Diabetes and Metabolism, Translational Health Sciences, Bristol Medical School, University of Bristol, Level 2, Learning and Research Building, Southmead Hospital, Bristol BS10 5NB, UK.
Clin Exp Immunol. 2022 Dec 15;210(2):151-162. doi: 10.1093/cei/uxac087.
The clinical usefulness of post-diagnosis islet autoantibody levels is unclear and factors that drive autoantibody persistence are poorly defined in type 1 diabetes (T1D). Our aim was to characterise the longitudinal loss of islet autoantibody responses after diagnosis in a large, prospectively sampled UK cohort. Participants with T1D [n = 577] providing a diagnosis sample [range -1.0 to 2.0 years] and at least one post-diagnosis sample (<32.0 years) were tested for autoantibodies to glutamate decarboxylase 65 (GADA), islet antigen-2 (IA-2A), and zinc transporter 8 (ZnT8A). Select HLA and non-HLA SNPs were considered. Non-genetic and genetic factors were assessed by multivariable logistic regression models for autoantibody positivity at initial sampling and autoantibody loss at final sampling. For GADA, IA-2A, and ZnT8A, 70.8%, 76.8%, and 40.1%, respectively, remained positive at the final sampling. Non-genetic predictors of autoantibody loss were low baseline autoantibody titres (P < 0.0001), longer diabetes duration (P < 0.0001), and age-at-onset under 8 years (P < 0.01--0.05). Adjusting for non-genetic covariates, GADA loss was associated with low-risk HLA class II genotypes (P = 0.005), and SNPs associated with autoimmunity RELA/11q13 (P = 0.017), LPP/3q28 (P = 0.004), and negatively with IFIH1/2q24 (P = 0.018). IA-2A loss was not associated with genetic factors independent of other covariates, while ZnT8A loss was associated with the presence of HLA A*24 (P = 0.019) and weakly negatively with RELA/11q13 (P = 0.049). The largest longitudinal study of islet autoantibody responses from diagnosis of T1D shows that autoantibody loss is heterogeneous and influenced by low titres at onset, longer duration, earlier age-at-onset, and genetic variants. These data may inform clinical trials where post-diagnosis participants are recruited.
胰岛自身抗体水平在诊断后的临床应用尚不清楚，1 型糖尿病（T1D）中驱动自身抗体持续存在的因素也尚未明确。我们的目的是在一个大型的、前瞻性采样的英国队列中，描述诊断后胰岛自身抗体反应的纵向丧失。入组的 T1D 患者[577 例]提供了诊断样本[范围-1.0 至 2.0 年]和至少一个诊断后样本（<32.0 岁），并检测了谷氨酸脱羧酶 65（GADA）、胰岛抗原 2（IA-2A）和锌转运体 8（ZnT8A）的自身抗体。考虑了特定的 HLA 和非 HLA SNP。通过多变量逻辑回归模型评估非遗传和遗传因素，用于初始采样时自身抗体阳性和最终采样时自身抗体丧失的预测。对于 GADA、IA-2A 和 ZnT8A，分别有 70.8%、76.8%和 40.1%在最终采样时仍为阳性。自身抗体丧失的非遗传预测因素包括基线自身抗体滴度较低（P<0.0001）、糖尿病病程较长（P<0.0001）和发病年龄<8 岁（P<0.01--0.05）。调整非遗传协变量后，GADA 丧失与低风险 HLA Ⅱ类基因型相关（P=0.005），与自身免疫相关的 RELA/11q13（P=0.017）、LPP/3q28（P=0.004）的 SNP 相关，与 IFIH1/2q24（P=0.018）呈负相关。IA-2A 丧失与独立于其他协变量的遗传因素无关，而 ZnT8A 丧失与 HLA A*24 有关（P=0.019），与 RELA/11q13 呈弱负相关（P=0.049）。这是 T1D 诊断后胰岛自身抗体反应的最大纵向研究，表明自身抗体丧失具有异质性，并且受到发病时低滴度、较长病程、发病年龄较早和遗传变异的影响。这些数据可能为招募诊断后参与者的临床试验提供信息。
