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Single-cell genomics predict germinal centre-associated etiology of autoimmune risk loci

ABSTRACT: The germinal centre (GC) response is critical for both effective adaptive immune responses and establishing peripheral tolerance by limiting auto-reactive B cells. To understand the gene regulatory principles underlying B cell maturation and the GC response we generated a single-cell transcriptomic and epigenomic atlas of the human tonsil, a widely studied, representative lymphoid tissue. We identify diverse immune cell subsets to help us map dynamic transcription factor activity during B cell activation, GC formation and plasma cell differentiation. We subsequently leverage cell type-specific transcriptomic and epigenomic maps to interpret the regulatory potential of fine-mapped autoimmune genetic variants. This reveals that many autoimmune disease-associated variants exhibit the greatest regulatory potential in GC-associated immune cell populations, providing a valuable cell-type resolved resource to understanding cellular and genetic causes underpinning autoimmune disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE165860 | GEO | 2021/09/16

REPOSITORIES: GEO

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Project description:Abstract: Epstein-Barr virus (EBV) infects germinal center (GC) B cells and establishes persistent infection in memory B cells. EBV-infected B cells sometimes cause B cell malignancies in humans with T- or NK-cell deficiency. We now find EBV-encoded Latent Membrane Protein 2A (LMP2A) to mimic B cell antigen receptor (BCR) signaling in murine GC B cells, causing altered humoral immune responses and autoimmune diseases. Investigation of the impact of LMP2A on B cell differentiation in mice that conditionally express LMP2A in GC B cells, or all B-lineage cells, found LMP2A expression enhanced not only BCR signals but also plasma-cell differentiation, in vitro and in vivo. Conditional LMP2A expression in GC B cells resulted in preferential selection of low-affinity antibody–producing B-cells despite apparently normal GC formation. GC B cell-specific LMP2A expression led to systemic lupus erythematosus-like autoimmune phenotypes in an age-dependent manner. Epigenetic profiling of LMP2A B cells found increased H3K27ac and H3K4me1 signals at the Zbtb20 locus. We conclude that LMP2A reduces the stringency of GC B cell selection and may contribute to persistent EBV infection and pathogenesis by providing GC B cells with pro-survival signals. Significance Statement: Epstein-Barr virus (EBV) is a human herpesvirus that establishes persistent infection of the B-cell compartment. EBV is associated with autoimmune diseases, including systemic lupus erythematosus (SLE). However, the molecular mechanisms by which EBV contributes to autoimmunity remain unclear. We used transgenic mouse models to study the role of EBV-encoded Latent membrane protein 2A (LMP2A), which mimics B-cell receptor signaling.　Interestingly, LMP2A not only enhanced B-cell survival, but also upregulated the transcription factor Zbtb20 and promoted plasma cell differentiation. When expressed late in B-cell development, LMP2A also caused prominent features of SLE, including autoantibody production with kidney immune complex deposition. Our findings suggest that LMP2A has important roles in B cell activation, differentiation and the development of EBV-associated autoimmune diseases.

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Single-cell genomics predict germinal centre-associated etiology of autoimmune risk loci

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