MICA Investigating the role of cytomegalovirus reactivation in amplifying monocyte driven renal damage in active ANCA associated vasculitis

在ANCA相关性脉管炎(AAV)中，身体自身的白细胞攻击血管。AAV最常累及肾脏，经常导致肾衰竭和透析。在需要透析的人中，10人中有2-3人死亡，10人中有4人无法恢复肾功能。重要的是，感染和心脏病是导致死亡的主要原因。如果不进行治疗，AAV将危及生命；治疗涉及到强有力的免疫抑制。虽然预后已显著改善，但疾病及其治疗造成损害的风险仍然很大，特别是在头12个月。巨细胞病毒(CMV)是一种常见病毒，存在于超过一半的人口中。最初感染病毒后，病毒会终生留在体内，并经历一段时间的重新激活。对于健康的人，免疫系统会控制病毒。我的主管团队最近的研究表明，大约四分之一的稳定AAV患者会发生无症状的CMV重新激活，并导致能够损害血管的有害免疫细胞扩张。我们知道这些有害细胞的CMV重新激活和扩张与肾功能降低、感染和心脏病风险增加有关。我们尚不知道新诊断或最近复发的AAV患者发生无症状CMV重新激活的频率。我们预计，在确诊或复发(急性期)后的前12个月，由于抑制免疫系统和血管炎引起的炎症所需的药物，CMV将更频繁地重新激活，这将与更糟糕的结果有关。我们也不知道CMV重新激活如何放大脉管炎对肾脏的损害。我们的初步工作表明，在AAV中，CMV的重新激活增加了一种称为单核细胞(CCR2表达单核细胞)的特定炎性细胞群的比例。我们的初步研究结果表明，在这些患者中，血液中表达CCR2的单核细胞越多，肾功能越差。现在也有越来越多的证据表明，在小鼠体内阻断CCR2单核细胞可以减少各种肾脏疾病的肾脏损害。这表明，这种单核细胞诱导的肾脏损伤途径并不局限于脉管炎患者。这项研究的主要目的是测量CMV在前12个月重新激活的频率，并确定这是否与疾病活动性增加、持续的透析需求和AAV造成的损害增加有关。然后，我们将探讨CMV重新激活是否会导致表达CCR2的单核细胞增加，以及这些单核细胞是否会导致AAV的持续性肾脏损害。我们的目标是招募所有新诊断或最近复发的AAV患者。患者将在12个月内接受10次研究访问。在每次访问时，参与者将被要求提供血液和尿液样本，以确定CMV是否重新激活，并测量其他炎症化学物质和蛋白质。参与者还将被要求填写一份关于他们的健康和生活质量的问卷。常规进行肾脏活检以确认甲型肝炎病毒的诊断。我们将使用其中的一些肾组织来确定组织中单核细胞的数量，并评估这是否与我们在活检中看到的肾脏损害有关。如果我们目前建议的研究证实，CMV重新激活在急性AAV期间是常见的，并与显著的并发症有关，这可能导致未来在试验中抑制CMV的研究，旨在改善AAV患者的预后。这项研究还将提高我们对巨细胞病毒在驱动肾脏损害中的重要性的理解，这可能与其他肾脏疾病有关。

In ANCA-associated vasculitis (AAV), the body's own white blood cells attack blood vessels. The kidneys are most commonly involved in AAV, frequently leading to kidney failure and dialysis. Amongst people that require dialysis, 2-3 out of 10 do not survive, and 4 out of 10 do not recover kidney function. Importantly, infection and heart disease are leading causes of death. Without treatment AAV is life-threatening; treatment involves powerful immunosuppression. Whilst prognosis has significantly improved, there remains significant risk of damage from the disease and its treatment, especially during the first 12 months. Cytomegalovirus (CMV) is a common virus, present in over half the population. After initial infection, the virus remains in the body for life and undergoes periods of reactivation. In a healthy person, the immune system keeps the virus under control. Recent research within my supervisors' group, showed that asymptomatic CMV reactivation occurs in roughly 1 in 4 people with stable AAV and leads to expansions of harmful immune cells able to damage blood vessels. We know that CMV reactivation and expansion of these harmful cells are associated with reduced kidney function and increased risk of infection and heart disease.What we do not yet know is how often asymptomatic CMV reactivation occurs in patients with newly diagnosed or recently relapsed AAV. We anticipate that CMV will reactivate much more frequently during the first 12 months following diagnosis or relapse (the acute phase), due to the medication needed to suppress the immune system and inflammation from the vasculitis, and that this will be linked with worse outcomes.We also do not yet know how CMV reactivation may amplify the damage that vasculitis can do to the kidney. Our preliminary work suggests that CMV reactivation increases the proportion of a specific inflammatory group of white blood cells called monocytes (CCR2 expressing monocytes) in AAV. Our preliminary findings suggest that in these patients, the more CCR2 expressing monocytes in the blood, the worse the kidney function. There is also an increasing amount of evidence now that blocking CCR2 monocytes in mice reduces kidney damage across a wide variety of kidney conditions. This suggests that this monocyte-induced kidney damage pathway is not just limited to patients with vasculitis. The main aims of this study are to measure the frequency of CMV reactivation during the first 12 months and determine whether this is linked to increased disease activity, ongoing dialysis requirement and increased damage from AAV. We will then explore whether CMV reactivation causes an increase in CCR2 expressing monocytes, and whether these monocytes cause persistent kidney damage in AAV.We will aim to recruit all patients with newly diagnosed or recently relapsed AAV. Patients will be followed up with 10 study visits over 12 months. At each visit, participants will be required to give blood and urine samples to determine if CMV has reactivated and measure other inflammatory chemicals and proteins. Participants will also be asked to fill in a questionnaire on their health and quality of life. A kidney biopsy is performed routinely to confirm a diagnosis of AAV. We will use some of this kidney tissue to identify the number of monocytes in the tissue and assess if this is related to the kidney damage we see on the biopsy. If our current proposed study confirms that CMV reactivation is common during acute AAV and is linked with significant complications, this may lead to future research of suppression of CMV in a trial, aiming to improve outcomes for people with AAV. This research will also improve our understanding of the importance of CMV in driving kidney damage which may be relevant to other kidney conditions.