VIB Center for Brain & Disease Research, Leuven, Belgium; KU Leuven, Department of Microbiology and Immunology, Leuven, Belgium.
GIGA I(3) and Department of Hematology, University of Liege, Liege, Belgium.
J Allergy Clin Immunol. 2017 Nov;140(5):1394-1403.e8. doi: 10.1016/j.jaci.2016.12.968. Epub 2017 Feb 7.
Severe combined immunodeficiency can be caused by loss-of-function mutations in genes involved in the DNA recombination machinery, such as recombination-activating gene 1 (RAG1), RAG2, or DNA cross-link repair 1C (DCLRE1C). Defective DNA recombination causes a developmental block in T and B cells, resulting in high susceptibility to infections. Hypomorphic mutations in the same genes can also give rise to a partial loss of T cells in a spectrum including leaky severe combined immunodeficiency (LS) and Omenn syndrome (OS). These patients not only experience life-threatening infections because of immunodeficiency but also experience inflammatory/autoimmune conditions caused by the presence of autoreactive T cells.
We sought to develop a preclinical model that fully recapitulates the symptoms of patients with LS/OS, including a model for testing therapeutic intervention.
We generated a novel mutant mouse (Dclre1c) that develops a LS phenotype. Mice were monitored for diseases, and immune phenotype and immune function were evaluated by using flow cytometry, ELISA, and histology.
Dclre1c mice present with a complete blockade of B-cell differentiation, with a leaky block in T-cell differentiation resulting in an oligoclonal T-cell receptor repertoire and enhanced cytokine secretion. Dclre1c mice also had inflammatory symptoms, including wasting, dermatitis, colitis, hypereosinophilia, and high IgE levels. Development of a preclinical murine model for LS allowed testing of potential treatment, with administration of cytotoxic T-lymphocyte-associated protein 4-Ig reducing disease symptoms and immunologic disturbance, resulting in increased survival.
These data suggest that cytotoxic T-lymphocyte-associated protein 4-Ig should be evaluated as a potential treatment of inflammatory symptoms in patients with LS and those with OS.
严重联合免疫缺陷症可由参与 DNA 重组机制的基因的功能丧失突变引起，例如重组激活基因 1（RAG1）、RAG2 或 DNA 交联修复 1C（DCLRE1C）。DNA 重组缺陷导致 T 和 B 细胞发育受阻，从而导致高度易感染。同一基因的低功能突变也可导致 T 细胞部分缺失，谱系包括渗漏性严重联合免疫缺陷症（LS）和 Omenn 综合征（OS）。这些患者不仅因免疫缺陷而面临危及生命的感染，而且还因存在自身反应性 T 细胞而经历炎症/自身免疫性疾病。
我们试图开发一种完全再现 LS/OS 患者症状的临床前模型，包括用于测试治疗干预的模型。
我们生成了一种新型突变小鼠（Dclre1c），其表现出 LS 表型。通过流式细胞术、ELISA 和组织学评估疾病、免疫表型和免疫功能来监测小鼠。
Dclre1c 小鼠表现出完全阻断 B 细胞分化，T 细胞分化存在渗漏性阻断，导致 T 细胞受体库呈寡克隆且细胞因子分泌增强。Dclre1c 小鼠还存在炎症症状，包括消瘦、皮炎、结肠炎、嗜酸性粒细胞增多和高 IgE 水平。LS 临床前小鼠模型的开发允许测试潜在的治疗方法，使用细胞毒性 T 淋巴细胞相关蛋白 4-Ig 可减轻疾病症状和免疫紊乱，从而提高生存率。
这些数据表明，细胞毒性 T 淋巴细胞相关蛋白 4-Ig 应作为 LS 患者和 OS 患者炎症症状的潜在治疗方法进行评估。
