Immune Evaluation in Patients with Autoimmune Lymphoproliferative Syndrome

美国国立卫生研究院的阿尔卑斯小组目前跟踪了400多个家庭。过去，我们基于562名ALPS患者及其家庭成员的评估，描述了与FAS（种系和体细胞）突变相关的ALPS生物标志物。这表明，双阴性T细胞水平高于4%，同时可溶性FasL、维生素B12或IL-10水平升高，对伴有种系和体细胞FAS突变的ALPS的预测价值高达98%。结果被纳入新的ALPS诊断标准。最近，我们发现影响FAS细胞外区域的大多数突变通过诱导单倍体功能不全来破坏蛋白质功能，从而导致FAS低表达、低DISC形成和抑制凋亡。与影响FAS细胞内结构域的突变相比，这些缺陷较轻，这可能解释了细胞外结构域突变患者的可变表达性和较低的外显率。

The NIH ALPS group currently follows a cohort of over 400 families. In the past we have described biomarkers for ALPS related to mutations in FAS (both germline and somatic) based on teh evaluation of 562 ALPS patients and their family members. This revealed that a level of double negative T cells above 4% together with an elevation of soluble FasL, Vitamin B12 or IL-10 has up to 98% of predictive value for ALPS with both germline and somatic FAS mutations. The results were incorporated into the new diagnostic criteria for ALPS. More recently we found that most mutations affecting the extracellular region of FAS disrupt protein function by inducing haploinsufficiency, with consequent low FAS expression, low DISC formation and suppressed apoptosis. These defects were milder as compared to mutations affecting the intracellular domains of FAS, potentially explaining the variable expressivity and lower penetrance seen in patients with mutations in the extracellular domains. During this reporting period we have collaborated with NIAID ALPS group assembled the first comprehensive clinical and laboratory report based on long term follow-up of 150 ALPS patients and over 60 mutation positive relatives to develop the most comprehensive long term report of the outcome in patients with ALPS as well as in those who harbor the same mutations but have little or no autoimmune symptoms. This work has defined the risk of lymphoma as almost a log higher than previously recognized. In addition, the use of splenectomy to control cytopenias has clearly identified as significantly increasing the risk of bacterial sepsis and a cause of death in a subgroup of these surgically managed patients. Importantly, many post-splenectomy patients have recurrence of their hematologic autoimmunity. Finally, this work has also identified that approximately 40% of mutation positive members of ALPS families have little or no clinical disease suggesting that other genetic and or environmental circumstances have a significant impact on the clinical outcome of individual patients.