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DOI: 10.1101/2022.10.13.512162

Single-cell Landscape Analysis of the Human Circulating B Cell Pool under Selective Pressure of Allogeneic Stem Cell Transplantation

J. C.Poe J. Fang D. Zhang ...+22 S. Sarantopoulos
A healthy immune state is achieved and maintained only if autoreactive B cells are eliminated or tolerized. After allogeneic hematopoietic stem cell transplantation (allo-HCT), donor-derived B cells develop under selective pressure from host alloantigens. Likewise, B cells play a substantiated role in the pathobiology of the allo-HCT-related autoimmune-like syndrome, chronic graft versus host disease (cGVHD). Allo-HCT thus represents a unique opportunity to study human peripheral B cell tolerance, since stem cell reconstitution occurs continuously in an alloantigen environment. Herein, we performed scRNA-Seq analysis on purified B cells from allo-HCT patients and resolved 10 clusters distinguishable by signature genes for maturation, activation and memory. Compared to single-cell RNA-Seq data from healthy or infected individuals, allo-HCT patients had striking transcriptional differences in the memory B cell compartment that suggested a propensity toward autoreactivity. To identify B-cell intrinsic properties linked to overt loss of immune tolerance in allo-HCT, we then assessed all 10 clusters for differentially expressed genes (DEGs) between patients with vs. without autoimmune-like manifestations (Active cGVHD vs. No cGVHD). In Active cGVHD, notable DEGs occurred in both naive and BCR-activated clusters, including a BCR-experienced cluster harboring a significantly expanded population of potentially pathologic, atypical/age-related memory B cells (ABCs). Pseudotime trajectory analyses plus use of a maturation agent in vitro also indicated that aberrant B-cell activation and diversification states after allo-HCT are potentially plastic and amenable to pharmacological manipulation. Our single-cell-level findings reveal potentially novel targets in cGVHD and provide new understanding of how alloreactivity may lead to human autoimmune diseases.