title: 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.
authors.affiliation: Department of Immunology & Microbial Science, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Roman
authors.initials: R
authors.lastname: Bashratyan
authors.affiliation: Department of Immunology & Microbial Science, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Danielle
authors.initials: D
authors.lastname: Regn
authors.affiliation: Torrey Pines Institute for Molecular Studies, San Diego, CA, USA.
authors.forename: M Jubayer
authors.initials: MJ
authors.lastname: Rahman
authors.affiliation: Department of Immunology & Microbial Science, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Kristi
authors.initials: K
authors.lastname: Marquardt
authors.affiliation: Department of Immunology & Microbial Science, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Fink
authors.affiliation: Department of Immunology & Microbial Science, The Scripps Research Institute, La Jolla, CA, USA.|Biosettia Inc., San Diego, CA, USA.
authors.forename: Wen-Yuan
authors.initials: WY
authors.lastname: Hu
authors.affiliation: Department of Immunology & Microbial Science, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: John H
authors.initials: JH
authors.lastname: Elder
authors.affiliation: San Diego Biomedical Research Institute, San Diego, CA, USA.
authors.forename: James
authors.initials: J
authors.lastname: Binley
authors.affiliation: Department of Immunology & Microbial Science, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Linda A
authors.initials: LA
authors.lastname: Sherman
authors.affiliation: Department of Immunology & Microbial Science, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Yang D
authors.initials: YD
authors.lastname: Dai
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001323:Autoantibodies / Q000097:blood; D015551:Autoimmunity; D055252:Cell-Derived Microparticles / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D020077:Endogenous Retroviruses / Q000276:immunology*; D005260:Female; D015686:Gene Products, env / Q000235:genetics / Q000378:metabolism*; D015683:Gene Products, gag / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007515:Islets of Langerhans / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation; D059630:Mesenchymal Stem Cells / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D034741:RNA, Small Interfering / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology* / Q000637:transplantation
chemical_list: D001323:Autoantibodies; D015686:Gene Products, env; D015683:Gene Products, gag; D034741:RNA, Small Interfering
keywords: Autoimmunity; Endogenous retrovirus; Microvesicles; NOD mice; Type 1 diabetes (T1D)