Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.
Department of Immunology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.
Front Immunol. 2021 Mar 18;12:655354. doi: 10.3389/fimmu.2021.655354. eCollection 2021.
Inborn errors of thymic stromal cell development and function lead to impaired T-cell development resulting in a susceptibility to opportunistic infections and autoimmunity. In their most severe form, congenital athymia, these disorders are life-threatening if left untreated. Athymia is rare and is typically associated with complete DiGeorge syndrome, which has multiple genetic and environmental etiologies. It is also found in rare cases of T-cell lymphopenia due to Nude SCID and Otofaciocervical Syndrome type 2, or in the context of genetically undefined defects. This group of disorders cannot be corrected by hematopoietic stem cell transplantation, but upon timely recognition as thymic defects, can successfully be treated by thymus transplantation using cultured postnatal thymic tissue with the generation of naïve T-cells showing a diverse repertoire. Mortality after this treatment usually occurs before immune reconstitution and is mainly associated with infections most often acquired pre-transplantation. In this review, we will discuss the current approaches to the diagnosis and management of thymic stromal cell defects, in particular those resulting in athymia. We will discuss the impact of the expanding implementation of newborn screening for T-cell lymphopenia, in combination with next generation sequencing, as well as the role of novel diagnostic tools distinguishing between hematopoietic and thymic stromal cell defects in facilitating the early consideration for thymus transplantation of an increasing number of patients and disorders. Immune reconstitution after the current treatment is usually incomplete with relatively common inflammatory and autoimmune complications, emphasizing the importance for improving strategies for thymus replacement therapy by optimizing the current use of postnatal thymus tissue and developing new approaches using engineered thymus tissue.
先天性胸腺基质细胞发育和功能障碍导致 T 细胞发育受损，从而易发生机会性感染和自身免疫。在最严重的形式中，先天性无胸腺，如果不治疗，这些疾病会危及生命。无胸腺非常罕见，通常与完全性 DiGeorge 综合征相关，该综合征有多种遗传和环境病因。在 Nude SCID 和 Otofaciocervical 综合征 2 型或遗传定义缺陷的罕见情况下也会发现无胸腺。这组疾病不能通过造血干细胞移植纠正，但如果及时识别为胸腺缺陷，可通过使用培养的产后胸腺组织进行胸腺移植成功治疗，产生具有多样化 repertoire 的幼稚 T 细胞。这种治疗后的死亡率通常发生在免疫重建之前，主要与感染有关，这些感染通常发生在移植前。在这篇综述中，我们将讨论目前诊断和管理胸腺基质细胞缺陷的方法，特别是导致无胸腺的缺陷。我们将讨论扩大实施 T 细胞淋巴细胞减少症新生儿筛查的影响，结合下一代测序，以及区分造血和胸腺基质细胞缺陷的新诊断工具在促进越来越多的患者和疾病进行早期考虑进行胸腺移植方面的作用。目前治疗后的免疫重建通常不完整，伴有相对常见的炎症和自身免疫并发症，这强调了通过优化产后胸腺组织的现有使用和开发使用工程化胸腺组织的新方法来改善胸腺替代治疗策略的重要性。
