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，它会导致对感染的易感性增加。受影响的患者经常遭受严重的肺部、鼻窦和耳朵细菌感染，往往导致永久性损伤；他们也可能遭受潜在的危及生命的病毒感染（特别是疱疹病毒，如引起水痘、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名为PI3Kdelta的酶（主要存在于免疫系统的细胞中）变得更活跃，“更努力地工作”。过度活跃的PI3Kdelta蛋白会干扰体内控制免疫细胞发育和功能的化学信号。B淋巴细胞和T淋巴细胞协同免疫系统对抗感染。我们发现，患者的b淋巴细胞不能产生高质量的抗体（帮助杀死入侵细菌的蛋白质），他们的t淋巴细胞（提供防止病毒感染的保护）的功能也不太有效。我们还不知道这种情况有多普遍，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。我们也不知道是否其他影响PI3Kdelta或相关蛋白活性的异常在更普遍的情况下有助于对感染的易感性。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老鼠，并将研究这只老鼠的免疫细胞是如何工作的。然后，我们将从这些小鼠细胞中获得这些发现，看看它们是否适用于患者细胞；这一策略将使我们能够更有效地利用有限的患者细胞。我们计划将转基因小鼠暴露在与患者相同的感染环境中，以找出它们如此易感的确切原因。我们还将测试保护策略，如降低PI3Kdelta活性的药物（PI3Kdelta抑制剂），看看它们是否能预防感染或降低其严重程度。如果是这种情况，我们也会用PI3Kdelta抑制剂治疗患有这种疾病的患者，并研究这种治疗的效果；我们相信这些药物会减少他们肺部的炎症，提高他们抵抗感染的能力。由于PI3Kdelta活性过低也对免疫有害，因此这些药物需要仔细滴定，因此我们需要监测对PI3Kdelta功能的一系列生物标志物以及感染和炎症的影响。这项工作将确定PI3Kdelta在感染中的作用和重要性。这一发现不仅有助于这种新发现的疾病的患者，还可能对为什么一些健康的人容易患上细菌和病毒感染提供新的见解。这在国家和全球都很重要，因为呼吸道感染导致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.