TPSAB1

宝子们，有没有过这样的经历：精心准备出门约会或参加重要聚会，临出门前对着镜子一看，脸上不知何时冒出了红斑，还有些小丘疹若隐若现，瞬间心情就像坠入了冰窖。又或者在日常工作中，总感觉面部灼热、瘙痒，让人坐立不安，严重影响了生活和社交。其实，这可能就是玫瑰痤疮在作祟。这种慢性炎症性皮肤病，困扰着许多人。 传统治疗手段如使用甲硝唑、壬二酸、异维A酸等药物，虽有一定疗效，但往往伴随着诸如皮肤瘙痒、灼烧感、潜在的视网膜病变及致畸风险等副作用。激光疗法虽能缓解红斑症状，但对于丘疹脓疱性病变效果不佳，且费用高昂。 近期一项发表在Int Immunopharmacol的研究Activation of aryl hydrocarbon receptor ameliorates degranulation of LL-37 induced mast cells in rosacea through enhancing autophagy为玫瑰痤疮治疗带来了新的希望。研究发现，肥大细胞在玫瑰痤疮的发病过程中起着关键作用。在患者的皮肤病变部位，肥大细胞数量显著增加，这些被激活的肥大细胞会释放出多种细胞因子，如白细胞介素-6（IL-6）、肿瘤坏死因子（TNF-α）、基质金属蛋白酶（MMP9）等，这些细胞因子进一步加剧炎症反应，推动病情发展。 在本研究中，科研人员以肥大细胞（RBL-2H3）为研究对象，用LL-37处理模拟玫瑰痤疮环境。随后加入AhR激动剂（tapinarof），并利用自噬激动剂（RAPA）和抑制剂（CQ）探究其机制。 研究结果显示，在细胞脱颗粒与炎症因子表达方面，LL-37处理后，肥大细胞内的脱颗粒标记物Cma1和Tpsab1在蛋白和mRNA水平上随时间显著上升，24小时达到高峰，同时炎症因子IL-6、MMP9和TNF-α的mRNA表达也在24小时明显增加。而tapinarof处理24小时后，Cma1和Tpsab1的蛋白及mRNA表达大幅降低，IL-6、MMP9和TNF-α的mRNA表达也显著下降，表明tapinarof能有效抑制肥大细胞脱颗粒及炎症反应。 观察自噬标记物变化发现，随着tapinarof浓度增加，Western blot检测发现LC3B-I逐渐向LC3B-II转化，p62含量减少。经Image J软件分析，证实自噬在tapinarof作用下增强。免疫荧光染色显示，tapinarof+LL-37组中LC3B-II点状聚集数量比仅LL-37诱导的肥大细胞明显增多，进一步证明tapinarof促进自噬。 在自噬调节剂与tapinarof协同关系方面，对于自噬激动剂RAPA，浓度高于5 μM会降低细胞活力，但5 μ MRAPA与10 μM tapinarof共同作用于16 μM LL-37诱导的肥大细胞24小时或48小时后，Western blot结果显示LC3B-II表达随tapinarof处理时间延长而上升，验证了自噬增强效果。 对于自噬抑制剂CQ，浓度高于5 μM显著降低细胞活力，在16 μM LL-37处理24小时的细胞中，先加5 μM CQ处理4小时再用tapinarof处理24小时后，与未加CQ组相比，CQ仅部分抑制tapinarof诱导的自噬，且RT-qPCR分析表明CQ使Cma1、Tpsab1、MMP9、TNF-α和IL-6表达增加，证实自噬在tapinarof缓解炎症中起关键作用，且CQ可逆转tapinarof的部分抗炎效果。 图 1. tapinarof减轻肥大细胞中的玫瑰痤疮样炎症 图 2. tapinarof诱导自噬以减少肥大细胞中的玫瑰痤疮样炎症反应 此前研究已表明AhR激活可改善小鼠玫瑰痤疮样皮疹并抑制相关细胞信号通路，此次研究进一步明确了其通过增强自噬减轻肥大细胞脱颗粒从而缓解玫瑰痤疮的机制。尽管目前该研究仅处于体外实验阶段，但已为玫瑰痤疮的治疗研究指明了新方向。未来还需开展动物及临床研究进一步验证，若能成功转化为临床应用，有望为玫瑰痤疮患者带来更有效、更安全的治疗方案，极大地改善患者的生活质量，推动皮肤病治疗的发展。 参考文献： Chen S, Hu H, Wu J, et al. Activation of aryl hydrocarbon receptor ameliorates degranulation of LL-37 induced mast cells in rosacea through enhancing autophagy. Int Immunopharmacol. Published online December 29, 2024. doi:10.1016/j.intimp.2024.113910 本文仅用于学术分享，转载请注明出处。若有侵权，请联系微信：bioonSir 删除或修改！ 点击下方「阅读原文」，前往生物谷官网查询更多生物相关资讯~

Researchers reported for the first time that a genetic biomarker may be able to help predict the severity of food allergy reactions. Currently there is no reliable or readily available clinical biomarker that accurately distinguishes patients with food allergies who are at risk for severe life-threatening reactions versus more mild symptoms. Researchers from Ann & Robert H. Lurie Children's Hospital of Chicago and colleagues reported for the first time that a genetic biomarker may be able to help predict the severity of food allergy reactions. Currently there is no reliable or readily available clinical biomarker that accurately distinguishes patients with food allergies who are at risk for severe life-threatening reactions versus more mild symptoms. Findings were published in the Journal of Allergy and Clinical Immunology. Dr. Lang and colleagues found that the presence of an enzyme isoform called α-tryptase, which is encoded by the TPSAB1 gene, correlates with increased prevalence of anaphylaxis or severe reaction to food as compared to subjects without any α-tryptase. "Determining whether or not a patient with food allergies has α-tryptase can easily be done in clinical practice using a commercially available test to perform genetic sequencing from cheek swabs," said lead author Abigail Lang, MD, MSc, attending physician and researcher at Lurie Children's and Assistant Professor of Pediatrics at Northwestern University Feinberg School of Medicine. "If the biomarker is detected, this may help us understand that the child is at a higher risk for a severe reaction or anaphylaxis from their food allergy and should use their epinephrine auto-injector if exposed to the allergen. Our findings also open the door to developing an entirely new treatment strategy for food allergies that would target or block α-tryptase. This is an exciting first step and more research is needed." Tryptase is found mainly in mast cells, which are white blood cells that are part of the immune system. Mast cells become activated during allergic reactions. Increased TPSAB1 copy number which leads to increased α-tryptase is already known to be associated with severe reactions in adults with Hymenoptera venom allergy (or anaphylaxis following a bee sting). Dr. Lang's study included 119 participants who underwent TPSAB1 genotyping, 82 from an observational food allergy cohort at the National Institute of Allergy and Infectious Diseases (NIAID) and 37 from a cohort of children who reacted to peanut oral food challenge at Lurie Children's. "We need to validate our preliminary findings in a much larger study, but these initial results are promising," says Dr. Lang. "We also still need a better understanding of why and how α-tryptase makes food allergy reactions more severe in order to pursue this avenue for potential treatment." Rajesh Kumar, MD, MSc, from Lurie Children's is the co-senior author on the study. Dr. Kumar is the Interim Division Head of Allergy and Immunology and Professor of Pediatrics at Northwestern University Feinberg School of Medicine. This work was supported in part by the Midwest Allergy Research Institute (MARI) Food Allergy Pilot Research Award and NIAID-sponsored T32 grant AI083216. This project was funded in part with federal funds from the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, NIH. This project has also been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. 75N91019D00024.

Researchers have published an assessment of 13 studies that took a genotype-first approach to patient care. This approach contrasts with the typical phenotype-first approach to clinical research, which starts with clinical findings. A genotype-first approach to patient care involves selecting patients with specific genomic variants and then studying their traits and symptoms; this finding uncovered new relationships between genes and clinical conditions, broadened the traits and symptoms associated with known disorders, and offered insights into newly described disorders. National Institutes of Health researchers have published an assessment of 13 studies that took a genotype-first approach to patient care. This approach contrasts with the typical phenotype-first approach to clinical research, which starts with clinical findings. A genotype-first approach to patient care involves selecting patients with specific genomic variants and then studying their traits and symptoms; this finding uncovered new relationships between genes and clinical conditions, broadened the traits and symptoms associated with known disorders, and offered insights into newly described disorders. The study was published in the American Journal of Human Genetics. "We demonstrated that genotype-first research can work, especially for identifying people with rare disorders who otherwise might not have been brought to clinical attention," says Caralynn Wilczewski, Ph.D., a genetic counselor at the National Human Genome Research Institute's (NHGRI) Reverse Phenotyping Core and first author of the paper. Typically, to treat genetic conditions, researchers first identify patients who are experiencing symptoms, then they look for variants in the patients' genomes that might explain those findings. However, this can lead to bias because the researchers are studying clinical findings based on their understanding of the disorder. The phenotype-first approach limits researchers from understanding the full spectrum of symptoms of the disorders and the associated genomic variants. "Genomics has the potential to change reactive medicine into preventative medicine," said Leslie Biesecker, M.D., NIH distinguished investigator, director of NHGRI's Center for Precision Health Research and a senior author of the article. "Studying how taking a genotype-first approach to research can help us learn how to model predictive and precision medicine in the future." The study documents three types of discoveries from a genotype-first approach. First, the researchers found that this approach helped discover new relationships between genomic variants and specific clinical traits. For example, one NIH study found that having more than two copies of the TPSAB1 gene was associated with symptoms related to the gastrointestinal tract, connective tissues, and the nervous system. Second, this approach helped researchers find novel symptoms related to a disorder that clinicians previously missed because the patient did not have the typical symptoms. NHGRI researchers identified a person with a genomic variant associated with a known metabolic disorder. Further testing found that the individual had high levels of certain chemicals in their body associated with the disorder, despite having only minor symptoms. Third, this approach allowed researchers to determine the function of specific genomic variants, which has the potential to help clinicians understand newly described disorders. For example, in one study, NHGRI researchers and their collaborators found that a genomic variant was associated with immune dysfunction at the molecular level in blood cells. The 13 studies that implemented a genotype-first approach used genomic data from NHGRI's Reverse Phenotyping Core in the Center for Precision Health Research. The core aggregates genomic data from programs such as ClinSeq(R) and the National Institute of Allergy and Infectious Disease (NIAID) Centralized Sequencing Protocol, which together allowed analyses to be performed on more than 16,000 research participants who have undergone genome or exome sequencing. Exome and genome sequencing data from participants who consented to broad genomic data sharing and recontact for future research studies are currently available to NIH intramural researchers through the Reverse Phenotyping Core Genomic Data Browser to identify genomic variants of interest for their own research. "Importantly, we provide a framework for other institutions to build research programs that allow for genotype-first studies. With more programs taking this approach, we can better study the predictive potential of genomic medicine," said Clesson Turner, M.D., director of NHGRI's Reverse Phenotyping Core and a senior author of the article. The framework includes broad genomic data sharing with the ability to recontact participants explicitly stated during the informed consent process. NHGRI researchers recommend institutions aiming to establish genotype-first centers create strategic plans, especially for deciding what genomic findings will be returned, which may involve genetic counseling services. Importantly, according to the study, researchers must actively communicate with study participants to build informed and trusting long-term relationships. "In the future, as more researchers adopt this approach, we hope to identify more people who may be helped by the availability of their genome sequence, especially as more diverse populations join genome-sequencing studies," says Dr. Wilczewski.