Study into the potentially therapeutic immunomodulatory effects of gp120 in autoimmune rheumatic disease

这个项目的重点是两种毁灭性的疾病，类风湿关节炎（RA）和系统性红斑狼疮（SLE）。这些都是自身免疫性疾病，免疫系统不仅会对抗感染，还会过度激活，导致炎症，对身体有害。在类风湿性关节炎中，这主要影响关节的内壁，而在系统性红斑狼疮中，它可以影响身体的许多部位，包括关节、皮肤、肺、肾和大脑。这些疾病可能危及生命，但迄今为止的治疗主要集中在抑制免疫系统，以控制和限制炎症造成的损害。这些治疗通常有副作用，特别是导致严重感染，或者不是对所有人都有效。随着医学的进步，我们对导致这些疾病的原因了解得更多，因此我们可以专注于开发所谓的靶向治疗方法来阻止它们。然而，并不是所有的免疫疾病都会引起炎症。在人类免疫缺陷病毒（HIV）感染中，病毒可以改变免疫系统的平衡，使其进入抗炎状态。虽然这有助于艾滋病毒的传播，但它也可以给我们上一课，并提出有针对性地抑制免疫系统的想法。HIV病毒表面有一种叫做gp120的蛋白质，正是这种蛋白质与免疫系统的元素相互作用，导致靶向抑制。从病毒中分离出来，这种蛋白质本身没有传染性，也没有危险。然而，研究表明gp120本身具有许多有趣的作用，它们共同降低免疫激活和抑制炎症。在炎症中，细胞可以产生一种叫做细胞因子的产物，这种产物进一步推动炎症循环。其中一个例子是干扰素- α (IFNa)，它主要由一种称为浆细胞样树突状细胞（pDCs）的细胞亚型产生。IFNa已被证明在类风湿关节炎和SLE中具有破坏性。然而，有趣的是，gp120可以减少pDCs产生这些破坏性的炎症细胞因子，包括IFNa。在pDCs中，gp120也可以增加一种叫做IDO的酶的水平。这是一种重要的酶，因为它可以减少炎症。它通过增加抗炎免疫细胞的数量和减少炎症免疫细胞的数量来做到这一点。最后，gp120处理过的pDCs可以影响其他细胞（b细胞），以降低血液中自身抗体的水平。自身抗体是自身免疫性疾病的标志物，见于类风湿性关节炎和系统性红斑狼疮。在这个项目中，我想更多地了解pDCs在RA和SLE疾病中的作用。我还想看看gp120是否可以帮助减少pDCs在这些疾病中的任何破坏性作用。如果有效，gp120可以作为RA和SLE的新治疗方法。我将首先研究gp120对从健康志愿者血液中提取的pDCs和其他细胞类型的作用。接下来我将看看使用风湿性关节炎和系统性红斑狼疮患者的血液会发生什么。对于类风湿性关节炎患者，我也会观察从滑膜液和滑膜（关节的内衬和周围的液体）中提取的pDCs，它们在类风湿性关节炎中受损。通过以上的研究，我相信我可以1)开始回答gp120是否可以作为一种新的治疗RA和SLE的问题，以及2)增加关于pDCs在RA和SLE中的作用的知识。

This project focuses on two devastating diseases called Rheumatoid Arthritis (RA) and Systemic Lupus Erythematous (SLE). These are autoimmune diseases where instead of the immune system only fighting infection, it becomes over activated and causes inflammation which is damaging to the body. In RA this mainly affects the lining of the joints, whereas in SLE it can affect lots of parts of the body including the joints, the skin, the lungs, kidney and brain. These diseases can be life-threatening but treatment so far has focused on dampening down the immune system to control and limit the damage caused by the inflammation. These treatments often have side effects, particularly leading to severe infections, or do not work in all people. As medical science progresses we learn more about what causes these diseases and so we can focus on developing so-called targeted treatments to stop them. Not all immune diseases cause inflammation however. In Human Immunodeficiency Virus (HIV) infection the virus can change the immune system's balance towards an anti-inflammatory state. Although this helps HIV spread, it can also teach us lessons and suggest ideas to suppress the immune system in a targeted way. HIV has a protein on its surface called gp120, and it is this protein that interacts with elements of the immune system, leading to targeted suppression. Taken away from the virus and by itself this protein is not infective and is not dangerous. However, research shows that gp120 by itself has a number of interesting effects that together decrease immune activation and dampen down inflammation.In inflammation, cells can produce products called cytokines that drive the cycle of inflammation further. One such example is interferon-alpha (IFNa) which is mainly produced by a cell subtype called plasmacytoid dendritic cells (pDCs). IFNa has been shown to be damaging in RA and in SLE. Interestingly however, gp120 can reduce pDCs from making these damaging inflammatory cytokines, including IFNa. In pDCs gp120 can also increase levels of an enzyme called IDO. This is an important enzyme as it works to reduce inflammation. It does this by both increasing the number of anti-inflammatory immune cells and also reducing the number of inflammatory immune cells. Finally pDCs that have been treated with gp120 can affect other cells (B-cells) to reduce the levels of autoantibodies in the blood. Autoantibodies are markers of autoimmune disease and are seen in RA and SLE.In this project I want to find out more about what part pDCs play in RA and SLE disease. I also want to see if gp120 can help to reduce any damaging actions of pDCs in these diseases. If this worked, gp120 could be developed as a new treatment for RA and SLE. I will research this by firstly looking at what the gp120 does on pDCs and other cell types taken from the blood of healthy volunteers. I will next see what happens when using blood from patients with RA and SLE. In patients with RA I will also look at pDCs taken from synovial fluid and synovium (this is the lining of the joint and the fluid that surrounds it) which becomes damaged in RA.By carrying out the above research I believe that I can 1) start to answer the question if gp120 can be developed as a new treatment for RA and SLE as well as 2) add to the knowledge about what role pDCs have in RA and SLE.