title: Apoptotic cells, autoantibodies, and the role of HMGB1 in the subcellular localization of an autoantigen.
abstract: A current model for the evolution of systemic lupus erythematosus hypothesizes that there is a genetic predisposition coupled with an environmental or infectious trigger. This study investigated whether apoptotic cells given with a proinflammatory signal could induce features of lupus. Balb/c mice were injected with an apoptotic Balb/c-derived myeloid cell line, J774.1, either with or without the DNA-binding protein HMGB1 for five injections over 16 days in an IACUC approved study. Mice were sacrificed at 6 weeks and 12 weeks after treatment. Renal disease was assessed by immunofluorescence and autoantibodies were defined by ELISA. Western blotting was performed to characterize autoantigens. Mice injected with apoptotic cells developed antibodies to histones, SSA, ssDNA, and phospholipids. Antibodies to SSA and ssDNA persisted; however, antibodies to histones, and phospholipid declined at 12 weeks. IgG deposits in the kidney were detected at 6 weeks and persisted through 12 weeks primarily in animals that received both apoptotic cells and HMGB1. Autoantibodies in mice were diverse but the mice that received apoptotic cells developed particularly high titer antibodies to an unknown 78kDa protein. This protein became externalized on the surface of J774.1 cells in the presence of HMGB1. Mice that received apoptotic J774.1 cells with HMGB1 developed more extensive renal IgG deposition. While the mechanism is uncertain, an important effect of HMGB1 was to alter the subcellular distribution of a major autoantigen, making the autoantigen accessible for immune responses. This is the first description of an inflammatory stimulus altering the immunologic availability of a potential autoantigen.
authors.affiliation: Division of Allergy and Immunology, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Amy N
authors.initials: AN
authors.lastname: Sanford
authors.forename: Kelly
authors.initials: K
authors.lastname: Dietzmann
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Sullivan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D001323:Autoantibodies / Q000096:biosynthesis; D001324:Autoantigens / Q000276:immunology / Q000378:metabolism*; D005260:Female; D024243:HMGB1 Protein / Q000008:administration & dosage / Q000502:physiology*; D007074:Immunoglobulin G / Q000378:metabolism; D018836:Inflammation Mediators / Q000008:administration & dosage / Q000502:physiology*; D007678:Kidney Glomerulus / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D013347:Subcellular Fractions / Q000276:immunology / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D024243:HMGB1 Protein; D007074:Immunoglobulin G; D018836:Inflammation Mediators