P734Leukocyte Bim deficiency induces T cell and immunoglobulin accumulation in atherosclerotic lesions without affecting plaque size

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Abstract

Introduction: Proapoptotic Bcl-2 family member Bim is particularly relevant for deletion of autoreactive and activated T and B cells, implicating Bim in autoimmunity. Atherosclerosis is a chronic inflammatory process with features of autoimmune disease. We therefore investigated impact of hematopoietic Bim deficiency on plaque formation. Hypothesis: Bim deficient leukocytes will be highly (auto)reactive in a hyperlipidemic setting, increasing plaque apoptosis and necrosis and thus contributing to plaque destabilization.

Methods: Bim-/- or wild type bone marrow transplanted LDLr-/- mice were fed a Western type diet for 5 weeks (n=7) or 10 weeks (n=12), after which they were sacrificed, immunophenotyped and atherosclerotic lesions were analyzed. Results: Bim-/- transplanted mice displayed splenomegaly (+81%) and a doubling of circulating lymphocyte counts. Both CD4+ and CD8+ T cells were more activated (increased CD69 and CD71 expression). In Bim deficient mice, a 59% increase in Tbet+ Th1 cells was observed in blood (P<0.001), concomitant with a 43% rise in interferon gamma producing CD4+ Tcells (P<0.001). B cells were elevated by 147%, with a relative shift towards the pro-atherogenic IgG-producing B2 cell phenotype, also reflected by a more than two-fold increase in IgG1 anti-oxLDL antibodies in the serum. Strikingly, plaque size as well as lesion composition or stability (necrotic core, collagen and macrophage content) was unaffected in Bim-/- transplanted mice. Despite massive deposits of IgG complexes in plaques of Bim-/- transplanted mice and a higher presence of lesional T cells (+51%, P<0.05), apoptotic cell content of atherosclerotic lesions remained unchanged. The surprising lack in plaque phenotype despite the profound pro-atherogenic effects on T and B cells may be attributable to a 30-48% (p<0.05) reduction of serum cholesterol levels in Bim-/- transplanted mice.

Conclusion: Bim deficient leukocytes are more activated in Western type diet fed LDLr-/- mice and induce high levels of anti-oxLDL autoantibodies. Nevertheless, those significant pro-atherogenic effects are most likely masked by an unexpected reduction in serum cholesterol.

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