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

作者：Xin Sun, Ridong Li, W X Wang, Danli Yang, Wenyu Tian, Xi Zhang, Linjiang Han, Xuyang Zhao, Xiaoyan Xing, RunTao Li, Yuhui Li, Jing He, Rui Song, Fuping You, Dan Lü · 发表于：Nature Communications · 年份：2026 · DOI：10.1038/s41467-026-74882-4 · 研究领域：Malaria Research and Control、Ubiquitin and proteasome pathways、Multiple Myeloma Research and Treatments

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. This study identifies a pathogenic anti-CD36 autoantibody produced through aberrant activation of the splenic macrophage-B cell axis, thereby linking humoral autoimmunity to systemic inflammation and cerebral malaria pa...