Department of Pediatrics, Laboratory for Pediatric Immunology, Willem-Alexander Children's Hospital, Leiden University Medical Center, Leiden, The Netherlands.
Department of Pediatric Neurology, Amalia Children's Hospital, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
J Allergy Clin Immunol. 2024 May;153(5):1392-1405. doi: 10.1016/j.jaci.2023.12.029. Epub 2024 Jan 26.
Ataxia telangiectasia (AT) is characterized by cerebellar ataxia, telangiectasia, immunodeficiency, and increased cancer susceptibility and is caused by mutations in the ataxia telangiectasia mutated (ATM) gene. The immunodeficiency comprises predominantly immunoglobulin deficiency, mainly IgA and IgG, with a variable severity. So far, the exact mechanisms underlying the immunoglobulin deficiency, especially the variable severity, remain unelucidated.
We characterized the clinical impact of immunoglobulin deficiencies in AT and elucidated their mechanisms in AT.
We analyzed long-term immunoglobulin levels, immunophenotyping, and survival time in our cohort (n = 87, median age 16 years; maximum 64 years). Somatic hypermutation and class-switch junctions in B cells were analyzed by next-generation sequencing. Furthermore, an in vitro class-switching induction assay was performed, followed by RNA sequencing, to assess the effect of ATM inhibition.
Only the hyper-IgM AT phenotype significantly worsened survival time, while IgA or IgG deficiencies did not. The immunoglobulin levels showed predominantly decreased IgG and IgA. Moreover, flow cytometric analysis demonstrated reduced naive B and T lymphocytes and a deficiency of class-switched IgG and IgA memory B cells. Somatic hypermutation frequencies were lowered in IgA- and IgG-deficient patients, indicating hampered germinal center reaction. In addition, the microhomology of switch junctions was elongated, suggesting alternative end joining during class-switch DNA repair. The in vitro class switching and proliferation were negatively affected by ATM inhibition. RNA sequencing analysis showed that ATM inhibitor influenced expression of germinal center reaction genes.
Immunoglobulin deficiency in AT is caused by disturbed development of class-switched memory B cells. ATM deficiency affects both germinal center reaction and choice of DNA-repair pathway in class switching.
毛细血管扩张共济失调症（AT）的特征是小脑共济失调、毛细血管扩张、免疫缺陷以及癌症易感性增加，由共济失调毛细血管扩张突变基因（ATM）的突变引起。免疫缺陷主要包括免疫球蛋白缺乏，主要是 IgA 和 IgG，严重程度不一。到目前为止，免疫球蛋白缺乏的确切机制，尤其是其严重程度的可变性，仍不清楚。
我们描述了 AT 中免疫球蛋白缺乏的临床影响，并阐明了其在 AT 中的机制。
我们分析了我们队列中的长期免疫球蛋白水平、免疫表型和生存时间（n=87，中位年龄 16 岁；最大 64 岁）。通过下一代测序分析 B 细胞的体细胞超突变和类别转换接头。此外，进行体外类别转换诱导测定，随后进行 RNA 测序，以评估 ATM 抑制的效果。
只有高 IgM AT 表型显著降低了生存时间，而 IgA 或 IgG 缺乏则没有。免疫球蛋白水平主要表现为 IgG 和 IgA 减少。此外，流式细胞术分析表明，幼稚 B 和 T 淋巴细胞减少，类别转换 IgG 和 IgA 记忆 B 细胞缺乏。IgA 和 IgG 缺乏患者的体细胞超突变频率降低，表明生发中心反应受损。此外，转换接头的微同源性延长，表明在类别转换 DNA 修复过程中存在替代性末端连接。体外类别转换和增殖受到 ATM 抑制的负面影响。RNA 测序分析表明，ATM 抑制剂影响生发中心反应基因的表达。
AT 中的免疫球蛋白缺乏是由类别转换记忆 B 细胞发育障碍引起的。ATM 缺乏影响生发中心反应和类别转换中 DNA 修复途径的选择。
