A viral epitope that mimics a self antigen can accelerate but not initiate autoimmune diabetes
Urs Christen, … , Michael B.A. Oldstone, Matthias G. von Herrath
Urs Christen, … , Michael B.A. Oldstone, Matthias G. von Herrath
Published November 1, 2004
Citation Information: J Clin Invest. 2004;114(9):1290-1298. https://doi.org/10.1172/JCI22557.
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Article Autoimmunity

A viral epitope that mimics a self antigen can accelerate but not initiate autoimmune diabetes

Abstract

We document here that infection of prediabetic mice with a virus expressing an H-2Kb–restricted mimic ligand to a self epitope present on β cells accelerates the development of autoimmune diabetes. Immunization with the mimic ligand expanded autoreactive T cell populations, which was followed by their trafficking to the islets, as visualized in situ by tetramer staining. In contrast, the mimic ligand did not generate sufficient autoreactive T cells in naive mice to initiate disease. Diabetes acceleration did not occur in H-2Kb–deficient mice or in mice tolerized to the mimic ligand. Thus, arenavirus-expressed mimics of self antigens accelerate a previously established autoimmune process. Sequential heterologous viral infections might therefore act in concert to precipitate clinical autoimmune disease, even if single exposure to a viral mimic does not always cause sufficient tissue destruction.

Authors

Urs Christen, Kurt H. Edelmann, Dorian B. McGavern, Tom Wolfe, Bryan Coon, Meghann K. Teague, Stephen D. Miller, Michael B.A. Oldstone, Matthias G. von Herrath

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H-2Kb–restricted, autoreactive, LCMV/PV-NP205–specific cross-reactive CD...
H-2Kb–restricted, autoreactive, LCMV/PV-NP205–specific cross-reactive CD8 T cells mediate the acceleration of diabetes. (A and B) RIP-LCMV-NP or RIP-LCMV-NP × Kb(–) mice were infected with LCMV or PV. After 4 weeks, the mice received a secondary infection of PV. (A) Blood glucose of RIP-LCMV-NP, RIP-LCMV-NP × Kb(–), and RIP-LCMV-NP × Kb(+) littermates was measured in weekly intervals. The diabetes onset curves (blood glucose values > 300 mg/dl) for the groups [RIP-LCMV-NP × Kb(–) vs. RIP-LCMV-NP × Kb(+)] are significantly different (log rank test; P = 0.0167). (B) Pancreas sections from 3–4 mice per group at week 3 after secondary infection with PV were stained for cellular infiltration of CD8 T cells. Sections of 1 representative RIP-LCMV-NP × Kb(–) and RIP-LCMV-NP × Kb(+) mouse are shown. Original magnification, ×20. (C) Mice were tolerized to PV-NP205 by injection of 2 × 107 ECDI–PV-NP205–coupled autologous splenocytes (ECDI + NP205) or with 2 × 107 splenocytes treated with EDCI alone, 5 days before infection with 105 PFU LCMV. After 4 weeks, mice were infected with PV. Diabetes incidence (blood glucose values > 300 mg/dl) at week 4 after PV infection is displayed; numbers of mice analyzed per group are indicated in parentheses. (D and E) Groups of 3–4 mice were infected with LCMV. After 4 weeks, the mice received 100 μg of PV-NP205 peptide or an H-2Kb–restricted control peptide (OVA; SIINFEKL). In addition, mice received three injections of poly(I:C) (7.5 μg/g body mass) at the time of peptide injection and then at days 2 and 4 thereafter. Controls received PV-NP205 only or PV infection. (D) The frequency of blood LCMV/PV-NP205–specific cross-reactive CD8 T cells was assessed by flow cytometry using H-2Kb–PV-NP205 tetramers (day 7 after peptide injection). (E) Mean blood glucose values (± SEM) measured at week 2 after peptide and/or poly(I:C) injection is displayed.