Clemente N, Boggio E, Gigliotti C L, Orilieri E, Cappellano G, Toth E, Valletti P A, Santoro C, Quinti I, Pignata C, Notarangelo L D, Dianzani C, Dianzani I, Ramenghi U, Dianzani U, Chiocchetti A
Interdisciplinary Research Center of Autoimmune Diseases (IRCAD) and Department of Health Sciences, University of Eastern Piedmont 'A Avogadro', Novara, Italy.
Department of Clinical Immunology, University of Rome 'La Sapienza', Rome, Italy.
Genes Immun. 2015 Mar;16(2):151-61. doi: 10.1038/gene.2014.74. Epub 2015 Jan 8.
Lymphocyte apoptosis is mainly induced by either death receptor-dependent activation of caspase-8 or mitochondria-dependent activation of caspase-9. Mutations in caspase-8 lead to autoimmunity/lymphoproliferation and immunodeficiency. This work describes a heterozygous H237P mutation in caspase-9 that can lead to similar disorders. H237P mutation was detected in two patients: Pt1 with autoimmunity/lymphoproliferation, severe hypogammaglobulinemia and Pt2 with mild hypogammaglobulinemia and Burkitt lymphoma. Their lymphocytes displayed defective caspase-9 activity and decreased apoptotic and activation responses. Transfection experiments showed that mutant caspase-9 display defective enzyme and proapoptotic activities and a dominant-negative effect on wild-type caspase-9. Ex vivo analysis of the patients' lymphocytes and in vitro transfection experiments showed that the expression of mutant caspase-9 correlated with a downregulation of BAFFR (B-cell-activating factor belonging to the TNF family (BAFF) receptor) in B cells and ICOS (inducible T-cell costimulator) in T cells. Both patients carried a second inherited heterozygous mutation missing in the relatives carrying H237P: Pt1 in the transmembrane activator and CAML interactor (TACI) gene (S144X) and Pt2 in the perforin (PRF1) gene (N252S). Both mutations have been previously associated with immunodeficiencies in homozygosis or compound heterozygosis. Taken together, these data suggest that caspase-9 mutations may predispose to immunodeficiency by cooperating with other genetic factors, possibly by downregulating the expression of BAFFR and ICOS.
淋巴细胞凋亡主要由半胱天冬酶 -8 的死亡受体依赖性激活或半胱天冬酶 -9 的线粒体依赖性激活诱导。半胱天冬酶 -8 的突变会导致自身免疫/淋巴细胞增殖和免疫缺陷。这项研究描述了半胱天冬酶 -9 中的一种杂合 H237P 突变，该突变可导致类似疾病。在两名患者中检测到 H237P 突变：患者 1 患有自身免疫/淋巴细胞增殖、严重低丙种球蛋白血症，患者 2 患有轻度低丙种球蛋白血症和伯基特淋巴瘤。他们的淋巴细胞显示出半胱天冬酶 -9 活性缺陷，凋亡和激活反应降低。转染实验表明突变型半胱天冬酶 -9 表现出酶活性和促凋亡活性缺陷，并对野生型半胱天冬酶 -9 具有显性负效应。对患者淋巴细胞的体外分析和体外转染实验表明，突变型半胱天冬酶 -9 的表达与 B 细胞中 BAFFR（肿瘤坏死因子家族（BAFF）受体中的 B 细胞激活因子）和 T 细胞中 ICOS（诱导性 T 细胞共刺激分子）的下调相关。两名患者均携带第二个遗传性杂合突变，携带 H237P 的亲属中未发现该突变：患者 1 在跨膜激活剂和 CAML 相互作用分子（TACI）基因中存在（S144X）突变，患者 2 在穿孔素（PRF1）基因中存在（N252S）突变。这两种突变先前在纯合子或复合杂合子中均与免疫缺陷相关。综上所述，这些数据表明半胱天冬酶 -9 突变可能通过与其他遗传因素协同作用，可能通过下调 BAFFR 和 ICOS 的表达而导致免疫缺陷。
