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DDIT3 deficiency ameliorates systemic lupus erythematosus by regulating B-cell activation and differentiation

ABSTRACT: Systemic lupus erythematosus (SLE) is characterized by the excessive production of autoantibodies, and B cells are considered to be the primary cells involved in the development of SLE. Recent studies have shown that DNA damage responses play a crucial role in B cell activity in SLE, and DNA damage induced transcript 3 (DDIT3) is involved in the innate immune response. However, the exact role of DDIT3 in humoral immune response and the pathogenesis of SLE is still unknown. In this study, we aim to investigate the regulatory role of DDIT3 in B-cell homeostasis and lupus pathogenesis. We observed an increased expression of DDIT3 in B cells from SLE patients, and this expression was positively correlated with disease activity. In DDIT3 deficient mice, we observed disturbances in B cell development and differentiation, as well as inhibition of B cell activation, actin cytoskeleton reorganization, and BCR signaling. Furthermore, DDIT3 deficiency resulted in a reduction in T-cell dependent humoral immune response and germinal center reaction. Mechanistically, we found that DDIT3 promotes the transcription and expression of Itgad, which enhances PI3K signaling and B cell activation. Additionally, in the BM12-induced lupus model, we found that DDIT3 deficiency attenuated lupus symptoms and decreased germinal center responses, levels of anti-dsDNA antibodies, plasmablast cell differentiation, and renal damage. In conclusion, our study reveals for the first time the regulatory role of DDIT3 in B cell homeostasis, B cell activation, BCR signaling, and B cell function. These findings provide a new potential target for intervention in the treatment of SLE.

ORGANISM(S): Mus musculus

PROVIDER: GSE252782 | GEO | 2024/12/31

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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DDIT3 deficiency ameliorates systemic lupus erythematosus by regulating B-cell activation and differentiation

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