CD300A

New research will explore key aspects of eczema from the science behind itch and inflammation, to the psychosocial burden, to new pathways for potential therapies NOVATO, Calif., Dec. 12, 2023 /PRNewswire/ -- The National Eczema Association (NEA) today announced the recipients for its 2023 research grants. From both U.S.-based and international applications, the research projects of 18 outstanding investigators were selected, representing grants totaling nearly $1 million. NEA's commitment to innovative eczema research has continued to expand with an increasing number of yearly awardees and an annual investment that has nearly tripled over the past three years. With 2023 marking the 20th anniversary of its grantmaking, NEA has invested nearly $4 million since its first grant was awarded in 2004. Collectively, NEA-funded grants for basic science, clinical and translational research have supported a deeper understanding of the symptoms, comorbidities and burdens of eczema, provided insights into new treatment strategies, and furthered the ability to improve care and prevention. Most notably, for every $1 NEA has invested in eczema research, grantees have collectively gone on to obtain an additional $10.12 in subsequent National Institutes of Health (NIH) funding to support further research. "Eczema is a chronic condition that affects over 31 million people in the U.S., many with severe, even debilitating impacts," says Julie Block, CEO of NEA. "We started the NEA grant program to fill a much-needed gap in research and, 20 years later, it's so encouraging to see the breadth and scope of work represented by the 2023 awardees. These are both new and longstanding investigators working across disciplines to identify opportunities for better eczema therapies, better care, better lives with eczema – and one day, we believe, a cure." The 2023 research grants were awarded as follows: Champion Research Grant– Encourages proven researchers to continue research on emerging or ongoing challenges in eczema or bring their expertise to the field of eczema. Katrina Abuabara MD, MA, MSCE, University of California at San Francisco, San Francisco, CA Dietary salt consumption as a predictor of atopic dermatitis heterogeneity and cardiac comorbidity Aaron Drucker MD, ScM, Women's College Hospital, Toronto, Canada Long-term safety of topical corticosteroids Henning Holle, PhD, University of Hull, Hull, England Understanding and reducing psychosocial burden of eczema: An attentional bias approach Francesca Levi-Schaffer, PharmD, PhD, Hebrew University of Jerusalem-Hadassah School of Medicine, Jerusalem, Israel Employing CD300a and Resolvin D1 to stop inflammation and induce resolution in atopic dermatitis Spotlight Research Grant – Promoting research tied to specific areas of interest, this year focuses on eczemas outside of atopic dermatitis. Zelma Chiesa Fuxench MD, MSCE, University of Pennsylvania, Philadelphia, PA Validity of diagnostic codes for identifying seborrheic dermatitis in the health improvement network Yin Li, PhD, Emory University School of Medicine, Atlanta, GA Occupational contact dermatitis among healthcare workers: Implications for healthcare system Childhood Eczema Challenge Grant – Created in collaboration with the Pediatric Dermatology Research Alliance (PeDRA), this award is intended to accelerate research that improves the health and quality of life of pediatric patients and their families. Hassan Vahidnezhad MSc, PhD, Children's Hospital of Philadelphia, Philadelphia, PA Genetic landscape of pediatric patients with monogenic susceptibilities to AD Catalyst Research Grant – Designed to support talented early-career scientists on the path toward becoming the next generation of eczema thought leaders by supporting hypothesis-driven research projects. Ofir Cohn PhD, Boston Children's Hospital, Boston, MA Deciphering how genetic variation associated with risk of eczema impacts human dendritic cell subset function Liwen Deng BS, PhD, President & Fellows of Harvard College, Boston, MA S. aureus neuroimmune signaling in itch and skin barrier damage Mengxu Ge, PhD, Boston Children's Hospital, Boston, MA Wnt/beta-catenin signaling in barrier function and allergic skin Inflammation Gerard Callejo Martin, PhD, University of Barcelona, Barcelona, Spain Smoothing the itch: Innovative strategies to alleviate chronic pruritus through modulation of TRESK channels Ge Peng, MD, Juntendo University Graduate School of Medicine, Tokyo, Japan Elucidation of the pathogenic mechanism of atopic dermatitis associated brain inflammation Yiannis Vasilopoulos MSc, PhD, University of Patras, Patras, Greece Decoding the complex architecture of atopic dermatitis in the post-genomic era (ATOMIC) Matthew Vesely, MD, PhD, Yale University, School of Medicine, New Haven, CT VISTA as a potential therapeutic target in eczema Sheng-Pei Wang, MD, MPH, University of California at San Francisco, San Francisco, CA Understanding body dissatisfaction, eating behaviors, and eating disorders in children with eczema Engagement Research Grant – Intended for emerging investigators exploring a new research concept, piloting a new experiment, or undertaking a novel or secondary data analysis. Sara Henderson MRes, PhD, Centre for Skin Sciences,, University of Bradford, Bradford, England The role of liquid hand and body soap in the dysbiosis of the skin microbiome during atopic dermatitis Ahnna Lee PhD, MSN, RN, University of California at San Francisco, San Francisco, CA Predictors of AD disease course in childhood Gil Yosipovitch MD, University of Miami School of Medicine, Miami, FL, Impact of an educational intervention on adolescent and medical student eczema knowledge (RASHE) Learn more about NEA's ongoing support of eczema research. About the National Eczema Association Founded in 1988, the National Eczema Association (NEA) is a 501(c)(3) nonprofit and the largest patient advocacy organization serving the over 31 million Americans who live with eczema and those who care for them. NEA provides programs and resources to elevate the diverse lived experience of eczema, and help patients and caregivers understand their disease, actively engage in their care, find strength in one another – and improve their lives. Additionally, NEA advances critical eczema research and partners with key stakeholders to ensure the patient voice is represented and valued in education, care and treatment decision-making. The eczema community is at an exciting juncture, with increased recognition of the seriousness and burden of eczema and a surge in scientific interest and development of new treatments. Bolstered by NEA's strategic plan, Blueprint 2025, we are driving toward the ultimate vision: a world without eczema. Learn more at NationalEczema.org. SOURCE National Eczema Association

在自免病狼疮中，自身核酸通过内体或溶酶体中的TLR7和TLR9触发免疫激活，分别介导对RNA和DNA耐受的丧失，激活自反应性B细胞和一些髓源抗原呈递细胞。尽管拥有共同信号通路MyD88，但使用单个TLR7和TLR9敲除(KO)狼疮易发MRL/lpr小鼠后显示，它们具有相反的作用：TLR7促进SLE，TLR9则抑制SLE。这一所谓“TLR悖论”提示二者存在信号传递机制的差异。TLR7促进SLE的机制越来越多的证据表明，SLE患者的表型与外周血中IgD- CD27-双阴性B细胞的CXCR5- CD11c+亚群TLR7信号升高相关。TLR7过表达导致自免疾病的矛盾表现：小鼠模型显示，由于TLR7编码Yaa位点的复制或转基因TLR7表达而增加的TLR7信号会加剧自身免疫；而在其他狼疮模型中，TLR7的缺失可预防或改善疾病。从机制而言，TLR7驱动的自发生发中心(GCs)与TLR7驱动的双阴性B细胞具有相对作用。目前认为，TLR7可以依赖于MyD88信号通路，独立于GCs造成疾病进展。Nature上的一项研究发现了一例与TLR7的功能获得突变有关的人类SLE病例，首次验证了人体内TLR7与SLE的因果关系，同时确定了TLR7中一个致病突变Y264H。小鼠模型显示该变体：可增强TLR7信号通路和下游NF-κB激活；可增加对鸟苷的亲和力，从而使其对通常不会刺激TLR7信号的单链RNA敏感；增强活化BCR细胞的生存能力；增强GCs、abc和浆细胞内抗体的扩增；临床表现包括：血小板减少、增值性肾小球肾炎加重、肝脏淋巴样浸润、局灶性心肌纤维化、血清中促炎细胞因子水平升高等等。TLR9保护和促进SLE发展的复杂调节此前有三种假说用于解释TLR9对疾病的调控：信号通路：TLR9-MyD88信号通路可诱导拮抗调控因子；DNA抗体：产生依赖于TLR9的DNA抗体可通过非炎症性方式清除自身抗原而具有保护作用；相互作用：TLR9蛋白可抑制TLR7的表达和功能，但其信号通路功能除外。但是这三种各自独立的理论无法解释为什么在实际实验中MyD88信号通路驱动的差异性结果。因此，研究人员通过小鼠模型来探索缺少配体或缺少结合MyD88信号通路的TLR9突变能够造成的影响：其小鼠模型选择了红斑狼疮易发的MRL/lpr株，引入内源性TLR9位点以分别阻断TLR9配体结合和阻断MyD88信号通路。TLR9配体结合和信号通路两种变量的控制Nat Immunol 23, 1457–1469 (2022).（1）整体可见，TLR9在狼疮中具有支架保护作用(scaffold protective role)。同时阻断了TLR9蛋白表达、配体结合与MyD88通路的TLR9-/-（TLR9K51E）小鼠显示：生存期增长，并改善了肾小球肾炎(GN)和间质性肾炎(IN)评分。原始CD4+细胞百分比增加，总B细胞和边缘区(MZ) B细胞频率增加，年龄相关B细胞(ABC)和浆母细胞(PB)频率减少。TLR9依赖性抗核小体自身抗体明显减少。这些数据表明：在没有TLR9配体结合的情况下，升高TLR9表达可以预防狼疮。生存曲线差异Nat Immunol 23, 1457–1469 (2022).（2）阻断配体结合情况下，TLR9-MyD88信号通路有促病表现。尽管已知TLR9的表达本身呈现保护作用，但是在表达TLR9水平的前提下，有配体结合也有MyD88通路的Tlr9+/−小鼠呈临床表现加重，存活率显著降低。在不依赖MyD88信号通路时，缺少抗核小体自身抗体并不会导致疾病进一步进展。因此，认为疾病加重与DNA抗体及其比例的变化无关。Nat Immunol 23, 1457–1469 (2022).因此这一致病性应该来自于单独的TLR9-MyD88信号通路。（3）由上述三种TLR9蛋白水平、配体结合能力阻断、信号通路阻断控制变量实验的不同小鼠模型结果，可以假设，TLR9保护疾病免于进展的机制中存在一种依赖配体结合但独立于MyD88的调节信号网络。Nat Immunol 23, 1457–1469 (2022).（4）Tlr9P915H小鼠中，TLR9的保护能力更明显。这表明TLR9具有独立于MyD88的配体依赖、调节信号和myd88介导的促炎信号。这种通路是B细胞中所独有的，会使其更容易分化为ABCs、CD80+PDL2+记忆样B细胞、PBs和PC，倾向于抑制B细胞激活。Tlr9−/−和Tlr9P915H不同的基因型可产生不同的PBs亚群。Nat Immunol 23, 1457–1469 (2022).二者也诱导不同的ABC和PB细胞状态。与Tlr9P915H相比，TLR9-/-模型能上调ABC中的共刺激(CD80, CD86和ITGB7)和PB标记(CD44, CD138和IRF4)。Tlr9P915H ABC则上调T-BET、BCL6和CD300a。TLR9和TLR7的相互作用（1）TLR9对TLR7分布的影响：在B细胞中，TLR9的分布较为均匀。相对地，TLR7的分布呈异质性。B细胞固有的应变差异或与IFN依赖性TLR7上调有关。Nat Immunol 23, 1457–1469 (2022).TLR9和TLR7在内质网退出和转运到晚期核内体的过程中存在对UNC93b伴侣的竞争。其中，UNC03bD34A突变可导致其优先与TLR7结合，从而增加TLR7内体转运和信号转导。换个角度来说，TLR7的转运和信号传递增加，那么TLR9的缺失也会导致更为严重的临床表现。不过，TLR9的缺失对TLR7在正常静息B细胞中的数量或定位的影响很小。（2）TLR9表达不影响TLR7信号传导：TLR7激动剂剂量反应实验和细胞RNA测序结果显示：在一定剂量范围内，TLR7诱导的NF-κB信号没有可检测到的差异。在TLR9存在或不存在的情况下，TLR7诱导的转录并不受到TLR9那种独立于MyD88、配体依赖的保护作用的影响。Nat Immunol 23, 1457–1469 (2022).整体而言，TLR7促进SLE疾病的作用大于TLR9的保护作用和/或TLR9和TLR7之间的直接相互作用。参考资料：1. Brown, G.J., Cañete, P.F., Wang, H. et al. TLR7 gain-of-function genetic variation causes human lupus. Nature 605, 349–356 (2022). https://doi-org.libproxy1.nus.edu.sg/10.1038/s41586-022-04642-z2. Leibler, C., John, S., Elsner, R.A. et al. Genetic dissection of TLR9 reveals complex regulatory and cryptic proinflammatory roles in mouse lupus. Nat Immunol 23, 1457–1469 (2022). https://doi-org.libproxy1.nus.edu.sg/10.1038/s41590-022-01310-23.Bernard, N.J. TLR7 drives human lupus. Nat Immunol 23, 817 (2022). https://doi-org.libproxy1.nus.edu.sg/10.1038/s41590-022-01235-w本周好文推荐如需转载请联系佰傲谷并在醒目位置注明出处﹀‍‍ ·········点亮在看，传递信息♥

前言在这篇文章中，我们讨论了针对肥大细胞的现有和新兴疗法，并考虑了这些治疗方法如何帮助我们了解肥大细胞在疾病中的功能。肥大细胞是组织驻留的造血细胞。作为局部组织的哨兵，肥大细胞在宿主防御某些寄生虫，细菌和毒素方面起着至关重要的作用。在对微生物的先天免疫反应中，肥大细胞可以在没有感染的情况下做出反应。例如，肥大细胞通过Toll样受体(TLR)直接激活，并释放杀菌活性物质，增强宿主防御机制，并通过不同的机制杀死病原体。同样，在对有毒毒素的反应中，肥大细胞可以直接被激活,释放蛋白酶，从而降解毒素。肥大细胞还通过Fc受体结合抗体来促进适应性免疫反应。肥大细胞可以”预武装”抗体，这使他们能够对毒素和细菌威胁做出快速反应。总而言之，这些特征表明肥大细胞在应对外部威胁方面具有重要而多样的作用。然而，立即做出反应并释放大量有效免疫介质的能力使肥大细胞成为人体最具潜在危险的细胞之一。肥大细胞的活化可导致慢性炎症和致病组织重塑，病理性活化则可通过过敏性休克导致快速死亡。当肥大细胞活动不是为了保护我们免受威胁时，它们通常会伤害我们并使我们生病，这是肥大细胞的“黑暗面”。关键问题是哪些疾病，这不是一个容易回答的问题。目前，支持人类肥大细胞致病作用的所有证据都是间接的。最近开发和使用的肥大细胞靶向治疗应该会改变这一点。这些治疗效果将帮助我们识别肥大细胞是驱动者还是旁观者。这些研究将进一步了解肥大细胞如何促进疾病的发病机制，并为患者提供新的治疗选择(图1)。图1 人类肥大细胞在疾病中功能我们可以在哪些疾病中靶向肥大细胞？大量证据支持荨麻疹、肥大细胞增多症和肥大细胞活化综合征是真正的肥大细胞驱动疾病的观点。(Box1）针对肥大细胞的疗法肥大细胞的靶向治疗进展多年来一直非常缓慢，但最近爆炸式增长，大多数新疗法都是最近开发的，并且仍在开发中(图2)。ASM，侵袭性系统性肥大细胞增多症；CIndU，慢性诱发性荨麻疹；CSU，慢性自发性荨麻疹；FDA，美国食品和药物管理局；H1，组胺H1受体；ISM，惰性系统性肥大细胞增多症；Siglec-8，唾液酸结合免疫球蛋白样凝集素8；TKI，酪氨酸激酶抑制剂。图2：肥大细胞靶向治疗的发展时间表活化的肥大细胞可以释放过多的预成型和从头合成的介质，激活靶细胞上的受体。阻断这些介质或其受体的药物可以消除肥大细胞相关效应(图3)。CysLTR，半胱氨酸白三烯受体；OSMRβ，抑菌素M受体；PGD2，前列腺素D2.图3 当前靶点和相关肥大细胞靶向治疗靶向组胺及其受体肥大细胞是组胺的主要组织来源，组胺激活其主要受体H1受体，以引起与过敏和其他炎症性疾病(包括荨麻疹)相关的症状的广泛反应。自发现以来，H1抗组胺药一直是许多肥大细胞驱动疾病的主要治疗方法(图 3a)。靶向胰蛋白酶四聚体β-类胰蛋白酶是主要的酶活性肥大细胞蛋白酶，在哮喘中独立于2型炎症而增加。靶向脂质介质：前列腺素和白三烯来源肥大细胞的PGD是一种脂质介质，通过其对CRTh2的作用与荨麻疹和过敏有关。靶向细胞因子及其受体IL-4和IL-5是2型细胞因子，可由人肥大细胞产生。这些细胞因子调节细胞分化，生长和细胞因子产生等细胞反应，影响肥大细胞和其他2型免疫细胞(包括嗜酸性粒细胞)的生物学功能。靶向 FcεRI 和 IgEFcεRI是高亲和力IgE受体，参与荨麻疹，哮喘和过敏反应。靶向2型细胞因子及其受体警报蛋白，胸腺基质淋巴生成素(TSLP)，IL-33和IL-25作用于下游细胞靶标，包括肥大细胞，以启动细胞因子的释放(图3b)。靶向细胞内信号通路有前景的药物可以靶向从质膜受体到细胞质的信号转导，并阻断肥大细胞活化和脱颗粒。在肥大细胞中，几种细胞质信号蛋白是潜在的靶标，包括脾脏酪氨酸激酶(SYK)和BTK(图3b)。靶向其他肥大细胞受体MRGPRX2对于肥大细胞释放IgE无关性介质至关重要。这种受体的独特之处还在于它可以被外源性和内源性物质激活，包括半胱氨酸蛋白酶，神经肽和一些药物。正在研究的另外两种肥大细胞表达受体是补体C5α受体(C5αR；也称为CD88)和细胞粘附分子1(CADM1)。C5αR由皮肤肥大细胞表达，并且已经提出它与C5α的相互作用来驱动CSU症状和其他自身免疫性疾病，例如类风湿性关节炎。沉默肥大细胞肥大细胞表达抑制性受体，如Siglec-8，CD200R，CD300a和FcγRIIb，在与抑制性受体的配体相互作用时阻断肥大细胞活化(图3c)。由于嗜酸性粒细胞也表达Siglec-8，抗Siglec-8抗体治疗显示出联合作用。消耗肥大细胞通过诱导细胞凋亡，来实现组织肥大细胞数量的减少，例如阻断SCF和/或其受体KIT(CD117),(图3d)。结语总而言之，使用肥大细胞靶向治疗，主要用于真正的肥大细胞驱动的疾病，如肥大细胞增多症和荨麻疹，促进我们对人类肥大细胞功能的理解(Box 2)。这些研究为肥大细胞驱动和肥大细胞相关疾病的发病机制提供见解，从而使受这些疾病影响的患者能得到更好的帮助。参考文献Kolkhir, P., Elieh-Ali-Komi, D., Metz, M. et al. Understanding human mast cells: lesson from therapies for allergic and non-allergic diseases. Nat Rev Immunol 22, 294–308 (2022). https://doi-org.libproxy1.nus.edu.sg/10.1038/s41577-021-00622-y识别微信二维码，添加生物制品圈小编，符合条件者即可加入微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。