The B cell survival factor (TNFSF13B/BAFF) is often elevated in autoimmune diseases and is targeted in the clinic for the treatment of systemic lupus erythematosus. BAFF contains a loop region designated the flap, which is dispensable for receptor binding. Here we show that the flap of BAFF has two functions. In addition to facilitating the formation of a highly active BAFF 60-mer as shown previously, it also converts binding of BAFF to TNFRSF13C (BAFFR) into a signaling event via oligomerization of individual BAFF-BAFFR complexes. Binding and activation of BAFFR can therefore be targeted independently to inhibit or activate the function of BAFF. Moreover, structural analyses suggest that the flap of BAFF 60-mer temporarily prevents binding of an anti-BAFF antibody (belimumab) but not of a decoy receptor (atacicept). The observed differences in profiles of BAFF inhibition may confer distinct biological and clinical efficacies to these therapeutically relevant inhibitors.

Atherosclerotic cardiovascular disease (CVD) is the leading cause of mortality worldwide 1,2 . Atherosclerotic plaque formation is initiated upon trapping of low-density lipoprotein (LDL) in the subendothelial space of large and medium size arteries that initially involves binding of LDL to heparan-sulfate proteoglycans (HSPGs) 3 , followed by a chronic inflammation and remodelling of the artery wall 3 . A Proliferation Inducing Ligand (APRIL), a cytokine produced by many cell types, binds to HSPGs 4 , but the physiology of this interaction is largely unknown. Here, we show that genetic ablation or antibody-mediated depletion of APRIL aggravates atherosclerosis in mice.Mechanistically, we demonstrate that APRIL confers atheroprotection via binding to heparan sulfate (HS) chains of heparan-sulfate proteoglycan 2 (HSPG2), which limits LDL retention, macrophage accumulation and necrotic core formation. Indeed, antibody-mediated depletion of APRIL in mice expressing HS-deficient HSPG2 had no effect on atherosclerosis development.Consistent with these data, treatment with a specific anti-APRIL antibody that promotes the binding of APRIL to HSPGs reduces experimental atherosclerosis. Furthermore, the serum levels of a previously unknown form of human APRIL protein that binds to HSPGs, which we termed non-canonical APRIL (nc-APRIL), are associated independently of traditional risk factors with long term (10-to 12-year follow up) cardiovascular mortality in patients with atherosclerosis. Our data reveal hitherto unknown properties of APRIL that have broad pathophysiological implications for vascular homeostasis.

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Background and PurposeThe TNF family ligands, B cell activating factor of the TNF family (BAFF, also known as B lymphocyte stimulator, BLyS) and a proliferation‐inducing ligand (APRIL), share the transmembrane activator and calcium‐modulator and cyclophilin ligand (CAML)‐interactor (TACI) as one of their common receptors. Atacicept, a chimeric recombinant TACI/IgG1‐Fc fusion protein, inhibits both ligands. TACI and APRIL also bind to proteoglycans and to heparin that is structurally related to proteoglycans. It is unknown whether the portion of TACI contained in atacicept can bind directly to proteoglycans, or indirectly via APRIL, and whether this could interfere with the anti‐coagulant properties of heparin.Experimental ApproachBinding of atacicept and APRIL to proteoglycan‐positive cells was measured by FACS. Activities of heparin and atacicept were measured with activated factor Xa inhibition and cell‐based assays. Effects of heparin on circulating atacicept was monitored in mice.Key ResultsAtacicept did not bind to proteoglycan‐positive cells, but when complexed to APRIL could do so indirectly via APRIL. Multimers of atacicept obtained after exposure to cysteine or BAFF 60‐mer bound directly to proteoglycans. Atacicept alone, or in complex with APRIL, or in a multimeric form did not interfere with heparin activity in vitro. Conversely, heparin did not influence inhibition of BAFF and APRIL by atacicept and did not change circulating levels of atacicept.Conclusions and ImplicationsLack of detectable interference of APRIL‐bound or free atacicept on heparin activity makes it unlikely that atacicept at therapeutic doses will interfere with the function of heparin in vivo.

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