Dynamics of Islet Autoantibodies During Prospective Follow-Up From Birth to Age 15 Years.

Petra M Pöllänen,Jorma Ilonen,Samppa J Ryhänen,Paula Vähäsalo,Mikael Knip,Heli Siljander,Jorma Toppari,Riitta Veijola

doi:10.1210/clinem/dgaa624

Abstract

ContextWe set out to characterize the dynamics of islet autoantibodies over the first 15 years of life in children carrying genetic susceptibility to type 1 diabetes (T1D). We also assessed systematically the role of zinc transporter 8 autoantibodies (ZnT8A) in this context.DesignHLA-predisposed children (N = 1006, 53.0% boys) recruited from the general population during 1994 to 1997 were observed from birth over a median time of 14.9 years (range, 1.9-15.5 years) for ZnT8A, islet cell (ICA), insulin (IAA), glutamate decarboxylase (GADA), and islet antigen-2 (IA-2A) antibodies, and for T1D. ResultsBy age 15.5 years, 35 (3.5%) children had progressed to T1D. Islet autoimmunity developed in 275 (27.3%) children at a median age of 7.4 years (range, 0.3-15.1 years). The ICA seroconversion rate increased toward puberty, but the biochemically defined autoantibodies peaked at a young age. Before age 2 years, ZnT8A and IAA appeared commonly as the first autoantibody, but in the preschool years IA-2A– and especially GADA-initiated autoimmunity increased. Thereafter, GADA-positive seroconversions continued to appear steadily until ages 10 to 15 years. Inverse IAA seroconversions occurred frequently (49.3% turned negative) and marked a prolonged delay from seroconversion to diagnosis compared to persistent IAA (8.2 vs 3.4 years; P = .01).ConclusionsIn HLA-predisposed children, the primary autoantibody is characteristic of age and might reflect the events driving the disease process toward clinical T1D. Autoantibody persistence affects the risk of T1D. These findings provide a framework for identifying disease subpopulations and for personalizing the efforts to predict and prevent T1D.

Highlights

Context: We set out to characterize the dynamics of islet autoantibodies over the first 15 years of life in children carrying genetic susceptibility to type 1 diabetes (T1D)
There is a need for more information on the natural dynamics of disease-associated autoantibodies in childhood to better distinguish between nonprogressive immunological activation and true progressive autoimmunity, and to further elucidate the mechanisms underlying the heterogeneity of the disease process
We examined the value of islet cell antibodies (ICA) in disease prediction as a part of the autoantibody repertoire and assessed systematically the role of zinc transporter 8 autoantibodies (ZnT8A) in this context

Summary

Introduction

Context: We set out to characterize the dynamics of islet autoantibodies over the first 15 years of life in children carrying genetic susceptibility to type 1 diabetes (T1D). Before the manifestation of clinical type 1 diabetes (T1D), autoantibodies against islet autoantigens are usually detected in the circulation of prediabetic individuals They are considered to reflect ongoing disease activity and are useful tools for identifying individuals at risk for T1D [1]. Autoantibody titer and affinity, and different antibody combinations, have been observed to increase the prognostic value of autoantibody testing in the prediction of T1D [3,4,5] Both genetic predisposition, mainly determined by the human leukocyte antigen (HLA) class II genes, and environmental factors, play an important role in the disease process leading to autoimmunity and eventually to clinical disease [6]. There is a need for more information on the natural dynamics of disease-associated autoantibodies in childhood to better distinguish between nonprogressive immunological activation and true progressive autoimmunity, and to further elucidate the mechanisms underlying the heterogeneity of the disease process

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Conclusion