Pediatric Department A and the Immunology Service, Jeffrey Modell Foundation Center, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, 52621, Tel Hashomer, Israel.
The Wohl Institute for Translational Medicine and Cancer Research Center, Sheba Medical Center, Tel Hashomer, Israel.
J Clin Immunol. 2019 May;39(4):401-413. doi: 10.1007/s10875-019-00629-0. Epub 2019 Apr 29.
MALT1 (mucosa-associated lymphoid tissue lymphoma-translocation gene 1) is an intracellular signaling protein that activates NFκB and is crucial for both the adaptive and innate immune responses. Only 6 patients with immune deficiencies secondary to inherited mutations in the MALT1 gene have been described.
To provide clinical and immunological insights from 2 patients diagnosed with MALT1 immunodeficiency syndrome due to a novel MALT1 mutation.
Two cousins with suspected combined immunodeficiency underwent immunological and genetic work-up, including lymphocyte phenotyping, lymphocyte activation by mitogen stimulation, and next-generation sequencing (NGS) of T cell receptor gamma chain (TRG) repertoire. Whole exome sequencing was performed to identify the underlying genetic defect.
Clinical findings included recurrent infections, failure to thrive, lymphadenopathy, dermatitis, and autoimmunity. Immune work-up revealed lymphocytosis, low to normal levels of immunoglobulins, absence of regulatory T cells, and low Th17 cells. A normal proliferative response was induced by phytohemagglutinin and IL-2 but was diminished with anti-CD3. TRG repertoire was diverse with a clonal expansion pattern. Genetic analysis identified a novel autosomal recessive homozygous c.1799T>A; p. I600N missense mutation in MALT1. MALT1 protein expression was markedly reduced, and in vitro IL-2 production and NFκB signaling pathway were significantly impaired.
Two patients harboring a novel MALT1 mutation presented with signs of immune deficiency and dysregulation and were found to have an abnormal T cell receptor repertoire. These findings reinforce the link between MALT1 deficiency and combined immunodeficiency. Early diagnosis is crucial, and curative treatment by hematopoietic stem cell transplantation may be warranted.
MALT1（黏膜相关淋巴组织淋巴瘤易位基因 1）是一种细胞内信号蛋白，可激活 NFκB，对于适应性和固有免疫反应都至关重要。仅有 6 例因 MALT1 基因突变导致免疫缺陷的患者被描述过。
提供 2 例因新型 MALT1 突变导致 MALT1 免疫缺陷综合征患者的临床和免疫学见解。
2 例疑似联合免疫缺陷的表亲接受了免疫学和遗传学检查，包括淋巴细胞表型、丝裂原刺激下的淋巴细胞活化以及 T 细胞受体γ链（TRG）库的下一代测序（NGS）。进行外显子组测序以确定潜在的遗传缺陷。
临床发现包括反复感染、生长迟缓、淋巴结病、皮炎和自身免疫。免疫检查显示淋巴细胞增多、免疫球蛋白水平低至正常、调节性 T 细胞缺失和 Th17 细胞减少。植物血凝素和 IL-2 可诱导正常的增殖反应，但抗-CD3 则减弱。TRG 库具有多样性和克隆性扩张模式。基因分析发现 MALT1 中一种新的常染色体隐性纯合 c.1799T>A；p.I600N 错义突变。MALT1 蛋白表达明显减少，体外 IL-2 产生和 NFκB 信号通路显著受损。
2 例携带新型 MALT1 突变的患者表现出免疫缺陷和失调的迹象，并且发现其 T 细胞受体库异常。这些发现加强了 MALT1 缺乏与联合免疫缺陷之间的联系。早期诊断至关重要，可能需要造血干细胞移植进行治愈性治疗。
