Uncovering Immune Surveillance Deficiency in B Cell-Driven Autoimmune Disease

Antiphospholipid syndrome (APS) serves as a prototypical disease model for investigating immune tolerance breakdown in systemic autoimmunity of B cell. Single-cell RNA and V(D)J repertoire sequencing on paired bone marrow and peripheral blood from untreated primary APS patients enabled an integral “central-to-periphery” B cell blueprint at single-cell resolution, wherein we observed a substantial increase in B cell subsets across nearly all developmental stages. Notably, interferon pathway activation is detected throughout the B cell developmental trajectory, indicating that B cell dysregulation may originate as early as the progenitor stages. Meanwhile, APS patients exhibit sharply decreased abundance, upregulated expressions of inhibitory receptor (PD1 and LAG3), energy supply shortage and loss of mitochondria homeostasis in terminal effector T and NK cells, which collectively suggest an exhausted phenotype. This exhaustion likely impairs immune surveillance, facilitating the escape of autoreactive B cells through HLA-E-NKG2A interactions. Our research presents an in-depth immune cell atlas, and reveal early-stage interferon-driven B cell abnormalities and effector cell exhaustion as shared mechanisms in B cell-driven autoimmunity, highlighting potential therapeutic targets for immune tolerance restoration.