Necroptotic cell binding of ß2 -glycoprotein I provides a potential autoantigenic stimulus in systemic lupus erythematosus.
Immunol Cell Biol
; 97(9): 799-814, 2019 10.
Article
em En
| MEDLINE
| ID: mdl-31187539
ABSTRACT
Systemic lupus erythematosus (SLE) is characterized by the development of autoantibodies against diverse self-antigens with damage to multiple organs. Immunization with the SLE autoantigen ß2 -glycoprotein I (ß2 GPI) and lipopolysaccharide (LPS), a known trigger of necroptosis, induces a murine model of SLE. We hypothesized that necroptotic cells, like apoptotic cells, provide a "scaffold" of cellular self-antigens, but, unlike apoptotic cells, necroptotic cells do so in a proinflammatory and immunogenic context. We demonstrate that ß2 GPI indeed binds to necroptotic cells and serves as a target for anti-ß2 GPI autoantibodies. We further demonstrate that necroptotic, but not apoptotic, cells promote antigenic presentation of ß2 GPI to CD4 T cells by dendritic cells. Finally, we show that ß2 GPI/LPS-immunized mice deficient in RIPK3 (receptor-interacting serine/threonine-protein kinase 3) or MLKL (mixed lineage kinase domain like), and consequently unable to undergo necroptosis, have reduced SLE autoantibody production and pathology. RIPK3-/- mice had low levels of SLE autoantibodies and no renal pathology, while MLKL-/- mice produced low levels of SLE autoantibodies initially, but later developed levels comparable with wild type (WT) mice and pathology intermediate to that of WT and RIPK3-/- mice. Serum cytokine levels induced by LPS tended to be lower in RIPK3-/- and MLKL-/- mice than in WT mice, suggesting that impaired proinflammatory cytokine production may impact the initiation of autoantibody production in both strains. Our data suggest that self-antigen (i.e. ß2 GPI) presented in the context of necroptosis and proinflammatory signals may be sufficient to overcome immune tolerance and induce SLE.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Autoantígenos
/
Beta 2-Glicoproteína I
/
Necroptose
/
Lúpus Eritematoso Sistêmico
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Immunol Cell Biol
Assunto da revista:
ALERGIA E IMUNOLOGIA
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Canadá