。人们还认为 IgA 能诱导对食物的耐受性,从而抵消食物特异性 IgE 的作用。然而,由于人们对食物特异性 IgA 的产生还知之甚少,因此这一点仍不清楚。特别是,IgA 诱导的位置、T 细胞帮助的作用以及食物特异性 B 细胞的命运仍然难以捉摸。在这篇综述中,我们概述了有关食物特异性 IgA 诱导的已知知识,并强调了需要进一步研究的领域。我们还探讨了如何通过食物特异性 IgA 诱导的知识来了解肠道免疫的整体知识,进而为这些知识做出贡献。
{"title":"All roads lead to IgA: Mapping the many pathways of IgA induction in the gut.","authors":"Emily R Siniscalco, Adam Williams, Stephanie C Eisenbarth","doi":"10.1111/imr.13369","DOIUrl":"https://doi.org/10.1111/imr.13369","url":null,"abstract":"<p><p>The increasing prevalence of food allergy and related pathologies in recent years has underscored the need to understand the factors affecting adverse reactions to food. Food allergy is caused when food-specific IgE triggers the release of histamine from mast cells. However, other food-specific antibody isotypes exist as well, including IgG and IgA. IgA is the main antibody isotype in the gut and mediates noninflammatory reactions to toxins, commensal bacteria, and food antigens. It has also been thought to induce tolerance to food, thus antagonizing the role of food-specific IgE. However, this has remained unclear as food-specific IgA generation is poorly understood. Particularly, the location of IgA induction, the role of T cell help, and the fates of food-specific B cells remain elusive. In this review, we outline what is known about food-specific IgA induction and highlight areas requiring further study. We also explore how knowledge of food-specific IgA induction can be informed by and subsequently contribute to our overall knowledge of gut immunity.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141750657","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rita Nocerino, Laura Carucci, Serena Coppola, Franca Oglio, Antonio Masino, Alessandra Agizza, Lorella Paparo, Roberto Berni Canani
Cow milk protein allergy (CMPA) is one of the most common food allergies in the pediatric age worldwide. Prevalence, persistence, and severity of this condition are on the rise, with a negative impact on the health-related quality of life of the patients and families and on the costs related to its management. Another relevant issue is that CMPA in early life may be the first stage of the "allergic march," leading to the occurrence of other atopic manifestations later in life, especially asthma, atopic eczema, urticaria, and rhinoconjunctivitis. Thus, "disease modification" options that are able to modulate the disease course of pediatric patients affected by CMPA would be very welcomed by affected families and healthcare systems. In this review, we report the most relevant progress on this topic.
{"title":"The journey toward disease modification in cow milk protein allergy.","authors":"Rita Nocerino, Laura Carucci, Serena Coppola, Franca Oglio, Antonio Masino, Alessandra Agizza, Lorella Paparo, Roberto Berni Canani","doi":"10.1111/imr.13372","DOIUrl":"https://doi.org/10.1111/imr.13372","url":null,"abstract":"<p><p>Cow milk protein allergy (CMPA) is one of the most common food allergies in the pediatric age worldwide. Prevalence, persistence, and severity of this condition are on the rise, with a negative impact on the health-related quality of life of the patients and families and on the costs related to its management. Another relevant issue is that CMPA in early life may be the first stage of the \"allergic march,\" leading to the occurrence of other atopic manifestations later in life, especially asthma, atopic eczema, urticaria, and rhinoconjunctivitis. Thus, \"disease modification\" options that are able to modulate the disease course of pediatric patients affected by CMPA would be very welcomed by affected families and healthcare systems. In this review, we report the most relevant progress on this topic.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141756011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Despite the near ubiquitous presence of Ig-based antibodies in vertebrates, IgE is unique to mammals. How and why it emerged remains mysterious. IgE expression is greatly constrained compared to other IgH isotypes. While other IgH isotypes are relatively abundant, soluble IgE has a truncated half-life, and IgE plasma cells are mostly short-lived. Despite its rarity, IgE is consequential and can trigger life-threatening anaphylaxis. IgE production reflects a dynamic steady state with IgG memory B cells feeding short-lived IgE production. Emerging evidence suggests that IgE may also potentially be produced in longer-lived plasma cells as well, perhaps as an aberrancy stemming from its evolutionary roots from an antibody isotype that likely functioned more like IgG. As a late derivative of an ancient systemic antibody system, the benefits of IgE in mammals likely stems from the antibody system's adaptive recognition and response capability. However, the tendency for massive, systemic, and long-lived production, common to IgH isotypes like IgG, were likely not a good fit for IgE. The evolutionary derivation of IgE from an antibody system that for millions of years was good at antigen de-sensitization to now functioning as a highly specialized antigen-sensitization function required heavy restrictions on antibody production-insufficiency of which may contribute to allergic disease.
{"title":"Whence and wherefore IgE?","authors":"Rifat S Rahman, Duane R Wesemann","doi":"10.1111/imr.13373","DOIUrl":"https://doi.org/10.1111/imr.13373","url":null,"abstract":"<p><p>Despite the near ubiquitous presence of Ig-based antibodies in vertebrates, IgE is unique to mammals. How and why it emerged remains mysterious. IgE expression is greatly constrained compared to other IgH isotypes. While other IgH isotypes are relatively abundant, soluble IgE has a truncated half-life, and IgE plasma cells are mostly short-lived. Despite its rarity, IgE is consequential and can trigger life-threatening anaphylaxis. IgE production reflects a dynamic steady state with IgG memory B cells feeding short-lived IgE production. Emerging evidence suggests that IgE may also potentially be produced in longer-lived plasma cells as well, perhaps as an aberrancy stemming from its evolutionary roots from an antibody isotype that likely functioned more like IgG. As a late derivative of an ancient systemic antibody system, the benefits of IgE in mammals likely stems from the antibody system's adaptive recognition and response capability. However, the tendency for massive, systemic, and long-lived production, common to IgH isotypes like IgG, were likely not a good fit for IgE. The evolutionary derivation of IgE from an antibody system that for millions of years was good at antigen de-sensitization to now functioning as a highly specialized antigen-sensitization function required heavy restrictions on antibody production-insufficiency of which may contribute to allergic disease.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141747038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hind Hussein, Samuel Van Remoortel, Guy E Boeckxstaens
Irritable bowel syndrome (IBS) is a chronic gastrointestinal condition associated with altered bowel habits and recurrent abdominal pain, often triggered by food intake. Current treatments focus on improving stool pattern, but effective treatments for pain in IBS are still lacking due to our limited understanding of pathophysiological mechanisms. Visceral hypersensitivity (VHS), or abnormal visceral pain perception, underlies abdominal pain development in IBS, and mast cell activation has been shown to play an important role in the development of VHS. Our work recently revealed that abdominal pain in response to food intake is induced by the sensitization of colonic pain-sensing neurons by histamine produced by activated mast cells following a local IgE response to food. In this review, we summarize the current knowledge on abdominal pain and VHS pathophysiology in IBS, we outline the work leading to the discovery of the role of histamine in abdominal pain, and we introduce antihistamines as a novel treatment option to manage chronic abdominal pain in patients with IBS.
{"title":"Irritable bowel syndrome: When food is a pain in the gut.","authors":"Hind Hussein, Samuel Van Remoortel, Guy E Boeckxstaens","doi":"10.1111/imr.13374","DOIUrl":"https://doi.org/10.1111/imr.13374","url":null,"abstract":"<p><p>Irritable bowel syndrome (IBS) is a chronic gastrointestinal condition associated with altered bowel habits and recurrent abdominal pain, often triggered by food intake. Current treatments focus on improving stool pattern, but effective treatments for pain in IBS are still lacking due to our limited understanding of pathophysiological mechanisms. Visceral hypersensitivity (VHS), or abnormal visceral pain perception, underlies abdominal pain development in IBS, and mast cell activation has been shown to play an important role in the development of VHS. Our work recently revealed that abdominal pain in response to food intake is induced by the sensitization of colonic pain-sensing neurons by histamine produced by activated mast cells following a local IgE response to food. In this review, we summarize the current knowledge on abdominal pain and VHS pathophysiology in IBS, we outline the work leading to the discovery of the role of histamine in abdominal pain, and we introduce antihistamines as a novel treatment option to manage chronic abdominal pain in patients with IBS.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141732992","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pamela A Frischmeyer-Guerrerio, Fernanda D Young, Ozge N Aktas, Tamara Haque
The last few decades have seen striking changes in the field of food allergy. The prevalence of the disease has risen dramatically in many parts of the globe, and management of the condition has undergone major revision. While delayed introduction of common allergenic foods during infancy was advised for many years, the learning early about peanut allergy (LEAP) trial and other studies led to a major shift in infant feeding practices, with deliberate early introduction of these foods now recommended. Additionally, the Food and Drug Administration approved the first treatment for food allergy in 2020-a peanut oral immunotherapy (OIT) product that likely represents just the beginning of new immunotherapy-based and other treatments for food allergy. Our knowledge of the environmental and genetic factors contributing to the pathogenesis of food allergy has also undergone transformational advances. Here, we will discuss our efforts to improve the clinical care of patients with food allergy and our understanding of the immunological mechanisms contributing to this common disease.
{"title":"Insights into the clinical, immunologic, and genetic underpinnings of food allergy.","authors":"Pamela A Frischmeyer-Guerrerio, Fernanda D Young, Ozge N Aktas, Tamara Haque","doi":"10.1111/imr.13371","DOIUrl":"https://doi.org/10.1111/imr.13371","url":null,"abstract":"<p><p>The last few decades have seen striking changes in the field of food allergy. The prevalence of the disease has risen dramatically in many parts of the globe, and management of the condition has undergone major revision. While delayed introduction of common allergenic foods during infancy was advised for many years, the learning early about peanut allergy (LEAP) trial and other studies led to a major shift in infant feeding practices, with deliberate early introduction of these foods now recommended. Additionally, the Food and Drug Administration approved the first treatment for food allergy in 2020-a peanut oral immunotherapy (OIT) product that likely represents just the beginning of new immunotherapy-based and other treatments for food allergy. Our knowledge of the environmental and genetic factors contributing to the pathogenesis of food allergy has also undergone transformational advances. Here, we will discuss our efforts to improve the clinical care of patients with food allergy and our understanding of the immunological mechanisms contributing to this common disease.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141732991","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Food allergy can be life-threatening and often develops early in life. In infants and children, loss-of-function mutations in skin barrier genes associate with food allergy. In a mouse model with skin barrier mutations (Flakey Tail, FT+/- mice), topical epicutaneous sensitization to a food allergen peanut extract (PNE), an environmental allergen Alternaria alternata (Alt) and a detergent induce food allergy and then an oral PNE-challenge induces anaphylaxis. Exposures to these allergens and detergents can occur for infants and children in a household setting. From the clinical and preclinical studies of neonates and children with skin barrier mutations, early oral exposure to allergenic foods before skin sensitization may induce tolerance to food allergens and thus protect against development of food allergy. In the FT+/- mice, oral food allergen prior to skin sensitization induce tolerance to food allergens. However, when the skin of FT+/- pups are exposed to a ubiquitous environmental allergen at the time of oral consumption of food allergens, this blocks the induction of tolerance to the food allergen and the mice can then be skin sensitized with the food allergen. The development of food allergy in neonatal FT+/- mice is mediated by altered skin responses to allergens with increases in skin expression of interleukin 33, oncostatin M and amphiregulin. The development of neonate food allergy is enhanced when born to an allergic mother, but it is inhibited by maternal supplementation with α-tocopherol. Moreover, preclinical studies suggest that food allergen skin sensitization can occur before manifestation of clinical features of atopic dermatitis. Thus, these parameters may impact design of clinical studies for food allergy, when stratifying individuals by loss of skin barrier function or maternal atopy before offspring development of atopic dermatitis.
{"title":"Mechanisms for initiation of food allergy by skin pre-disposed to atopic dermatitis.","authors":"Haoran Gao, Allison E Kosins, Joan M Cook-Mills","doi":"10.1111/imr.13367","DOIUrl":"https://doi.org/10.1111/imr.13367","url":null,"abstract":"<p><p>Food allergy can be life-threatening and often develops early in life. In infants and children, loss-of-function mutations in skin barrier genes associate with food allergy. In a mouse model with skin barrier mutations (Flakey Tail, FT+/- mice), topical epicutaneous sensitization to a food allergen peanut extract (PNE), an environmental allergen Alternaria alternata (Alt) and a detergent induce food allergy and then an oral PNE-challenge induces anaphylaxis. Exposures to these allergens and detergents can occur for infants and children in a household setting. From the clinical and preclinical studies of neonates and children with skin barrier mutations, early oral exposure to allergenic foods before skin sensitization may induce tolerance to food allergens and thus protect against development of food allergy. In the FT+/- mice, oral food allergen prior to skin sensitization induce tolerance to food allergens. However, when the skin of FT+/- pups are exposed to a ubiquitous environmental allergen at the time of oral consumption of food allergens, this blocks the induction of tolerance to the food allergen and the mice can then be skin sensitized with the food allergen. The development of food allergy in neonatal FT+/- mice is mediated by altered skin responses to allergens with increases in skin expression of interleukin 33, oncostatin M and amphiregulin. The development of neonate food allergy is enhanced when born to an allergic mother, but it is inhibited by maternal supplementation with α-tocopherol. Moreover, preclinical studies suggest that food allergen skin sensitization can occur before manifestation of clinical features of atopic dermatitis. Thus, these parameters may impact design of clinical studies for food allergy, when stratifying individuals by loss of skin barrier function or maternal atopy before offspring development of atopic dermatitis.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141615415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Oral tolerance promotes the suppression of immune responses to innocuous antigen and is primarily mediated by regulatory T cell (Tregs). The development of oral tolerance begins in early life during a "window of tolerance," which occurs around weaning and is mediated by components in breastmilk. Herein, we review the factors dictating this window and how Tregs are uniquely educated in early life. In early life, the translocation of luminal antigen for Treg induction is primarily dictated by goblet cell-associated antigen passages (GAPs). GAPs in the colon are negatively regulated by maternally-derived epidermal growth factor and the microbiota, restricting GAP formation to the "periweaning" period (postnatal day 11-21 in mice, 4-6 months in humans). The induction of solid food also promotes the diversification of the bacteria such that bacterially-derived metabolites known to promote Tregs-short-chain fatty acids, tryptophan metabolites, and bile acids-peak during the periweaning phase. Further, breastmilk immunoglobulins-IgA and IgG-regulate both microbial diversity and the interaction of microbes with the epithelium, further controlling which antigens are presented to T cells. Overall, these elements work in conjunction to induce a long-lived population of Tregs, around weaning, that are crucial for maintaining homeostasis in adults.
口腔耐受促进抑制对无害抗原的免疫反应,主要由调节性 T 细胞(Tregs)介导。口腔耐受性的发展始于生命早期的 "耐受窗口期",发生在断奶前后,由母乳中的成分介导。在此,我们将回顾决定这一窗口期的因素以及Tregs如何在生命早期接受独特的教育。在生命早期,用于诱导 Treg 的管腔抗原转运主要由上皮细胞相关抗原通道(GAPs)决定。结肠中的 GAP 受母体来源的表皮生长因子和微生物群的负向调节,从而将 GAP 的形成限制在 "围断奶期"(小鼠出生后第 11-21 天,人类 4-6 个月)。固体食物的诱导也会促进细菌的多样化,因此细菌衍生的代谢物--短链脂肪酸、色氨酸代谢物和胆汁酸--在围断奶期达到峰值,而这些代谢物已知会促进 Tregs 的形成。此外,母乳中的免疫球蛋白--IgA 和 IgG--可调节微生物的多样性以及微生物与上皮细胞的相互作用,从而进一步控制哪些抗原可呈现给 T 细胞。总之,这些因素共同作用,在断奶前后诱导出长寿命的 Tregs 群体,这对维持成人体内平衡至关重要。
{"title":"The right educational environment: Oral tolerance in early life.","authors":"Talia R Cheifetz, Kathryn A Knoop","doi":"10.1111/imr.13366","DOIUrl":"https://doi.org/10.1111/imr.13366","url":null,"abstract":"<p><p>Oral tolerance promotes the suppression of immune responses to innocuous antigen and is primarily mediated by regulatory T cell (Tregs). The development of oral tolerance begins in early life during a \"window of tolerance,\" which occurs around weaning and is mediated by components in breastmilk. Herein, we review the factors dictating this window and how Tregs are uniquely educated in early life. In early life, the translocation of luminal antigen for Treg induction is primarily dictated by goblet cell-associated antigen passages (GAPs). GAPs in the colon are negatively regulated by maternally-derived epidermal growth factor and the microbiota, restricting GAP formation to the \"periweaning\" period (postnatal day 11-21 in mice, 4-6 months in humans). The induction of solid food also promotes the diversification of the bacteria such that bacterially-derived metabolites known to promote Tregs-short-chain fatty acids, tryptophan metabolites, and bile acids-peak during the periweaning phase. Further, breastmilk immunoglobulins-IgA and IgG-regulate both microbial diversity and the interaction of microbes with the epithelium, further controlling which antigens are presented to T cells. Overall, these elements work in conjunction to induce a long-lived population of Tregs, around weaning, that are crucial for maintaining homeostasis in adults.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141597970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alzheimer's disease (AD) is a degenerative brain disorder and the most common form of dementia. AD pathology is characterized by senile plaques and neurofibrillary tangles (NFTs) composed of amyloid-β (Aβ) and hyperphosphorylated tau, respectively. Neuroinflammation has been shown to drive Aβ and tau pathology, with evidence suggesting the nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome as a key pathway in AD pathogenesis. NLRP3 inflammasome activation in microglia, the primary immune effector cells of the brain, results in caspase-1 activation and secretion of IL-1β and IL-18. Recent studies have demonstrated a dramatic interplay between the metabolic state and effector functions of immune cells. Microglial metabolism in AD is of particular interest, as ketone bodies (acetone, acetoacetate (AcAc), and β-hydroxybutyrate (BHB)) serve as an alternative energy source when glucose utilization is compromised in the brain of patients with AD. Furthermore, reduced cerebral glucose metabolism concomitant with increased BHB levels has been demonstrated to inhibit NLRP3 inflammasome activation. Here, we review the role of the NLRP3 inflammasome and microglial ketone body metabolism in AD pathogenesis. We also highlight NLRP3 inflammasome inhibition by several ketone body therapies as a promising new treatment strategy for AD.
阿尔茨海默病(AD)是一种退化性脑部疾病,也是最常见的痴呆症。阿尔茨海默病的病理特征是分别由淀粉样蛋白-β(Aβ)和高磷酸化tau组成的老年斑和神经纤维缠结(NFT)。神经炎症已被证明是Aβ和tau病理学的驱动因素,有证据表明类点头受体家族含吡咯啉结构域3(NLRP3)炎性体是AD发病机制中的一个关键途径。小胶质细胞是大脑的主要免疫效应细胞,其 NLRP3 炎症体的激活会导致 Caspase-1 的激活以及 IL-1β 和 IL-18 的分泌。最近的研究表明,免疫细胞的新陈代谢状态和效应功能之间存在着巨大的相互作用。由于酮体(丙酮、乙酰乙酸(AcAc)和β-羟基丁酸(BHB))可在 AD 患者大脑葡萄糖利用受损时作为替代能量来源,因此 AD 中的小胶质细胞代谢尤其值得关注。此外,在脑葡萄糖代谢降低的同时,BHB 水平升高已被证实可抑制 NLRP3 炎性体的激活。在此,我们回顾了NLRP3炎性体和小胶质细胞酮体代谢在AD发病机制中的作用。我们还强调了几种酮体疗法对 NLRP3 炎症体的抑制作用,认为这是一种很有希望的治疗 AD 的新策略。
{"title":"Ketone body metabolism and the NLRP3 inflammasome in Alzheimer's disease.","authors":"Daniel C Shippy, Abigail H Evered, Tyler K Ulland","doi":"10.1111/imr.13365","DOIUrl":"10.1111/imr.13365","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a degenerative brain disorder and the most common form of dementia. AD pathology is characterized by senile plaques and neurofibrillary tangles (NFTs) composed of amyloid-β (Aβ) and hyperphosphorylated tau, respectively. Neuroinflammation has been shown to drive Aβ and tau pathology, with evidence suggesting the nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome as a key pathway in AD pathogenesis. NLRP3 inflammasome activation in microglia, the primary immune effector cells of the brain, results in caspase-1 activation and secretion of IL-1β and IL-18. Recent studies have demonstrated a dramatic interplay between the metabolic state and effector functions of immune cells. Microglial metabolism in AD is of particular interest, as ketone bodies (acetone, acetoacetate (AcAc), and β-hydroxybutyrate (BHB)) serve as an alternative energy source when glucose utilization is compromised in the brain of patients with AD. Furthermore, reduced cerebral glucose metabolism concomitant with increased BHB levels has been demonstrated to inhibit NLRP3 inflammasome activation. Here, we review the role of the NLRP3 inflammasome and microglial ketone body metabolism in AD pathogenesis. We also highlight NLRP3 inflammasome inhibition by several ketone body therapies as a promising new treatment strategy for AD.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141578431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}