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 β2 -glycoprotein I (β2 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 β2 GPI indeed binds to necroptotic cells and serves as a target for anti-β2 GPI autoantibodies. We further demonstrate that necroptotic, but not apoptotic, cells promote antigenic presentation of β2 GPI to CD4 T cells by dendritic cells. Finally, we show that β2 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. β2 GPI) presented in the context of necroptosis and proinflammatory signals may be sufficient to overcome immune tolerance and induce SLE.

中文翻译：

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坏死性细胞结合β2-糖蛋白I在系统性红斑狼疮中提供了潜在的自身抗原刺激。

系统性红斑狼疮（SLE）的特征是针对多种自身抗原并破坏多个器官的自身抗体的发展。用SLE自身抗原β2-糖蛋白I（β2GPI）和脂多糖（LPS）（一种已知的坏死病引发剂）免疫后，可诱发SLE小鼠模型。我们假设坏死性细胞像凋亡细胞一样，提供了细胞自身抗原的“支架”，但是，与凋亡性细胞不同，坏死性细胞在促炎和免疫原性的情况下这样做。我们证明，β2GPI确实结合了肾病细胞，并作为抗β2GPI自身抗体的靶标。我们进一步证明，坏死性而不是凋亡性细胞通过树突状细胞促进β2GPI向CD4 T细胞的抗原呈递。最后，我们发现，β2GPI / LPS免疫小鼠缺乏RIPK3（与受体相互作用的丝氨酸/苏氨酸-蛋白激酶3）或MLKL（混合谱系激酶结构域），因此无法进行尸检，降低了SLE自身抗体的产生和病理。RIPK3-/-小鼠的SLE自身抗体水平低且没有肾脏病理，而MLKL-/-小鼠最初产生的SLE自身抗体水平低，但后来发展出与野生型（WT）小鼠相当的水平，且病理学与WT和RIPK3-/-小鼠。在LIPK3-/-和MLKL-/-小鼠中，LPS诱导的血清细胞因子水平往往低于WT小鼠，表明促炎性细胞因子产生受损可能会影响这两种菌株中自身抗体产生的开始。我们的数据表明，自身抗原（即