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

该项目的重点是两种毁灭性的疾病，称为风湿性关节炎（RA）和系统性红斑狼疮（SLE）。这些都是自身免疫性疾病，而不是免疫系统只对抗感染，它变得过度激活，并导致炎症，这是损害身体。在RA中，这主要影响关节的衬里，而在SLE中，它可以影响身体的许多部分，包括关节，皮肤，肺，肾脏和大脑。这些疾病可能危及生命，但到目前为止，治疗的重点是抑制免疫系统，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，或者并非对所有人都有效。随着医学的进步，我们对这些疾病的病因有了更多的了解，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，并非所有的免疫性疾病都会引起炎症。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，使其处于抗炎状态。虽然这有助于艾滋病毒的传播，但它也可以给我们一些教训，并提出有针对性地抑制免疫系统的想法。HIV表面有一种叫做gp 120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，这种蛋白质本身不具有感染性，也不危险。然而，研究表明，gp 120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，细胞可以产生称为细胞因子的产物，进一步推动炎症循环。一个这样的例子是干扰素-α（IFNa），其主要由称为浆细胞样树突细胞（pDC）的细胞亚型产生。IFNa已被证明在RA和SLE中是有害的。然而，有趣的是，gp 120可以减少pDC产生这些破坏性的炎性细胞因子，包括IFNa。在pDC中，gp 120还可以增加称为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实现这一点。最后，已经用gp 120处理的pDC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，在RA和SLE中可见。在这个项目中，我想了解更多关于pDCs在RA和SLE疾病中的作用。我还想看看gp 120是否有助于减少pDC在这些疾病中的任何破坏性作用。如果这一方法有效，gp 120可能被开发为治疗RA和SLE的新方法。我将首先研究gp 120对从健康志愿者血液中提取的pDC和其他细胞类型的作用。接下来，我将看看使用RA和SLE患者的血液时会发生什么。在RA患者中，我也将观察从滑液和滑膜中提取的pDC通过进行上述研究，我相信我可以1）开始回答这个问题，如果gp 120可以作为一种新的治疗RA和SLE的开发，以及2）增加了关于pDC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.