Abstract 008: Depletion of Antibody-Secreting Plasma Cells Attenuates Hypertension in an Experimental Model of Autoimmune Disease

Abstract

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that is characterized by aberrant immunoglobulin (Ig) production, notably pathogenic autoantibodies, and is associated with prevalent hypertension, renal injury, and cardiovascular disease. Recent studies by our laboratory have shown that chronic B cell depletion with anti-CD20 monoclonal antibody reduces autoantibody production and prevents the development of hypertension in an experimental female mouse model of SLE (NZBWF1). However, the treatment was only effective when administered before the onset of autoantibody production. Because long-lived plasma cells produce the majority of serum Ig and are the primary source of autoantibodies in SLE, we hypothesized that depletion of plasma cells using the proteasome inhibitor bortezomib would lower autoantibody production and attenuate hypertension. Thirty week old female NZBWF1 and control (NZW) mice were injected i.v. with vehicle (0.9% saline) or bortezomib (0.75 mg/kg) twice weekly for four weeks. Percentages of CD138 + intracellular-κ light chain + plasma cells in the bone marrow were lower in bortezomib treated SLE mice compared to vehicle-treated SLE mice (1.7±0.19% vs. 0.95±0.18%, p<0.05), as assessed by flow cytometry. Total plasma IgG was higher in SLE mice as compared to control mice (5.02±1.2 mg/mL vs. 2.88±0.78, p<0.05), and were lower in SLE mice treated with bortezomib (1.5±0.5 mg/mL, p<0.05 vs. SLE-vehicle). In addition, bortezomib treatment reduced circulating anti-dsDNA IgG levels in SLE mice (OD450 1.36±0.25 vs. 0.44±0.11 p<0.01). Urinary albumin excretion, an indicator of glomerular injury, was increased in SLE mice as compared to control mice (16.8±10.1 vs. 0.015±0.002 mg/day, p<0.05) and was lower in SLE mice treated with bortezomib (0.24±00.16 mg/day, p<0.05 vs. SLE-vehicle). Mean arterial pressure (MAP; mmHg) measured in conscious mice by carotid artery catheter was higher in SLE mice than in control mice (142±5 vs. 118±3, p<0.001). MAP was significantly lower in SLE mice treated with bortezomib when compared to vehicle treated mice (119±4 vs. 142±5, p<0.001). These data suggest that production of autoantibodies by plasma cells in SLE mechanistically contribute to the pathogenesis of hypertension.