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<p>Cerebral malaria (CM) is a severe complication of <i>Plasmodium</i> infection, classically attributed to parasite sequestration and neuroinflammation. Here, we uncover a spleen-centered humoral autoimmune circuit that drives CM pathology. Proteomic analyses identify CD36 as a dominant host-derived antigen enriched in infected red blood cells (iRBCs), triggering anti-CD36 autoantibody production in patients with <i>falciparum</i> malaria. Although contributing to iRBCs clearance, these autoantibodies also target other CD36-expressing cells, thereby driving thrombocytopenia, endothelial injury, and macrophage activation, ultimately amplifying systemic inflammation. Mechanistically, <i>Plasmodium</i> infection recruits Ly6c<sup>+</sup>Glut1<sup>hi</sup> macrophages to the spleen through the CCL2-CCR2 axis. These macrophages exhibit elevated proteasome activity and drive B cell activation and anti-CD36 antibody production. Targeting Ly6c<sup>+</sup>Glut1<sup>hi</sup> macrophages, we develop Glutoborin, a GLUT1-directed proteasome inhibitor that preferentially suppresses their function, reduces autoantibody production, and alleviates CM-associated pathology in vivo. Together, these findings establish a spleen-centered anti-CD36 autoimmune circuit as a key driver of CM and nominate Ly6c<sup>+</sup>Glut1<sup>hi</sup> macrophages as therapeutic targets.</p>

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Splenic macrophage-B cell axis drives systemic autoimmune-like pathology in Cerebral Malaria

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年6月27日

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  • Xin Sun,
  • Ridong Li,
  • Weixuan Wang,
  • Danli Yang,
  • Wenyu Tian,
  • Xin Zhang,
  • Linjiang Han,
  • Xuyang Zhao,
  • Xiaoyan Xing,
  • Runtao Li,
  • Yuhui Li,
  • Jing He,
  • Rui Song,
  • Fuping You,
  • Dan Lu

摘要

Cerebral malaria (CM) is a severe complication of Plasmodium infection, classically attributed to parasite sequestration and neuroinflammation. Here, we uncover a spleen-centered humoral autoimmune circuit that drives CM pathology. Proteomic analyses identify CD36 as a dominant host-derived antigen enriched in infected red blood cells (iRBCs), triggering anti-CD36 autoantibody production in patients with falciparum malaria. Although contributing to iRBCs clearance, these autoantibodies also target other CD36-expressing cells, thereby driving thrombocytopenia, endothelial injury, and macrophage activation, ultimately amplifying systemic inflammation. Mechanistically, Plasmodium infection recruits Ly6c+Glut1hi macrophages to the spleen through the CCL2-CCR2 axis. These macrophages exhibit elevated proteasome activity and drive B cell activation and anti-CD36 antibody production. Targeting Ly6c+Glut1hi macrophages, we develop Glutoborin, a GLUT1-directed proteasome inhibitor that preferentially suppresses their function, reduces autoantibody production, and alleviates CM-associated pathology in vivo. Together, these findings establish a spleen-centered anti-CD36 autoimmune circuit as a key driver of CM and nominate Ly6c+Glut1hi macrophages as therapeutic targets.