Extrapancreatic Autoantibody Profiles in Type I Diabetes

<div><p>Type I diabetes (T1D) is an autoimmune disease characterized by destruction of insulin-producing β-cells in the pancreas. Although several islet cell autoantigens are known, the breadth and spectrum of autoantibody targets has not been fully explored. Here the luciferase immunoprecipitation systems (LIPS) antibody profiling technology was used to study islet and other organ-specific autoantibody responses in parallel. Examination of an initial cohort of 93 controls and 50 T1D subjects revealed that 16% of the diabetic subjects showed anti-gastric ATPase autoantibodies which did not correlate with autoantibodies against GAD65, IA2, or IA2-β. A more detailed study of a second cohort with 18 potential autoantibody targets revealed marked heterogeneity in autoantibody responses against islet cell autoantigens including two polymorphic variants of ZnT8. A subset of T1D subjects exhibited autoantibodies against several organ-specific targets including gastric ATPase (11%), thyroid peroxidase (14%), and anti-IgA autoantibodies against tissue transglutaminase (12%). Although a few T1D subjects showed autoantibodies against a lung-associated protein KCNRG (6%) and S100-β (8%), no statistically significant autoantibodies were detected against several cytokines. Analysis of the overall autoantibody profiles using a heatmap revealed two major subgroups of approximately similar numbers, consisting of T1D subjects with and without organ-specific autoantibodies. Within the organ-specific subgroup, there was minimal overlap among anti-gastric ATPase, anti-thyroid peroxidase, and anti-transglutaminase seropositivity, and these autoantibodies did not correlate with islet cell autoantibodies. Examination of a third cohort, comprising prospectively collected longitudinal samples from high-risk individuals, revealed that anti-gastric ATPase autoantibodies were present in several individuals prior to detection of islet autoantibodies and before clinical onset of T1D. Taken together, these results suggest that autoantibody portraits derived from islet and organ-specific targets will likely be useful for enhancing the clinical management of T1D.</p> </div

Predictive value of anti-gastric autoantibodies in high risk children.

<p>(<b>A</b>) Anti-ATP4B autoantibodies were evaluated in pediatric serum samples (n = 75) from the high risk DAISY cohort containing three clinically defined subgroups: islet autoantibody negative and T1D negative (AAB−/T1D−), islet autoantibody positive but currently without T1D (AAB+/T1D), and islet autoantibody positive and diagnosed with T1D (AAB+/T1D+). Only the last available longitudinal serum sample from these children was initially evaluated. The autoantibody titers are plotted on the Y-axis using a log₁₀ scale. The dashed line represents the previous cut-off level for determining seropositivity. (<b>B</b>) The five seropositive children were further analyzed for anti-ATP4B autoantibodies using available longitudinal serum samples. The titer value shown for the last serum sample was taken from the results obtained in panel A. The stippled arrow represents the age of first detectable islet autoantibodies and the solid arrow marks the time of T1D onset. The dashed line represents the cut-off for determining seropositivity and was represents the ATP4B cut-off value from the DASP 2010 samples.</p

Autoantibodies in T1D and control subjects from DASP 2009.

<p>The mean antibody titer and 95% confidence interval for (<b>A</b>) GAD65 (<b>B</b>) IA2, (<b>C</b>) IA2-β, and (<b>D</b>) ATP4B titers in the 89 controls and 50 T1D subjects were plotted on the Y-axis using a log₁₀ scale. Each symbol represents a sample from one individual. The dashed line represents the cut-off level for determining seropositivity and is derived from the mean plus 3 standard deviations of the antibody titer of the controls. <i>P</i> values for the different groups were calculated using the Mann Whitney <i>U</i> test.</p

Autoantibody portraits in T1D subjects.

<p>Individual autoantibody titers in the 50 T1D subjects from the DASP 2010 cohort are presented as a heatmap. As described in the material and methods, color code reflects the relative titers in standard deviations above the mean plus three SD of the control subjects for each of the 10 antibody-antigen pairs. Individual antibody profiles were then manually assembled based on the presence or absence of particular organ-specific autoantibodies and then by autoantibodies to the major islet autoantigens.</p