Extrapancreatic Autoantibody Profiles in Type I Diabetes

Abstract

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.

Naturally presented HLA class l–restricted epitopes from the neurotrophic factor S100‐β are targets of the autoimmune response in type 1 diabetes

“…2C, black squares) T1D patients. A similar result is seen for S100 [20][21][22][23][24][25][26][27][28] in HLA-A2.1-positive (n = 7; Fig. 2D, red squares) and HLA-A2.1-negative (n = 6; Fig.…”

“…1C). Comparison of proteasome-generated peptides with A2.1-eluted peptide MS data (Table 1) indicates that the carboxy-terminal end of peptides S100 [10][11][12][13][14][15][16][17][18] (ALIDVFHQY) and S100 [20][21][22][23][24][25][26][27][28] ΔDa, difference between experimental and theoretical m/z (in Da); Experimental m/z, unique m/z present only in the peptide mix derived from K562/A2.1-S100-b cells; Position, amino acid position in the S100-b protein of the predicted peptide; Sequence, amino acid sequence of the predicted peptide; Theoretical m/z, m/z predicted by Findpept.…”

A Luciferase Immunoprecipitation System (LIPS) assay for profiling human norovirus antibodies

“…The HuNoV LIPS assay is a high-throughput and sensitive method that should prove useful for profiling serum antibodies recognizing diverse HuNoV strains. Thus, further research is warranted for its refinement, such as to detect antibodies in stool or IgA antibodies (Burbelo et al 2012). Such information would facilitate future studies elucidating the immunogenic role of different regions of the major capsid protein, as well as the understudied host antibody responses against HuNoV nonstructural proteins to advance vaccine and antiviral development.…”

Gluten‐free diet during pregnancy alleviates signs of diabetes and celiac disease in NOD mouse offspring

“…The pathogenesis includes destruction of intestinal epithelium, which manifests in intra‐epithelial lymphocyte infiltration, villus atrophy, crypt hyperplasia, and increased intestinal permeability . Most NOD mice and a subset (12%) of type 1 diabetes patients are seropositive for anti‐tTG. Furthermore, NOD mice exhibit enteropathy, whereas pre‐type 1 diabetes humans show signs of enteropathy and increased intestinal permeability .…”