Type 1 diabetes pathogenesis is modulated by spontaneous autoimmune responses to endogenous retrovirus antigens in NOD mice

Abstract

Secreted microvesicles (MVs) are potent inflammatory triggers that stimulate autoreactive B and T cells, causing Type 1 Diabetes in non-obese diabetic (NOD) mice. Proteomic analysis of purified MVs released from islet cells detected the presence of endogenous retrovirus (ERV) antigens, including Env and Gag sequences similar to the well-characterized murine leukemia retroviruses. This raises the possibility that ERV antigens may be expressed in the pancreatic islets via MV secretion. Using virus-like particles produced by co-expressing ERV Env and Gag antigens, and a recombinant gp70 Env protein, we demonstrated that NOD but not diabetes-resistant mice developed anti-Env autoantibodies that increase in titer as disease progresses. A lentiviral-based RNA interference knockdown of Gag revealed that Gag contributes to the MV-induced T-cell response, whose diabetogenic function can be demonstrated via cell-transfer into immune-deficient mice. Finally, we observed that Gag and Env are expressed in NOD islet-derived primary mesenchymal stem cells (MSCs). However, MSCs derived from the islets of diabetes-resistant mice do not express the antigens. Taken together, abnormal ERV activation and secretion of MVs may induce anti-retroviral responses to trigger autoimmunity.

Effects of partially dismantling the CD4 binding site glycan fence of HIV-1 Envelope glycoprotein trimers on neutralizing antibody induction

“…Another set of plasmids encoded a series of domain-exchanged hybrid gp160s using sequences from the JR-FL and JR-CSF isolates (Narayan et al, 2013). Plasmids used to make VLPs included pMV-ERV Gag (expresses endogenous murine leukemia virus Gag under the control of a CMV promoter (Bashratyan et al, 2017) and pMV-Rev 0932 (expresses codon-optimized HIV-1 Rev under the control of a CMV promoter).…”

Innate Viral Receptor Signaling Determines Type 1 Diabetes Onset

“…This analysis indicates a positive correlation between summer diarrhea and influenza-like infections at 1–3 years of age with eventual development of T1D while there was negative relationship between varicella. Additionally, evidence suggests autoreactivity in NOD mice may be induced as a consequence of an immunological response against endogenous retrovirus-secreted microvesicles in the islets ( 106 ). Recently, a study using high-throughput proteomic profiling of antibodies in new-onset T1D patients found serum antibodies exhibit a significant reactivity against Epstein–Barr virus viral antigens ( 107 ).…”

Immune Relevant and Immune Deficient Mice: Options and Opportunities in Translational Research

“…440,444 Strain-specific variations in the composition and activity of endogenous retroviruses/retroelements and immune response against retroviral antigens also play a role in the susceptibility of specific mouse backgrounds to experimental autoimmune conditions including SLE and T1D. [445][446][447][448] While the parvoviruses, herpesviruses, and exogenous retroviruses have been eliminated from commercial sources of contemporary laboratory mice because of disease or other confounding effects on research, recent interest in the "normal" immunity of wild or pet store mice may render these agents, as well as historically important mouse disease problems and zoonotic concerns, more relevant. 449,450…”