The natural history of the autoimmune response to zinc transporter 8 (ZnT8) in type 1 diabetes

Student thesis: Doctoral ThesisDoctor of Philosophy (PhD)

Abstract

Type 1 diabetes (T1D) results from progressive autoimmune-mediated destruction of insulin-producing beta (β)-cells in pancreatic islets. The most effective biomarkers used to predict the development of T1D are four islet autoantibodies that recognise β-cell antigens with high specificity. Islet autoantibodies can be detected years before diagnosis, but progression rate can vary from months to decades. Autoantibodies directed to zinc transporter 8 (ZnT8A) were discovered in 2007, are common in individuals that slowly and rapidly progress to T1D and are usually detected by radioimmunoassay, but characteristics of the response (affinity, IgG subclasses, epitope specificity) are under-investigated.

We hypothesised that (1) characterisation of ZnT8A responses prior and close to T1D onset utilising adapted radioimmunoassays will inform the pathogenesis of T1D (2) factors associated with loss of ZnT8A after T1D onset will be different to those at onset and may provide insights into ongoing β-cell destruction, and (3) a novel luciferase-based immunoprecipitation system (LIPS) assay could replace the radioimmunoassay for ZnT8A detection.

Prior to and close to T1D onset, ZnT8A responses are dynamic, showing loss or gain of autoantibody status and titre, and some alteration in affinity, epitope specificity, and IgG subclasses. There did not appear to be clear differences between individuals who slowly or rapidly progress to T1D. After T1D onset, ZnT8A were lost rapidly compared to other autoantibodies, but the non-genetic and genetic factors associated with ZnT8A at and after T1D onset were comparable. The LIPS assay offered improvement in sensitivity and specificity over the radioimmunoassay and identified a small additional subset of at-risk individuals with a 20-year T1D risk of 26%.

These studies provide the first in-depth analysis of ZnT8A throughout the autoimmune response in T1D, describe methods to examine ZnT8A characteristics, and detail the optimisation of an improved low blood volume test suitable for general population screening.
Date of Award25 Jan 2022
Original languageEnglish
Awarding Institution
  • University of Bristol
SupervisorAnna E Long (Supervisor), Alistair J K Williams (Supervisor) & Kathleen M Gillespie (Supervisor)

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