Lu Henry Y, Vaseghi-Shanjani Maryam, Lam Avery J, Sharma Mehul, Mohajeri Arezoo, Silva Leandro B R, Gillies Jana, Yang Gui Xiang, Lin Susan, Fu Maggie P, Salman Areesha, Rahmanian Ronak, Armstrong Linlea, Halparin Jessica, Yang Connie L, Chilvers Mark, Henkelman Erika, Rehmus Wingfield, Morrison Douglas, Setiadi Audi, Mostafavi Sara, Kobor Michael S, Kozak Frederick K, Biggs Catherine M, van Karnebeek Clara, Hildebrand Kyla J, Levings Megan K, Turvey Stuart E
Department of Pediatrics, BC Children's Hospital, The University of British Columbia, 950 West 28 th Avenue, Vancouver, BC, V5Z 4H4, Canada.
Experimental Medicine Program, Faculty of Medicine, The University of British Columbia, Vancouver, BC, Canada.
J Clin Immunol. 2025 Apr 28;45(1):89. doi: 10.1007/s10875-025-01882-2.
Monogenic defects that impair the control of inflammation and tolerance lead to profound immune dysregulation, including autoimmunity and atopy. Studying these disorders reveals important molecular and cellular factors that regulate human immune homeostasis and identifies potential precision medicine targets. Here, we provide a detailed immunological assessment of a pediatric patient with a recently discovered syndrome causing Immunodysregulation, Craniofacial anomalies, Hearing impairment, Athelia, and Developmental delay (or ICHAD syndrome). The immunodysregulation resulted in autoimmune hemolytic anemia (AIHA) and atopic dermatitis. The patient carried a de novo germline heterozygous c.406+540_574+13477dup;p.Gly136_Ser191dup variant in IKAROS family zinc finger 2 (IKZF2), which encodes HELIOS. This variant led to reduced HELIOS protein expression and dominant interference of wild-type HELIOS-mediated repression of the IL2 promoter. Multi-parameter flow cytometry analyses of patient peripheral blood mononuclear cells revealed strongly impaired natural killer cell differentiation and function, and increased CD8 T cell activation and cytokine secretion. Strikingly, patient CD4 T cells were hyperactive, produced elevated levels of nearly all T helper (T) cytokines, and readily proliferated in response to stimulation. Patient regulatory T cells (Tregs) developed normally but aberrantly produced high levels of many T cytokines. Single-cell RNA sequencing revealed largely normal Tregs (albeit mostly memory), but naïve CD4 T cells that were more enriched in genes related to activation, proliferation, metabolism, and T differentiation. This work describes the immunological phenotype of one of the first reported cases of germline dominant negative HELIOS deficiency, expands our understanding of the pathogenesis of AIHA on a single cell level, and provides valuable insights into HELIOS function in a variety of lymphocyte subsets.
损害炎症和耐受性控制的单基因缺陷会导致严重的免疫失调，包括自身免疫和特应性。研究这些疾病可揭示调节人类免疫稳态的重要分子和细胞因子，并确定潜在的精准医学靶点。在此，我们对一名患有最近发现的导致免疫失调、颅面畸形、听力障碍、无汗症和发育迟缓（或ICHAD综合征）综合征的儿科患者进行了详细的免疫学评估。免疫失调导致自身免疫性溶血性贫血（AIHA）和特应性皮炎。该患者在IKAROS家族锌指2（IKZF2）中携带了一个新生的种系杂合c.406+540_574+13477dup;p.Gly136_Ser191dup变体，该基因编码HELIOS。这种变体导致HELIOS蛋白表达降低，并对野生型HELIOS介导的IL2启动子抑制产生显性干扰。对患者外周血单个核细胞的多参数流式细胞术分析显示，自然杀伤细胞的分化和功能严重受损，CD8 T细胞活化和细胞因子分泌增加。令人惊讶的是，患者的CD4 T细胞过度活跃，几乎所有辅助性T（T）细胞因子的水平都升高，并且在受到刺激时容易增殖。患者调节性T细胞（Tregs）发育正常，但异常产生高水平的许多T细胞因子。单细胞RNA测序显示Tregs在很大程度上是正常的（尽管大多是记忆性的），但初始CD4 T细胞在与活化、增殖、代谢和T细胞分化相关的基因中更为富集。这项工作描述了首例报道的种系显性负性HELIOS缺陷病例之一的免疫表型，在单细胞水平上扩展了我们对AIHA发病机制的理解，并为HELIOS在多种淋巴细胞亚群中的功能提供了有价值的见解。
