Fanny Saidoune1, Guillaume Even2, Yasmine Lamri1, Julie Chezel3, Anh-Thu Gaston2, Brigitte Escoubet4, Thomas Papo3, Nicolas Charles1, Antonino Nicoletti2, Karim Sacre3. 1. Centre de Recherche sur l'Inflammation, INSERM UMR1149, CNRS ERL8252, Laboratoire d'Excellence Inflamex, Université de Paris, Paris, France. 2. Université de Paris, INSERM U1148, Laboratoire d'Excellence Inflamex, Paris, France. 3. Centre de Recherche sur l'Inflammation, INSERM UMR1149, CNRS ERL8252, Laboratoire d'Excellence Inflamex, Université de Paris, Hôpital Bichat-Claude-Bernard, AP-HP, Paris, France. 4. Université de Paris, Hôpital Bichat-Claude-Bernard, AP-HP, Paris, France.
Abstract
OBJECTIVE: Cardiovascular disease (CVD) is the leading cause of death in systemic lupus erythematosus (SLE). B cells play a key role in the pathogenesis of lupus, and anti-BAFF therapy has been approved for use in SLE. Since mature B cells also promote atherosclerosis, we undertook this study to evaluate, in a mouse model and in SLE patients, whether BAFF neutralization has an atheroprotective effect in SLE. METHODS: The effect of BAFF on atherosclerosis associated with lupus was investigated in the atherosclerosis/lupus-prone apolipoprotein E-knockout D227K mouse model and in a cohort of SLE patients. Mice were treated with a blocking anti-BAFF monoclonal antibody (mAb), while fed a standard chow diet. Carotid plaque and carotid intima-media thickness were assessed by ultrasound at baseline and during follow-up in SLE patients who were asymptomatic for CVD. RESULTS: Anti-BAFF mAb in ApoE-/- D227K mice induced B cell depletion, efficiently treated lupus, and improved atherosclerosis lesions (21% decrease; P = 0.007) in mice with low plasma cholesterol levels but worsened the lesions (17% increase; P = 0.06) in mice with high cholesterol levels. The atheroprotective effect of the BAFF-BAFF receptor signaling inhibition on B cells was counterbalanced by the proatherogenic effect of the BAFF-TACI signaling inhibition on macrophages. In SLE patients, blood BAFF levels were associated with subclinical atherosclerosis (r = 0.26, P = 0.03). Anti-BAFF mAb treatment had a differential effect on the intima-media thickness progression in SLE patients depending on body mass index. CONCLUSION: Depending on the balance between lipid-induced and B cell-induced proatherogenic conditions, anti-BAFF could be detrimental or beneficial, respectively, to atherosclerosis development in SLE.
OBJECTIVE:Cardiovascular disease (CVD) is the leading cause of death in systemic lupus erythematosus (SLE). B cells play a key role in the pathogenesis of lupus, and anti-BAFF therapy has been approved for use in SLE. Since mature B cells also promote atherosclerosis, we undertook this study to evaluate, in a mouse model and in SLEpatients, whether BAFF neutralization has an atheroprotective effect in SLE. METHODS: The effect of BAFF on atherosclerosis associated with lupus was investigated in the atherosclerosis/lupus-prone apolipoprotein E-knockout D227Kmouse model and in a cohort of SLEpatients. Mice were treated with a blocking anti-BAFF monoclonal antibody (mAb), while fed a standard chow diet. Carotid plaque and carotid intima-media thickness were assessed by ultrasound at baseline and during follow-up in SLEpatients who were asymptomatic for CVD. RESULTS: Anti-BAFF mAb in ApoE-/- D227Kmice induced B cell depletion, efficiently treated lupus, and improved atherosclerosis lesions (21% decrease; P = 0.007) in mice with low plasma cholesterol levels but worsened the lesions (17% increase; P = 0.06) in mice with high cholesterol levels. The atheroprotective effect of the BAFF-BAFF receptor signaling inhibition on B cells was counterbalanced by the proatherogenic effect of the BAFF-TACI signaling inhibition on macrophages. In SLEpatients, blood BAFF levels were associated with subclinical atherosclerosis (r = 0.26, P = 0.03). Anti-BAFF mAb treatment had a differential effect on the intima-media thickness progression in SLEpatients depending on body mass index. CONCLUSION: Depending on the balance between lipid-induced and B cell-induced proatherogenic conditions, anti-BAFF could be detrimental or beneficial, respectively, to atherosclerosis development in SLE.