Background and aims There are numerous endogenous Bcl-2 antagonists that share similar homology, structure, topology and expression pattern, yet only the loss of Bim in mice is sufficient to lead to the development of a systemic autoimmunity.
Methods We investigated the contribution of Bim in monocytes/macrophages and its effect on systemic autoimmunity by establishing conditionally Bim-deleted mice in the monocyte/macrophage compartment (CreLysMBimfl/fl mice) and examined the development of lupus-like disease over time.
Results Patients with lupus display decreased expression of Bim in circulating monocytes and reduced Bim expression in kidney macrophages. CreLysMBimflox/flox mice develop a lupus-like disease that mirrors aged Bim-/- mice including loss of the marginal zone macrophages, splenomegaly, lymphadenopathy, autoantibodies including anti-DNA IgG, and a type I interferon signature as compared to control mice. CreLysMBimflox/flox mice also exhibit increased mortality attributed to immune complex deposition and increased numbers of kidney macrophages all of which contribute to glomerulonephritis. The loss of Bim in macrophages is sufficient to break tolerance as adoptive transfer of wild-type lymphocytes into CreLysMBimflox/floxRag-/- mice leads to systemic autoimmunity. We also identified that the loss of TLR signalling adaptor protein TRIF but not MyD88 is essential for progression to GN phase but is dispensable for systemic autoimmunity. RNA seq analysis of sorted kidney macrophages revealed a novel Bim and lupus specific signatures.
Conclusions These data add another facet to the conventional dogma that Bim’s central role in autoimmune disease is to prevent the escape of autoreactive lymphocytes from apoptosis. Thus, Bim may be a novel therapeutic target for treating SLE.
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