Cutting Edge: BAFF Overexpression Reduces Atherosclerosis via TACI-Dependent B Cell Activation.
Patients with systemic lupus erythematosus exhibit accelerated atherosclerosis, a chronic inflammatory disease of the arterial wall. The impact of B cells in atherosclerosis is controversial, with both protective and pathogenic roles described. For example, natural IgM binding conserved oxidized lipid epitopes protect against atherosclerosis, whereas anti-oxidized low-density lipoprotein (oxLDL) IgG likely promotes disease. Because BAFF promotes B cell class-switch recombination and humoral autoimmunity, we hypothesized that excess BAFF would accelerate atherosclerosis. In contrast, BAFF overexpression markedly reduced hypercholesterolemia and atherosclerosis in hyperlipidemic mice. BAFF-mediated atheroprotection required B cells and was associated with increased protective anti-oxLDL IgM. Surprisingly, high-titer anti-oxLDL IgM production and reduced atherosclerosis was dependent on the BAFF family receptor transmembrane activator and CAML interactor. In summary, we identified a novel role for B cell-specific, BAFF-dependent transmembrane activator and CAML interactor signals in atherosclerosis pathogenesis, of particular relevance to the use of BAFF-targeted therapies in systemic lupus erythematosus.
Seattle Children's Research Institute, Seattle, WA 98101.|Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98195.
Shaun W
0000-0002-7024-5252
SW
Jackson
Seattle Children's Research Institute, Seattle, WA 98101.
Nicole E
NE
Scharping
Seattle Children's Research Institute, Seattle, WA 98101.
Holly M
0000-0003-3250-8258
HM
Jacobs
Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195; and.
Shari
S
Wang
Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195; and.
Alan
A
Chait
Seattle Children's Research Institute, Seattle, WA 98101; drawling@uw.edu.|Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98195.|Department of Immunology, University of Washington School of Medicine, Seattle, WA 98195.
David J
0000-0002-0810-1776
DJ
Rawlings
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D050197:Atherosclerosis / Q000276:immunology*; D001323:Autoantibodies / Q000097:blood; D053264:B-Cell Activating Factor / Q000235:genetics / Q000378:metabolism*; D001402:B-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D006801:Humans; D017578:Immunoglobulin Class Switching; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D053303:Transmembrane Activator and CAML Interactor Protein / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D001323:Autoantibodies; D053264:B-Cell Activating Factor; C490314:Caml protein, mouse; C486361:Tnfrsf13b protein, mouse; C505720:Tnfsf13b protein, mouse; D053303:Transmembrane Activator and CAML Interactor Protein