Autoantibodies to nuclear antigens are hallmarks of systemic lupus erythematosus (SLE) where they contribute to pathogenesis. However, there remains a gap in our knowledge regarding how different isotypes of autoantibodies contribute to this autoimmune disease, including the production of the critical type I interferon (IFN) cytokines by plasmacytoid dendritic cells (pDCs) in response to immune complexes (ICs). We focused on IgA, which is the second-most prevalent isotype in serum and, along with IgG, is deposited in glomeruli in individuals with lupus nephritis. We show that individuals with SLE have serum IgA autoantibodies against most nuclear antigens, correlating with IgG against the same antigen. We investigated whether IgA autoantibodies against a major SLE autoantigen, Smith ribonucleoprotein (Sm/RNP), played a role in IC activation of pDCs. We found that pDCs expressed the IgA-specific Fc receptor, FcαR, and IgA1 autoantibodies synergized with IgG in RNA-containing ICs to generate robust primary blood pDC IFN-α responses in vitro. pDC responses to these ICs required both FcαR and FcγRIIa, showing synergy between these Fc receptors. Sm/RNP IC binding to and internalization by pDCs were greater when ICs contained both IgA1 and IgG. Circulating pDCs from individuals with SLE had higher binding of IgA1-containing ICs and higher expression of FcαR than pDCs from healthy control individuals. Although pDC FcαR expression correlated with the blood IFN-stimulated gene signature in SLE, Toll-like receptor 7 agonists, but not IFN-α, up-regulated pDC FcαR expression in vitro. Together, we show a mechanism by which IgA1 autoantibodies contribute to SLE pathogenesis.

中文翻译：

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狼疮 IgA1 自身抗体与 IgG 协同作用，增强浆细胞样树突状细胞对含有 RNA 的免疫复合物的反应


核抗原自身抗体是系统性红斑狼疮 (SLE) 的标志，它们参与发病机制。然而，关于不同同种型自身抗体如何导致这种自身免疫性疾病，包括浆细胞样树突细胞 (pDC) 响应免疫复合物 (IC) 产生关键的 I 型干扰素 (IFN) 细胞因子，我们的知识仍然存在差距。我们重点关注 IgA，它是血清中第二常见的同种型，与 IgG 一起沉积在狼疮性肾炎患者的肾小球中。我们发现，患有 SLE 的个体具有针对大多数核抗原的血清 IgA 自身抗体，与针对相同抗原的 IgG 相关。我们研究了针对主要 SLE 自身抗原史密斯核糖核蛋白 (Sm/RNP) 的 IgA 自身抗体是否在 pDC 的 IC 激活中发挥作用。我们发现 pDC 表达 IgA 特异性 Fc 受体、FcαR 和 IgA1 自身抗体，与含 RNA IC 中的 IgG 协同作用，在体外产生强大的原代血 pDC IFN-α 反应。 pDC 对这些 IC 的反应需要 FcαR 和 FcγRIIa，这显示了这些 Fc 受体之间的协同作用。当 IC 同时含有 IgA1 和 IgG 时，Sm/RNP IC 与 pDC 的结合和内化程度更高。与来自健康对照个体的 pDC 相比，来自 SLE 个体的循环 pDC 具有更高的含 IgA1 IC 结合和更高的 FcαR 表达。尽管 pDC FcαR 表达与 SLE 中血液 IFN 刺激的基因特征相关，但 Toll 样受体 7 激动剂（而非 IFN-α）在体外上调 pDC FcαR 表达。我们共同展示了 IgA1 自身抗体促进 SLE 发病机制的机制。