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

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，这种疾病会增加感染的易感性。受影响的患者经常遭受肺部，鼻窦和耳朵的严重细菌感染，通常导致永久性损伤;他们也可能经历潜在的危及生命的病毒感染（特别是疱疹病毒，如引起水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。我们发现这种疾病是由于一种基因突变导致一种称为PI 3 Kdelta的酶（主要存在于免疫系统细胞中）更加活跃并且“工作更努力”。过度活跃的PI 3 Kdelta蛋白干扰了控制免疫细胞在体内发育和功能的化学信号。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），他们的T淋巴细胞（提供病毒感染的保护）的功能也不那么有效。我们还不知道这种情况有多常见，为什么B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。我们也不知道其他影响PI 3 K δ或相关蛋白活性的异常是否会在更普遍的情况下导致感染易感性。很难研究患者的免疫细胞，因为他们中的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得发现，看看它们是否适用于患者细胞;这种策略将使我们能够更有效地利用有限数量的患者细胞。我们计划将基因改变的小鼠暴露于与患者相同的感染中，以确切地找出它们如此易感的原因。我们还将测试保护性策略，如降低PI 3 Kdelta活性的药物（PI 3 Kdelta抑制剂），以确定它们是否能预防感染或降低其严重程度。如果是这样的话，我们也将用PI 3 Kdelta抑制剂治疗患有这种疾病的患者，并研究这种治疗的效果;我们相信这样的药物会减少他们肺部的炎症，提高他们对抗感染的能力。由于PI 3 Kdelta活性太少也会对免疫有害，因此这些药物需要仔细滴定，因此我们需要监测PI 3 Kdelta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PI 3 Kdelta在感染中的作用和重要性。这些知识不仅有助于患有这种新描述疾病的患者，而且还可能为为什么一些健康的人容易发生细菌和病毒感染提供新的见解。这在国家和全球都很重要，因为呼吸道感染引起的疾病和死亡人数超过所有癌症的总和。

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.