(106) B cell intrinsic Ube2l3 is central to spontaneous germinal center formation and autoimmunity

Introduction/Rationale: UBE2L3, a ubiquitin-conjugating enzyme, is associated with increased susceptibility to systemic lupus erythematosus (SLE) and other autoimmune diseases. Spontaneously developed germinal centers (Spt-GCs) generate pathogenic autoantibodies (Auto-Abs) that promote SLE. Here, our goal is to elucidate the previously unknown B cell-intrinsic role of Ube2l3 in Spt-GC, auto-Ab responses, and systemic autoimmunity.

Methods: We generated B-cell-specific Ube2l3-deficient mice (FcR2bKO.Ube2l3BKO) on an SLE-prone FcR2bKO background. We determined spontaneous and imiquimod (a TLR7 ligand)- induced autoimmune and foreign antigen-driven B and T cell responses using flow cytometry. Auto-Ab forming cells (AFCs) and auto-Ab titers were measured by ELISpot, ELISA, and Hep-2 assays. C3 and IgG immune complex (IC) deposition in the kidneys was examined by immunofluorescence.

Results: B cell intrinsic Ube2l3 deletion resulted in significantly reduced splenomegaly, Spt-GC, Tfh cell, age-associated B cell, and auto-Ab responses, and kidney IC deposition and glomerulonephritis. While marginal zone B cells were increased, the pathogenic CD138+TACI+CD19-B220+ plasma cells were reduced in the spleen and bone marrow of Ube2l3BKO mice. These results were recapitulated in the TLR7-induced SLE model. In contrast, Ube2l3 deletion in B cells did not overtly affect foreign antigen-specific B cell and Ab responses.

Conclusion: We report for the first time that B-cell-intrinsic Ube2l3 is required for Spt-GC formation and SLE-autoimmunity development.