Plasma Cell Depletion Attenuates Hypertension in an Experimental Model of Autoimmune Disease

Abstract

Numerous studies show a direct relation between circulating autoantibodies, characteristic of systemic autoimmune disorders, and primary hypertension in humans. Whether these autoantibodies mechanistically contribute to the development of hypertension remains unclear. Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder characterized by aberrant immunoglobulin production, notably pathogenic autoantibodies, and is associated with prevalent hypertension, renal injury, and cardiovascular disease. Because plasma cells produce the majority of serum immunoglobulins and are the primary source of autoantibodies in SLE, we hypothesized that plasma cell depletion using the proteasome inhibitor bortezomib would lower autoantibody production and attenuate hypertension. Thirty-week-old female SLE (NZBWF1) and control (NZW [New Zealand White]) mice were injected IV with vehicle (0.9% saline) or bortezomib (0.75 mg/kg) twice weekly for 4 weeks. Bortezomib treatment significantly lowered the percentage of bone marrow plasma cells in SLE mice. Total plasma IgG and anti-dsDNA IgG levels were higher in SLE mice compared with control mice but were lowered by bortezomib treatment. Mean arterial pressure (mm Hg) measured in conscious mice by carotid artery catheter was higher in SLE mice than in control mice, but mean arterial pressure was significantly lower in bortezomib-treated SLE mice. Bortezomib also attenuated renal injury, as assessed by albuminuria and glomerulosclerosis, and reduced glomerular immunoglobulin deposition and B and T lymphocytes infiltration into the kidneys. Taken together, these data show that the production of autoantibodies by plasma cells mechanistically contributes to autoimmune-associated hypertension and suggests a potential role for patients with primary hypertension who have increased circulating immunoglobulins.

Cyclophosphamide treatment for hypertension and renal injury in an experimental model of systemic lupus erythematosus

“…; Taylor et al. ), thus adding to the overall understanding of the role immune system has in hypertensive disorders (Rodriguez‐Iturbe ; Taylor and Ryan ). The purpose of the present study was to test whether CYC, another commonly prescribed chemotherapy for induction therapy in LN, attenuates hypertension during SLE.…”

“…), plasma cells, and the associated immunoglobulins (Taylor et al. ) in the development of hypertension during SLE. This body of work points to autoimmunity as a driving mechanism for the development of hypertension, a concept that is further supported by clinical studies showing that patients with primary hypertension have increased circulating autoantibodies (Ebringer and Doyle ; Suryaprabha et al.…”

“…Renal immune cells were prepared for flow cytometry as published previously by our laboratory (Taylor and Ryan ; Taylor et al. ). Briefly, 5 mL of Roswell Park Memorial Institute (RPIM) containing 200 U/mL DNase and 10 mg/mL collagenase IV was used to homogenize a single kidney from each mouse with the GentleMACS Octo Dissociator (Miltenyi Biotec) with a user‐defined protocol.…”

Freedom isn’t always free: immunoglobulin free light chains promote renal fibrosis

“…In addition, bortezomib inhibits both NF-κB and MAPK pathways (24), which have been shown to act downstream of FLCs in the kidney. The effect of bortezomib in MM with renal involvement has been well documented (22), and it has also been effective in ameliorating renal injury in autoantibodymediated diseases such as systemic lupus erythematosus (SLE) (25)(26)(27). It should be noted that numerous autoimmune and inflammatory diseases, including SLE, rheumatoid arthritis, multiple sclerosis, and diabetes, feature elevated circulating polyclonal FLCs (28).…”

Hypertension: a new treatment for an old disease? Targeting the immune system

“…Bortezomib (Figure ), a proteasome inhibitor approved for the treatment of multiple myeloma, attenuated BP increase and aortic vascular remodelling in AngII‐infused mice (Li et al ., ). Also, recent data on a rat model of SLE demonstrated significant reduction on BP and improvement of renal function by bortezomib, and these effects were associated with the bortezomib‐induced decrease of plasma immunoglobulin levels and B‐cell and T‐cell infiltration in the kidneys (Taylor et al ., ). Although bortezomib emerges as a modulator of the adaptive immune responses driven by B‐cells and T‐cells in hypertension, common adverse effects in patients with myeloma include dose‐limiting toxicity leading to sensory neuropathy, asthenic conditions, gastrointestinal disorders and no dose‐limiting responses such as thrombocytopenia and anaemia (Bross et al ., ).…”