The longitudinal loss of islet autoantibody responses from diagnosis of type 1 diabetes occurs progressively over follow-up and is determined by low autoantibody titres, early-onset, and genetic variants

Abstract

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 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 -1.0-2.0 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 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.

Correlation analysis between cytokines’ profile, autoimmune antibodies and the duration of type 1 diabetes: A case control study in a specialized children’s centre in Riyadh

“…However, a recent large cohort study in the UK has reported a reduction in autoantibodies of the same patients when followed longitudinally. 36 Despite an overall reduction in autoantibody prevalence, number, and titer as a function of increasing diabetes duration, the degree of autoantibody loss was not influenced by the number or combination of autoantibodies present at onset as cytokines mainly play a role in the early stages of the disease, we understandably found few associations between their levels and high autoimmune markers in our study. This was especially true for IL-21 with ICA, IL-10 with GAD Abs and IL-4, IL-10, IL-18, and IL-21 with IA.…”

The INNODIA Type 1 Diabetes Natural History Study: a European cohort of newly diagnosed children, adolescents and adults

“…Overall, a combination of IAA/IA, GAD65A, IA-2A and ZnT8A was found in around 97% of the study participants, with the highest frequency in children younger than 10 years old. As expected [ 43 , 44 ], GAD65A were the most common autoantibody type in those aged ≥18 years, whereas IA-2A were the most frequent type in younger children. The prevalence of most autoantibodies remained unchanged when reassessed at 12 months, apart from a higher prevalence of IA, as expected following insulin therapy [ 29 ].…”

Autoantibodies to truncated GAD(96-585) antigen stratify risk of early insulin requirement in adult-onset diabetes

“…The difference in the presence of IgG4 subclass in our type 1 diabetes reference cohort may be due to the differences in duration of diabetes at analysis, with Hillman et al testing samples within days of diagnosis while we tested at a median of 16 years post diagnosis. The presence of IgG4 subclasses in our study could be due to prolonged stimulation and maturation of B cells and GADA responses remaining highly prevalent post-diagnosis (29).…”