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.

中文翻译：

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幼年型1型糖尿病的胰岛自身免疫特征与临床和遗传相关。

目的/假设1型糖尿病患者的异质性已得到普遍认可，但尚未得到广泛而系统的表征。在这里，我们的目的是通过在横断面研究中为青少年型1型糖尿病患者创建免疫，遗传和临床资料来表征1型糖尿病异质性。方法对参与者进行HLA基因分型以确定HLA-DR-DQ风险，并根据MHC区域外的93种1型糖尿病相关SNP变异对SNP基因分型以产生非HLA遗传风险评分（GRS）。胰岛自身免疫性被评估为β细胞抗原GAD65，胰岛抗原2（IA-2），胰岛素原（PPI）和胰岛素基因的核糖体缺陷产物（INS-DRIP）刺激后的T细胞增殖。回顾性收集临床参数。结果在80个个体中，有67个对一种或多种胰岛抗原具有增殖反应，但增殖程度差异很大。根据增殖反应的数量和幅度，将个体分为非，中，高反应者。高反应者不能完全通过高风险HLA-DR3-DQ2 / DR4-DQ8基因型的富集来表征。但是，高应答者的非HLA GRS明显更高。临床上，对β细胞抗原的高T细胞反应未反映在血糖控制恶化，并发症增加，相关的自身免疫性发展或疾病发作时年龄较小。个体对β细胞抗原的反应数量随疾病持续时间的增加而增加，这表明慢性胰岛自身免疫和表位扩散。