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}
The gut microbiome is a diverse collection of bacteria, fungi, and viruses that have coevolved with the immune system. The microbiome plays a central role in shaping immunologic development as well as regulating other physiologic processes, including metabolic and neurologic functions. Several of the key mechanisms relate to (a) the activation of innate immune system and induction of specific immune cell subsets by pathogen-associated molecular patterns (PAMPS); (b) microbial adherence to the intestinal epithelia surface; (c) the secretion of immunomodulatory metabolites; and (d) biomimicry. While these interactions may be crucial for normal immunologic development, overactivation of these same microbe-immune signaling pathways may lead to the induction of tissue inflammation and autoimmunity.1 This special issue will cover the mechanisms by which the gut microbiome influences autoimmune diseases, including type 1 diabetes (T1D),2, 3 systemic lupus erythematosus (SLE),4, 5 rheumatoid arthritis (RA),6, 7 and multiple sclerosis (MS).8-10 Also covered are considerations for host factors such as genetics, aging, and sex, as well as translation for prevention and treatment of autoimmune disease (Figure 1).
Th17 cells are highly responsive to the gut microbiota,11 play a central role in autoimmunity, and also play important roles in tissue repair, and protection against infection.1 Major questions in the field relate to (a) what factors determine a pathogenic versus homeostatic/protective Th17 cells and (b) what role the gut microbiota play in shaping these responses. This topic is reviewed by Schnell in this special issue.1 In groundbreaking work using single cell sequencing, Schnell and colleagues identified a novel stem-like and self-renewing Th17 population denoted by TCF1+ transcription factor and SLAMF6+ receptor expression.12 The stem-like SLAMF6+ Th17 cells largely reside in the intestinal mucosa, and migrate to the intestinal mucosal following adoptive transfer. Further, they are depleted by oral antibiotics, suggesting that the gut microbiota plays an essential role in maintaining them. In models of autoimmune diseases, stem-like Th17 cells can differentiate into pathogenic CXCR6+ Th17 cells that traffic to the extraintestinal sites where they induce tissue inflammation (e.g., the CNS in EAE). Other studies confirm the finding of the presence of stem-like SLAMF6+ Th17 cells in the gut and demonstrate that they can also differentiate into IL-10 producing Th17 cells, which have anti-inflammatory functions. This first article in our special issue on the Autoimmunity and the Microbiome sets the stage to understand specific signaling mechanisms at the mucosal interf
{"title":"Autoimmunity and the microbiome","authors":"Laura M. Cox, Vijay K. Kuchroo","doi":"10.1111/imr.13363","DOIUrl":"10.1111/imr.13363","url":null,"abstract":"<p>The gut microbiome is a diverse collection of bacteria, fungi, and viruses that have coevolved with the immune system. The microbiome plays a central role in shaping immunologic development as well as regulating other physiologic processes, including metabolic and neurologic functions. Several of the key mechanisms relate to (a) the activation of innate immune system and induction of specific immune cell subsets by pathogen-associated molecular patterns (PAMPS); (b) microbial adherence to the intestinal epithelia surface; (c) the secretion of immunomodulatory metabolites; and (d) biomimicry. While these interactions may be crucial for normal immunologic development, overactivation of these same microbe-immune signaling pathways may lead to the induction of tissue inflammation and autoimmunity.<span><sup>1</sup></span> This special issue will cover the mechanisms by which the gut microbiome influences autoimmune diseases, including type 1 diabetes (T1D),<span><sup>2, 3</sup></span> systemic lupus erythematosus (SLE),<span><sup>4, 5</sup></span> rheumatoid arthritis (RA),<span><sup>6, 7</sup></span> and multiple sclerosis (MS).<span><sup>8-10</sup></span> Also covered are considerations for host factors such as genetics, aging, and sex, as well as translation for prevention and treatment of autoimmune disease (Figure 1).</p><p><i>Th17 cells</i> are highly responsive to the gut microbiota,<span><sup>11</sup></span> play a central role in autoimmunity, and also play important roles in tissue repair, and protection against infection.<span><sup>1</sup></span> Major questions in the field relate to (a) what factors determine a pathogenic versus homeostatic/protective Th17 cells and (b) what role the gut microbiota play in shaping these responses. This topic is reviewed by Schnell in this special issue.<span><sup>1</sup></span> In groundbreaking work using single cell sequencing, Schnell and colleagues identified a novel stem-like and self-renewing Th17 population denoted by TCF1<sup>+</sup> transcription factor and SLAMF6<sup>+</sup> receptor expression.<span><sup>12</sup></span> The stem-like SLAMF6<sup>+</sup> Th17 cells largely reside in the intestinal mucosa, and migrate to the intestinal mucosal following adoptive transfer. Further, they are depleted by oral antibiotics, suggesting that the gut microbiota plays an essential role in maintaining them. In models of autoimmune diseases, stem-like Th17 cells can differentiate into pathogenic CXCR6<sup>+</sup> Th17 cells that traffic to the extraintestinal sites where they induce tissue inflammation (e.g., the CNS in EAE). Other studies confirm the finding of the presence of stem-like SLAMF6<sup>+</sup> Th17 cells in the gut and demonstrate that they can also differentiate into IL-10 producing Th17 cells, which have anti-inflammatory functions. This first article in our special issue on the Autoimmunity and the Microbiome sets the stage to understand specific signaling mechanisms at the mucosal interf","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imr.13363","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141557650","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Type 1 diabetes (T1D) results from a complex interplay of genetic predisposition, immunological dysregulation, and environmental triggers, that culminate in the destruction of insulin-secreting pancreatic β cells. This review provides a comprehensive examination of the multiple factors underpinning T1D pathogenesis, to elucidate key mechanisms and potential therapeutic targets. Beginning with an exploration of genetic risk factors, we dissect the roles of human leukocyte antigen (HLA) haplotypes and non-HLA gene variants associated with T1D susceptibility. Mechanistic insights gleaned from the NOD mouse model provide valuable parallels to the human disease, particularly immunological intricacies underlying β cell–directed autoimmunity. Immunological drivers of T1D pathogenesis are examined, highlighting the pivotal contributions of both effector and regulatory T cells and the multiple functions of B cells and autoantibodies in β-cell destruction. Furthermore, the impact of environmental risk factors, notably modulation of host immune development by the intestinal microbiome, is examined. Lastly, the review probes human longitudinal studies, unveiling the dynamic interplay between mucosal immunity, systemic antimicrobial antibody responses, and the trajectories of T1D development. Insights garnered from these interconnected factors pave the way for targeted interventions and the identification of biomarkers to enhance T1D management and prevention strategies.
{"title":"Cracking the type 1 diabetes code: Genes, microbes, immunity, and the early life environment","authors":"Christopher Yau, Jayne S. Danska","doi":"10.1111/imr.13362","DOIUrl":"10.1111/imr.13362","url":null,"abstract":"<p>Type 1 diabetes (T1D) results from a complex interplay of genetic predisposition, immunological dysregulation, and environmental triggers, that culminate in the destruction of insulin-secreting pancreatic β cells. This review provides a comprehensive examination of the multiple factors underpinning T1D pathogenesis, to elucidate key mechanisms and potential therapeutic targets. Beginning with an exploration of genetic risk factors, we dissect the roles of human leukocyte antigen (HLA) haplotypes and non-HLA gene variants associated with T1D susceptibility. Mechanistic insights gleaned from the NOD mouse model provide valuable parallels to the human disease, particularly immunological intricacies underlying β cell–directed autoimmunity. Immunological drivers of T1D pathogenesis are examined, highlighting the pivotal contributions of both effector and regulatory T cells and the multiple functions of B cells and autoantibodies in β-cell destruction. Furthermore, the impact of environmental risk factors, notably modulation of host immune development by the intestinal microbiome, is examined. Lastly, the review probes human longitudinal studies, unveiling the dynamic interplay between mucosal immunity, systemic antimicrobial antibody responses, and the trajectories of T1D development. Insights garnered from these interconnected factors pave the way for targeted interventions and the identification of biomarkers to enhance T1D management and prevention strategies.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imr.13362","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141503734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}