Single-cell landscape analysis unravels molecular programming of the human B cell compartment in chronic GVHD
Jonathan C. Poe, Jiyuan Fang, Dadong Zhang, Marissa R. Lee, Rachel A. DiCioccio, Hsuan Su, Xiaodi Qin, Jennifer Y. Zhang, Jonathan Visentin, Sonali J. Bracken, Vincent T. Ho, Kathy S. Wang, Jeremy J. Rose, Steven Z. Pavletic, Frances T. Hakim, Wei Jia, Amy N. Suthers, Itaevia M. Curry-Chisolm, Mitchell E. Horwitz, David A. Rizzieri, William C. McManigle, Nelson J. Chao, Adela R. Cardones, Jichun Xie, Kouros Owzar, Stefanie Sarantopoulos
Jonathan C. Poe, Jiyuan Fang, Dadong Zhang, Marissa R. Lee, Rachel A. DiCioccio, Hsuan Su, Xiaodi Qin, Jennifer Y. Zhang, Jonathan Visentin, Sonali J. Bracken, Vincent T. Ho, Kathy S. Wang, Jeremy J. Rose, Steven Z. Pavletic, Frances T. Hakim, Wei Jia, Amy N. Suthers, Itaevia M. Curry-Chisolm, Mitchell E. Horwitz, David A. Rizzieri, William C. McManigle, Nelson J. Chao, Adela R. Cardones, Jichun Xie, Kouros Owzar, Stefanie Sarantopoulos
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Resource and Technical Advance Immunology

Single-cell landscape analysis unravels molecular programming of the human B cell compartment in chronic GVHD

Abstract

Alloreactivity can drive autoimmune syndromes. After allogeneic hematopoietic stem cell transplantation (allo-HCT), chronic graft-versus-host disease (cGVHD), a B cell–associated autoimmune-like syndrome, commonly occurs. Because donor-derived B cells continually develop under selective pressure from host alloantigens, aberrant B cell receptor (BCR) activation and IgG production can emerge and contribute to cGVHD pathobiology. To better understand molecular programing of B cells in allo-HCT, we performed scRNA-Seq analysis on high numbers of purified B cells from patients. An unsupervised analysis revealed 10 clusters, distinguishable by signature genes for maturation, activation, and memory. Within the memory B cell compartment, we found striking transcriptional differences in allo-HCT patients compared with healthy or infected individuals, including potentially pathogenic atypical B cells (ABCs) that were expanded in active cGVHD. To identify intrinsic alterations in potentially pathological B cells, we interrogated all clusters for differentially expressed genes (DEGs) in active cGVHD versus patients who never had signs of immune tolerance loss (no cGVHD). Active cGVHD DEGs occurred in both naive and BCR-activated B cell clusters. Remarkably, some DEGs occurred across most clusters, suggesting common molecular programs that may promote B cell plasticity. Our study of human allo-HCT and cGVHD provides understanding of altered B cell memory during chronic alloantigen stimulation.

Authors

Jonathan C. Poe, Jiyuan Fang, Dadong Zhang, Marissa R. Lee, Rachel A. DiCioccio, Hsuan Su, Xiaodi Qin, Jennifer Y. Zhang, Jonathan Visentin, Sonali J. Bracken, Vincent T. Ho, Kathy S. Wang, Jeremy J. Rose, Steven Z. Pavletic, Frances T. Hakim, Wei Jia, Amy N. Suthers, Itaevia M. Curry-Chisolm, Mitchell E. Horwitz, David A. Rizzieri, William C. McManigle, Nelson J. Chao, Adela R. Cardones, Jichun Xie, Kouros Owzar, Stefanie Sarantopoulos

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Figure 7

Molecules critical to B cell function are altered within clusters in active cGVHD.

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Molecules critical to B cell function are altered within clusters in act...
(A–D) DEG analysis within the 10 B cell clusters in the scRNA-Seq data set based on disease status (as described in Figure 1: active cGVHD, n = 4; no cGVHD, n = 4). Bar graphs indicate total DEG number by cluster, up (A) or down (B), in active cGVHD. The heatmaps in C and D depict DEGs selected from the entire data set (Supplemental Table 3), critical for various aspects of B cell function (select DEGs). Colored squares represent significant (Padj < 0.05) log2 fold change (log2 FC) values for DEGs shown (rows) within the cluster(s) indicated (columns), either up (C) or down (D), in active cGVHD B cells. (E) Panels at left show Slingshot pseudotime trajectory predictions (Traj A–E) for untreated B cells from patients with active cGVHD (top) and no cGVHD (bottom). The origin of the pseudotime analysis (asterisks) was set as cluster 1 based on our knowledge of its transitional like IGKC signature gene profile (Figure 1, E and F, and Figure 2, A and B), suggesting it is the earliest peripheral B cell population emerging from the BM. Panels at right represent each trajectory in isolation (dashed line for reference), along with its associated B cells. B cell clusters are colored and numbered per original unbiased clustering (Figure 1, B, C, and I). Black numbers indicate major clusters that lie along each trajectory, while clusters present but having only a small number of B cells represented are indicated in gray.