T-Cell Epitopes in Type 1 Diabetes Autoantigen Tyrosine Phosphatase IA-2: Potential for Mimicry with Rotavirus and Other Environmental Agents

Abstract

The tyrosine phosphatase IA-2 is a molecular target of pancreatic islet autoimmunity in type 1 diabetes. T-cell epitope peptides in autoantigens have potential diagnostic and therapeutic applications, and they may hold clues to environmental agents with similar sequences that could trigger or exacerbate autoimmune disease. We identified 13 epitope peptides in IA-2 by measuring peripheral blood T-cell proliferation to 68 overlapping, synthetic peptides encompassing the intracytoplasmic domain of IA-2 in six at-risk type 1 diabetes relatives selected for HLA susceptibility haplotypes. The dominant epitope, VIVMLTPLVEDGVKQC (aa 805-820), which elicited the highest T-cell responses in all at-risk relatives, has 56% identity and 100% similarity over 9 amino acids (aa) with a sequence in VP7, a major immunogenic protein of human rotavirus. Both peptides bind to HLA-DR4(*0401) and are deduced to present identical aa to the T-cell receptor. The contiguous sequence of VP7 has 75% identity and 92% similarity over 12 aa with a known T-cell epitope in glutamic acid decarboxylase (GAD), another autoantigen in type 1 diabetes. This dominant epitope peptide also has 75-45% identity and 88-64% similarity over 8-14 aa to sequences in Dengue, cytomegalovirus, measles, hepatitis C, and canine distemper viruses, and the bacterium Haemophilus influenzae. Three other IA-2 epitope peptides are 71-100% similar over 7-12 aa to herpes, rhino-, hantaand flaviviruses. Two others are 80-82% similar over 10-11 aa to sequences in milk, wheat, and bean proteins. Further studies should now be carried out to directly test the hypothesis that T-cell activation by rotavirus and possibly other viruses, and dietary proteins, could trigger or exacerbate X3-cell autoimmunity through molecular mimicry with IA-2 and (for rotavirus) GAD.

Intestinal virome changes precede autoimmunity in type I diabetes-susceptible children

“…No significant difference in relative abundance or prevalence was detected between cases and controls ( Table 2). Rotavirus has been identified as a candidate trigger or exacerbating factor for T1D (44,45). We detected rotavirus in multiple subjects, including three cases and six controls (Fig.…”

Type 1 Diabetes-Predisposing MHC Alleles Influence the Selection of Glutamic Acid Decarboxylase (GAD) 65-Specific T Cells in a Transgenic Model

“…However, binding studies are fraught with difficulties in interpretation, because peptides that stimulate CD4 ϩ T cells have dramatically varying affinities for the restricting MHC class II molecules (58,59). Also, the relationship between T cell responsiveness and peptide binding affinity to MHC is extremely complex, with certain weakly binding self-peptides capable of potent T cell stimulation and, sometimes, even induction of autoimmunity (60).…”

Environmental Triggers and Determinants of Type 1 Diabetes

“…An Australian study reported a few years ago molecular homology between the VP7 protein of rotavirus and T-cell epitopes in the protein tyrosine phosphatase-related IA-2 molecule and in the GAD65 molecule (54). In a prospective study of infants genetically predisposed to type 1 diabetes, the appearance of diabetes-associated autoantibodies was associated with a significant rise in rotavirus antibodies, indicating that rotavirus infections may induce ␤-cell autoimmunity in genetically susceptible infants (55).…”