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

• 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

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.

作为一个合作的医生，遗传学家和科学家，我们最近发现了一种新的遗传疾病，这会增加感染的易感性。受影响的患者经常患肺，鼻窦和耳朵的细菌感染，通常会导致永久损害。他们还可以体验潜在的威胁生命的病毒感染（尤其是疱疹病毒，例如引起鸡肉痘和带状疱疹或腺热的病毒）。许多患者死于这些毁灭性的感染。我们发现该疾病是由于一种遗传突变引起的，该突变导致一种称为PI3KDELTA（主要在免疫系统细胞中）的酶更加活跃，并且“更努力地工作”。过度活跃的PI3KDELTA蛋白会扰乱控制免疫细胞如何在体内发育和起作用的化学信号。 B和T淋巴细胞协调免疫系统以抵抗感染。我们发现，来自患者的B淋巴细胞不会产生高质量的抗体（有助于杀死入侵细菌的蛋白质），并且其T-淋巴细胞（可提供免受病毒感染的保护）也不太有效地发挥作用。我们尚不知道病情的普遍性，为什么B和T细胞无法正常工作，或者其他免疫细胞或肺部细胞也受到影响。我们也不知道影响PI3KDELTA或相关蛋白质活性的其他异常是否有助于在更一般的环境中易感感染。很难研究患者的免疫细胞，因为其中大多数是不适的儿童，并且由于该疾病的特征是免疫细胞在体外迅速死亡。为了解决这个问题，我们已经设计了具有相同遗传缺陷的小鼠，并将研究该小鼠的免疫细胞的工作方式。然后，我们将从这些小鼠细胞中获取发现，看看它们是否在患者细胞中成立；该策略将使我们能够更有效地使用有限数量的患者细胞。我们计划将遗传学改变的小鼠暴露于患者发育的相同感染中，以确切地找出为什么它们如此敏感的原因。我们还将测试诸如减少PI3KDELTA活性（PI3KDELTA抑制剂）的药物，以查看它们是否防止感染或减少其严重程度。如果是这种情况，我们还将治疗患有PI3KDELTA抑制剂并研究该疗法的影响的患者。我们认为，这种药物将减少肺部炎症，并提高其对抗感染的能力。由于PI3Kdelta活性太少也有害免疫，因此需要仔细滴定这些药物，因此我们需要监视对PI3KDELTA功能以及感染和炎症的一系列生物学标记的影响。这将确定PI3KDELTA在感染中的作用和重要性。这些知识不仅可以帮助患有新描述的疾病的患者，而且还可以给出新的见解，说明为什么某些健康的人容易发展细菌和病毒感染。这在全国和全球都很重要，因为呼吸道感染会导致比所有癌症总和的疾病更多和更多的死亡。

项目成果

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.)
• 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

MO064TISSUE-RESIDENT B CELLS DETERMINE SUSCEPTIBILITY TO URINARY TRACT INFECTION BY ORCHESTRATING MACROPHAGE POLARISATION

MO064组织驻留 B 细胞通过协调巨噬细胞极化来确定尿路感染的易感性

• DOI: 10.1093/ndt/gfaa140.mo064
• 发表时间: 2020
• 期刊: Nephrology Dialysis Transplantation
• 影响因子: 6.1
• 作者: Clatworthy M