Non-SCID combined immunodeficiencies: a diagnostic and therapeutic challenge

非SCID联合免疫缺陷（CID）是一种罕见的免疫缺陷，其定义为T细胞免疫功能受损，导致严重感染，自身免疫和恶性肿瘤。CID的遗传基础是异质性的。造血干细胞移植（HSCT）具有治愈性，但尚不清楚T细胞缺乏何时严重到足以证明HSCT的风险是合理的。我们假设T细胞缺陷的性质和程度及其随时间的演变是决定CID患者预后的关键因素，在一定程度上独立于遗传诊断。这证明将单个罕见CID视为一组是合理的。EuroCID成员于2011年启动了一项关于重度CID患者自然史（P-CID）的前瞻性研究。在这里，我们建议进行详细的遗传和纵向的CID患者通过P-CID研究或TREC为基础的新生儿筛查确定的免疫学特征。EuroCID还将包括Nijmegen断裂综合征患者作为遗传学明确定义的CID。将遗传学和免疫学研究结果与临床数据相关联，将（1）通过识别新基因和基因型-免疫型-表型关系，为人类T细胞免疫的限制因素提供新的见解，（2）有助于识别预测不良结局的生物标志物，（3）允许制定有关HSCT适应症和时间点的治疗建议。这是首次通过前瞻性研究系统地收集基因型-免疫型-表型信息来确定CID患者的最佳治疗方案。

Non-SCID combined immunodeficiencies (CID) are rare immunodeficiencies defined by impaired T cell immunity leading to severe infections, autoimmunity and malignancies. The genetic basis of CID is heterogeneous. Haematopoietic stem cell transplantation (HSCT) iscurative, but it is unclear when a T cell deficiency is severe enough to justify the risks of HSCT. We postulate that nature and extent of the T cell deficiency and their evolution over time are key factors determining the prognosis for CID patients that are to some extent independent of the genetic diagnosis. This justifies consideration of individual rare CIDs as a group. EuroCID members have initiated in 2011 a prospective study on the natural history ofpatients with profound CID (P-CID). Here, we propose to perform a detailed genetic and longitudinal immunologic characterization of CID patients identified through the P-CID study or by TREC-based newborn screening. EuroCID will also include patients with Nijmegen breakage syndrome as genetically well-defined CID. Correlation of genetic and immunological findings with clinical data will (1) provide new insights into the limiting factorsof human T cell immunity by identification of new genes and genotype-immunotypephenotype relationships, (2) help to identify biomarkers predictive of a poor outcome and (3) allow the development of treatment recommendations concerning indication and time-point of HSCT. This is the first time that a prospective study systematically collects information ongenotype-immunotype-phenotype to define optimal treatment for CID patients.