Clinical and genetic correlates of islet-autoimmune signatures in juvenile-onset type 1 diabetes
Clinical and genetic correlates of islet-autoimmune signatures in juvenile-onset type 1 diabetes
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DOI：
10.1007/s00125-019-05032-3
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发表时间：
2019-11-21
期刊：
影响因子：
8.2
通讯作者：
Roep, Bart O.
中科院分区：
文献类型：
--
作者：
Claessens, Laura A.;Wesselius, Joris;Roep, Bart O.
目的/假说1型糖尿病患者个体的异质性已得到更普遍的认识，但尚未被广泛和系统地描述。在这里，我们的目标是在一项横断面研究中，通过创建幼年型1型糖尿病患者的免疫学、遗传学和临床资料来表征1型糖尿病的异质性。方法对受试者进行HLA基因分型以确定HLADR-DQ风险，并根据MHC区外93个与1型糖尿病相关的SNP变异体进行SNP分型以生成非人类白细胞抗原遗传风险评分(GRS)。用胰岛抗原GAD65、胰岛抗原-2(IA-2)、胰岛素原(PPI)和胰岛素核糖体缺陷产物(INS-DROP)刺激T细胞增殖。对临床资料进行回顾性收集。结果在80例患者中，67例对一种或多种胰岛抗原有增殖反应，其增殖程度差异很大。根据增殖反应的数量和幅度，将个体分为无反应者、中等反应者和高反应者。高应答者不能完全通过增加最高风险的HLA-DR3-DQ2/DR4-DQ8基因来表征。然而，高应答者确实有显著更高的非人类白细胞抗原GRS。临床上，高T细胞对β细胞抗原的反应不能反映血糖控制的恶化、并发症的增加、相关自身免疫的发展或发病时年龄较小。个体对β细胞抗原的反应数量随着病程的延长而增加，这表明慢性胰岛自身免疫和表位扩散。结论/解释综合起来，这些数据为1型糖尿病疾病的异质性提供了新的见解，并突出了根据患者的遗传和自身免疫特征对患者进行分层对免疫治疗和个性化疾病管理的重要性。
Aims/hypothesis Heterogeneity in individuals with type 1 diabetes has become more generally appreciated, but has not yet been extensively and systematically characterised. Here, we aimed to characterise type 1 diabetes heterogeneity by creating immunological, genetic and clinical profiles for individuals with juvenile-onset type 1 diabetes in a cross-sectional study. Methods Participants were HLA-genotyped to determine HLA-DR-DQ risk, and SNP-genotyped to generate a non-HLA genetic risk score (GRS) based on 93 type 1 diabetes-associated SNP variants outside the MHC region. Islet autoimmunity was assessed as T cell proliferation upon stimulation with the beta cell antigens GAD65, islet antigen-2 (IA-2), preproinsulin (PPI) and defective ribosomal product of the insulin gene (INS-DRIP). Clinical parameters were collected retrospectively. Results Of 80 individuals, 67 had proliferation responses to one or more islet antigens, with vast differences in the extent of proliferation. Based on the multitude and amplitude of the proliferation responses, individuals were clustered into non-, intermediate and high responders. High responders could not be characterised entirely by enrichment for the highest risk HLA-DR3-DQ2/DR4-DQ8 genotype. However, high responders did have a significantly higher non-HLA GRS. Clinically, high T cell responses to beta cell antigens did not reflect in worsened glycaemic control, increased complications, development of associated autoimmunity or younger age at disease onset. The number of beta cell antigens that an individual responded to increased with disease duration, pointing to chronic islet autoimmunity and epitope spreading. Conclusions/interpretation Collectively, these data provide new insights into type 1 diabetes disease heterogeneity and highlight the importance of stratifying patients on the basis of their genetic and autoimmune signatures for immunotherapy and personalised disease management.