MICA: Fundamental Role of Phosphoinositide 3-kinase delta in Infection and Immunity: Insights from a Novel Primary Immune Deficiency Syndrome, APDS

MICA：磷酸肌醇 3-激酶 δ 在感染和免疫中的基本作用：来自新型原发性免疫缺陷综合征 (APDS) 的见解

基本信息

批准号：
MR/M012328/1
负责人：
Alison Condliffe
金额：
$ 163.15万
依托单位：
University of Cambridge
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2015
资助国家：
英国
起止时间：
2015 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FM012328%2F1
关键词：
MICA Fundamental Role Phosphoinositide kinase

项目摘要

As a collaborative group of doctors, geneticists and scientists, we have recently discovered a new inherited disease, which causes increased susceptibility to infection. Affected patients suffer frequent and often severe bacterial infections of the lungs, sinuses and ears, often leading to permanent damage; they can also experience potentially life-threatening viral infections (particularly with the Herpes viruses such as those which cause chicken pox and shingles or glandular fever). Many of the patients die young from these devastating infections. We found that this disease is due to a genetic mutation that causes an enzyme called PI3Kdelta (which is found mainly in the cells of the immune system) to be more active and to 'work harder'. The overactive PI3Kdelta protein disturbs the chemical signals that control how immune cells develop and function in the body. B and T lymphocytes coordinate the immune system to fight infections. We found that the B-lymphocytes from our patients do not make good quality antibodies (proteins which help to kill invading bacteria), and that their T-lymphocytes (which provide protection from viral infection) also function less effectively. We do not yet know how common the condition is, why the B and T cells don't work properly, or if other immune cells or lung cells are also affected. We also don't know if other abnormalities that affect the activity of PI3Kdelta or related proteins contribute to susceptibility to infection in a more general setting. It is difficult to study immune cells from the patients, as most of them are unwell children, and because a feature of the disease is that the immune cells die rapidly outside the body. To solve this problem we have engineered a mouse with the same genetic defect, and will study how the immune cells of this mouse work. We will then take the findings from these mouse cells and see if they hold true in patients' cells; this strategy will enable us to use the limited number of patient cells available to us more effectively. We plan to expose the genetically altered mice to the same infections that the patients develop, to find out precisely why they are so susceptible. We will also test protective strategies such as drugs that reduce PI3Kdelta activity (PI3Kdelta inhibitors) to see if they prevent infection or reduce its severity. If this is the case, we will also treat patients who suffer from this disease with PI3Kdelta inhibitors and study the effects of this treatment; we believe such drugs will reduce the inflammation in their lungs and improve their ability to fight infection. Since too little PI3Kdelta activity is also detrimental immune, these medications will need to be carefully titrated, so we will need to monitor the effects on a range of biological markers of PI3Kdelta function as well as infection and inflammation.This work will determine the role and importance of PI3Kdelta in infection. This knowledge will help not only patients with the newly described disease, but may also give new insights into why some otherwise healthy people are prone to develop bacterial and viral infections. This is of importance nationally and globally, since respiratory infections cause more illness and more deaths than all cancers combined.

作为一个由医生、遗传学家和科学家组成的合作小组，我们最近发现了一种新的遗传性疾病，它会导致感染的易感性增加。受影响的患者经常遭受肺部、鼻窦和耳朵的严重细菌感染，常常导致永久性损伤；他们还可能经历潜在危及生命的病毒感染（特别是疱疹病毒，例如引起水痘和带状疱疹或腺热的病毒）。许多患者因这些毁灭性感染而英年早逝。我们发现这种疾病是由于基因突变引起的，这种突变导致一种叫做 PI3Kdelta 的酶（主要存在于免疫系统的细胞中）更加活跃并且“更加努力地工作”。过度活跃的 PI3Kdelta 蛋白会扰乱控制免疫细胞在体内发育和发挥功能的化学信号。 B 和 T 淋巴细胞协调免疫系统对抗感染。我们发现患者的 B 淋巴细胞不能产生高质量的抗体（有助于杀死入侵细菌的蛋白质），而且他们的 T 淋巴细胞（提供病毒感染保护）的功能也较差。我们还不知道这种情况有多常见，为什么 B 细胞和 T 细胞不能正常工作，或者其他免疫细胞或肺细胞是否也受到影响。我们也不知道影响 PI3Kdelta 或相关蛋白活性的其他异常是否会导致更一般情况下的感染易感性。研究患者的免疫细胞很困难，因为他们大多数是身体不适的儿童，而且这种疾病的一个特点是免疫细胞在体外迅速死亡。为了解决这个问题，我们设计了一只具有相同遗传缺陷的小鼠，并将研究这只小鼠的免疫细胞如何工作。然后，我们将从这些小鼠细胞中获取这些发现，看看它们在患者细胞中是否成立；这一策略将使我们能够更有效地利用有限数量的患者细胞。我们计划让经过基因改造的小鼠接触与患者相同的感染，以准确找出它们为何如此容易受到感染。我们还将测试保护策略，例如降低 PI3Kdelta 活性的药物（PI3Kdelta 抑制剂），看看它们是否可以预防感染或减轻其严重程度。如果是这样的话，我们也会用PI3Kdelta抑制剂来治疗患有这种疾病的患者，并研究这种治疗的效果；我们相信这些药物将减少他们肺部的炎症并提高他们抵抗感染的能力。由于 PI3Kdelta 活性太低也不利于免疫，因此需要仔细滴定这些药物，因此我们需要监测对 PI3Kdelta 功能以及感染和炎症的一系列生物标志物的影响。这项工作将确定其作用和效果。 PI3Kdelta 在感染中的重要性。这些知识不仅可以帮助患有新描述的疾病的患者，还可以为为什么一些原本健康的人容易发生细菌和病毒感染提供新的见解。这在全国和全球范围内都具有重要意义，因为呼吸道感染导致的疾病和死亡人数比所有癌症的总和还要多。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Biallelic RIPK1 mutations in humans cause severe immunodeficiency, arthritis, and intestinal inflammation.

DOI：
10.1126/science.aar2641
发表时间：
2018-08-24
期刊：
Science (New York, N.Y.)
影响因子：
0
作者：
Cuchet-Lourenço D;Eletto D;Wu C;Plagnol V;Papapietro O;Curtis J;Ceron-Gutierrez L;Bacon CM;Hackett S;Alsaleem B;Maes M;Gaspar M;Alisaac A;Goss E;AlIdrissi E;Siegmund D;Wajant H;Kumararatne D;AlZahrani MS;Arkwright PD;Abinun M;Doffinger R;Nejentsev S
通讯作者：
Nejentsev S

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