Immune Checkpoint-Related Gene Polymorphisms Are Associated With Primary Immune Thrombocytopenia.
Immune Checkpoint-Related Gene Polymorphisms Are Associated With Primary Immune Thrombocytopenia.
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免疫检查点相关基因多态性与原发性免疫性血小板减少症相关
DOI：
10.3389/fimmu.2020.615941
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发表时间：
2020
影响因子：
7.3
通讯作者：
Hu X
中科院分区：
文献类型：
--
作者：
Wang S;Zhang X;Leng S;Xu Q;Sheng Z;Zhang Y;Yu J;Feng Q;Hou M;Peng J;Hu X
免疫检查点阻断的肿瘤免疫治疗在某些肿瘤的治疗中是有效的。然而，免疫检查点和自身免疫性疾病之间的联系仍然难以捉摸，需要紧急调查。原发性免疫性血小板减少症（ITP）是一种T细胞反应过度激活的自身免疫性疾病，其特征是血小板计数减少，随之而来的出血风险增加。在这里，我们研究了免疫检查点相关的单核苷酸多态性（snp），包括CD28、ICOS、PD1、TNFSF4、DNAM1、TIM3、CTLA4和LAG3对ITP易感性和治疗效果的贡献。在这项病例对照研究中，招募了307名ITP患者和295名年龄匹配的健康参与者。我们使用MassARRAY系统对免疫检查点相关snp进行基因分型。我们的研究结果显示，在错误发现率校正后，CD28中的rs1980422与ITP风险增加相关（共优势，CT vs TT, OR = 1.788, 95% CI = 1.178-2.713, p = 0.006）。此外，CT患者的CD28 mRNA和蛋白表达水平均显著高于TT基因型患者（p = 0.028和p = 0.001）。此外，PD1 rs36084323的T等位基因是ITP严重程度的危险因素，DNAM1 rs763361的T等位基因是皮质激素抵抗的危险因素。相比之下，LAG3 rs870849的T等位基因是ITP严重程度的保护因子，ICOS rs6726035的T等位基因对皮质激素抵抗具有保护作用。PD1 rs36084323的TT/CT基因型也显示难治性ITP发生风险增加8.889倍。本研究提示免疫检查点相关snp，特别是CD28 rs1980422可能是与ITP患者的发展和治疗相关的遗传因素。我们的结果为预后预测、疾病严重程度和发现新的治疗靶点提供了新的线索。
Cancer immunotherapy by immune checkpoint blockade has been effective in the treatment of certain tumors. However, the association between immune checkpoints and autoimmune diseases remains elusive and requires urgent investigation. Primary immune thrombocytopenia (ITP), characterized by reduced platelet count and a consequent increased risk of bleeding, is an autoimmune disorder with a hyper-activated T cell response. Here, we investigated the contribution of immune checkpoint-related single-nucleotide polymorphisms (SNPs), including CD28, ICOS, PD1, TNFSF4, DNAM1, TIM3, CTLA4, and LAG3 to the susceptibility and therapeutic effects of ITP. In this case-control study, 307 ITP patients and 295 age-matched healthy participants were recruited. We used the MassARRAY system for genotyping immune checkpoint-related SNPs. Our results revealed that rs1980422 in CD28 was associated with an increased risk of ITP after false discovery rate correction (codominant, CT vs. TT, OR = 1.788, 95% CI = 1.178–2.713, p = 0.006). In addition, CD28 expression at both the mRNA and protein levels was significantly higher in patients with CT than in those with the TT genotype (p = 0.028 and p = 0.001, respectively). Furthermore, the T allele of PD1 rs36084323 was a risk factor for ITP severity and the T allele of DNAM1 rs763361 for corticosteroid-resistance. In contrast, the T allele of LAG3 rs870849 was a protective factor for ITP severity, and the T allele of ICOS rs6726035 was protective against corticosteroid-resistance. The TT/CT genotypes of PD1 rs36084323 also showed an 8.889-fold increase in the risk of developing refractory ITP. This study indicates that immune checkpoint-related SNPs, especially CD28 rs1980422, may be genetic factors associated with the development and treatment of ITP patients. Our results shed new light on prognosis prediction, disease severity, and discovering new therapeutic targets.
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T细胞共刺激和共抑制的分子机制。
DOI：
10.1038/nri3405
发表时间：
2013-04
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1038/s41577-019-0218-4
发表时间：
2020-01
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
Kalbasi A;Ribas A
通讯作者：
Ribas A
影响因子：
2.7
作者：
Elghzaly, Ashraf A.;Metwally, Shereen S.;Ibrahim, Saleh M.
通讯作者：
Ibrahim, Saleh M.
影响因子：
3.7
作者：
Colinas J;Schmidler SC;Bohrer G;Iordanov B;Benfey PN
通讯作者：
Benfey PN
影响因子：
32.4
作者：
Esensten JH;Helou YA;Chopra G;Weiss A;Bluestone JA
通讯作者：
Bluestone JA