Immune Evaluation in Patients with Autoimmune Lymphoproliferative Syndrome

NIH ALPS小组目前跟踪了400多个家庭的队列。在过去，我们已经描述了与FAS突变相关的ALPS生物标志物（包括生殖细胞和体细胞），基于对562例ALPS患者及其家庭成员的评估。这表明，高于4%的双阴性T细胞水平以及可溶性FasL、维生素B12或IL-10的升高对于具有生殖系和体细胞FAS突变的ALPS具有高达98%的预测值。该结果被纳入ALPS的新诊断标准。最近，我们发现影响FAS胞外区的大多数突变通过诱导单倍不足来破坏蛋白质功能，从而导致低FAS表达、低DISC形成和抑制细胞凋亡。与影响FAS胞内结构域的突变相比，这些缺陷较轻，这可能解释了在胞外结构域突变患者中观察到的可变表达率和较低表达率。 在本报告期内，我们与NIAID ALPS小组合作，根据对150名ALPS患者和60多名突变阳性亲属的长期随访，编写了第一份全面的临床和实验室报告，以开发关于ALPS患者以及携带相同突变但很少或没有自身免疫症状的患者结局的最全面的长期报告。这项工作将淋巴瘤的风险定义为比以前认识到的高出几乎一个对数。此外，使用脾切除术来控制血细胞减少已被明确确定为显著增加细菌性败血症的风险，并成为这些手术治疗患者亚组的死亡原因。重要的是，许多脾切除术后患者的血液学自身免疫性复发。最后，这项工作还确定了大约40%的ALPS家族突变阳性成员很少或没有临床疾病，这表明其他遗传和/或环境条件对个体患者的临床结果有显著影响。

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.