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Implication of a lysosomal antigen in the pathogenesis of lupus erythematosus
Journal of Autoimmunity ( IF 7.9 ) Pub Date : 2021-04-28 , DOI: 10.1016/j.jaut.2021.102633
Maud Wilhelm 1 , Srinivasa Reddy Bonam 1 , Nicolas Schall 1 , Mykolas Bendorius 1 , Anne-Sophie Korganow 2 , Catherine Lumbroso 3 , Sylviane Muller 4
Affiliation  

Naturally-occurring autoantibodies to certain components of autophagy processes have been described in a few autoimmune diseases, but their fine specificity, their relationships with clinical phenotypes, and their potential pathogenic functions remain elusive. Here, we explored IgG autoantibodies reacting with a panel of cytoplasmic endosomal/lysosomal antigens and individual heat-shock proteins, all of which share links to autophagy. Sera from autoimmune patients and from MRL/lpr and NZB/W lupus-prone mice reacted with the C-terminal residues of lysosome-associated membrane glycoprotein (LAMP)2A. No cross-reaction was observed with LAMP2B or LAMP2C variants, with dsDNA or mononucleosomes, or with heat-shock protein A8. Moreover, administering chromatography-purified LAMP2A autoantibodies to MRL/lpr mice accelerated mortality. Furthermore, flow cytometry revealed elevated cell-surface expression of LAMP2A on MRL/lpr B cells. These findings reveal the involvement of a new class of autoantibodies targeting the C-terminus of LAMP2A, a receptor for cytosolic proteins targeted for degradation via chaperone-mediated autophagy. These autoantibodies could affect the autophagy process, which is abnormally upregulated in lupus. The data presented support a novel connection between autophagy dysregulation, autoimmune processes and pathophysiology in lupus.



中文翻译:

溶酶体抗原在红斑狼疮发病机制中的意义

已经在一些自身免疫性疾病中描述了针对自噬过程的某些成分的自然发生的自身抗体,但它们的精细特异性、它们与临床表型的关系以及它们潜在的致病功能仍然难以捉摸。在这里,我们探索了与一组细胞质内体/溶酶体抗原和单个热休克蛋白反应的 IgG 自身抗体,所有这些都与自噬有关。来自自身免疫患者和 MRL/lpr 和 NZB/W 狼疮易感小鼠的血清与溶酶体相关膜糖蛋白 (LAMP)2A 的 C 末端残基发生反应。未观察到与 LAMP2B 或 LAMP2C 变体、与 dsDNA 或单核小体或与热休克蛋白 A8 的交叉反应。此外,对 MRL/lpr 小鼠施用色谱纯化的 LAMP2A 自身抗体会加速死亡率。此外,流式细胞术显示 MRL/lpr B 细胞上 LAMP2A 的细胞表面表达升高。这些发现揭示了一类新的靶向 LAMP2A C 末端的自身抗体的参与,LAMP2A 是一种靶向降解的细胞溶质蛋白受体通过伴侣介导的自噬。这些自身抗体可能影响狼疮中异常上调的自噬过程。所提供的数据支持狼疮中自噬失调、自身免疫过程和病理生理学之间的新联系。

更新日期:2021-04-29
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