Pfeuffer Steffen, Nelke Christopher, Pawlitzki Marc, Ruck Tobias, Schroeter Christina B, Thomas Christian, Kobbe Guido, Dietrich Sascha, Zimprich Alexander A, Wiendl Heinz, Meuth Sven G
Department of Neurology, Justus-Liebig-University Giessen, Germany.
Department of Neurology, Medical Faculty and University Hospital Duesseldorf, Germany.
Neurol Neuroimmunol Neuroinflamm. 2025 Mar;12(2):e200351. doi: 10.1212/NXI.0000000000200351. Epub 2024 Dec 17.
Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) haploinsufficiency is a rare genetic condition characterized by development of immune cytopenia, hypogammaglobulinemia, and/or lymphoproliferative disorder, as well as multiple autoimmunity. Treatment with abatacept was shown to alleviate autoimmune conditions, yet its long-lasting impact on bone marrow function remains undetermined.
We here present the case of a now 39-year-old woman with CTLA-4 haploinsufficiency with predominant CNS affection, yet multiorgan autoimmunity and lymphopenia. We conducted single-cell RNA sequencing (scRNA-seq) of peripheral mononuclear blood cells before and after abatacept induction.
After several high-efficacy immunosuppressive treatments with little-to-no response, she started abatacept in 2017 and experienced ongoing remission including resolution of pre-existing immune cytopenia and hypogammaglobulinemia. Using scRNA-seq, we were able to demonstrate reconstitution of peripheral B cells accompanied by reduction of CD8 T cells. CD4 and CD8 T cells were characterized by downregulation of pathways involved in activation of innate immune cells.
Our findings demonstrate long-lasting resolution of lymphopenia after abatacept treatment in CTLA-4 haploinsufficiency despite severity and duration of symptoms. Thus, abatacept should be considered throughout before stem cell transplantation also in CTLA-4 haploinsufficiency with severe symptoms.
As a single report without controls, this report provides class IV evidence that abatacept might revert lymphopenia in patients with CTLA-4 haploinsufficiency.
细胞毒性T淋巴细胞相关蛋白4（CTLA-4）单倍体不足是一种罕见的遗传疾病，其特征为免疫细胞减少、低丙种球蛋白血症和/或淋巴细胞增殖性疾病，以及多种自身免疫性疾病。已证明使用阿巴西普治疗可缓解自身免疫性疾病，但其对骨髓功能的长期影响仍未确定。
我们在此报告一例39岁女性，患有以中枢神经系统为主的CTLA-4单倍体不足，同时存在多器官自身免疫和淋巴细胞减少。我们在阿巴西普诱导前后对外周单个核血细胞进行了单细胞RNA测序（scRNA-seq）。
在经过几种疗效甚微或无反应的高效免疫抑制治疗后，她于2017年开始使用阿巴西普，并持续缓解，包括先前存在的免疫细胞减少和低丙种球蛋白血症得到缓解。通过scRNA-seq，我们能够证明外周B细胞的重建，同时CD8 T细胞减少。CD4和CD8 T细胞的特征是参与先天免疫细胞激活的信号通路下调。
我们的研究结果表明，尽管症状严重且持续时间长，但在CTLA-4单倍体不足患者中，阿巴西普治疗后淋巴细胞减少可得到长期缓解。因此，对于症状严重的CTLA-4单倍体不足患者，在进行干细胞移植之前也应考虑使用阿巴西普。
作为一份无对照的单一报告，本报告提供了IV级证据，表明阿巴西普可能使CTLA-4单倍体不足患者的淋巴细胞减少得到逆转。
