Preventing Autoantibody Production Improves Endothelial Function in an Experimental Model of Autoimmune Disease
Authors: Taylor Erin , Bruno Christian , Ryan Michael 
Published: June 2021

Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disorder that predominately affects women of childbearing age and is associated with high rates of hypertension, renal injury, and cardiovascular disease. SLE disease is characterized by B and T lymphocyte dysfunction, leading to the production of pathogenic autoantibodies to a variety of self components. Autoantibodies produced during SLE form immune complexes that deposit in endothelial basement membranes and contribute to vascular inflammation. Autoantibodies also directly bind to endothelial cells in vitro in an antigen‐specific manner. However, whether vascular function is directly affected by autoantibodies in SLE is unknown. Our laboratory previously reported that an established female mouse model of SLE (NZBWF1) progressively develops impaired vascular relaxation when compared to age matched healthy controls (female NZW). We hypothesize that the depletion of plasma cells, which are responsible for the majority of immunoglobulin production, with the proteasome inhibitor bortezomib will improve endothelial function in NZBWF1 mice. To test this, 12 week old control (n=14) and SLE (n=12) mice were injected i.v. with vehicle (0.9% NaCl) or bortezomib (0.75 mg/kg) twice weekly for 12 weeks. Treatment with bortezomib lowered the percentages of CD138+plasma cells in the spleen of SLE animals, as assessed by flow cytometry (0.51±0.21 vs. 0.26±0.06%, p=0.06). In addition, total circulating IgG concentrations were determined using ELISA. Plasma IgG levels were higher in SLE mice as compared to control animals (2.0±0.15 vs. 6.1±1.0 mg/mL, p<0.01), and bortezomib treatment significantly lowered IgG levels in both SLE and control animals (SLE‐ 6.1±1.0 vs. 2.3±0.46 mg/mL, p<0.001; Control‐2.0±0.15 vs. 1.1±0.09 mg/mL, p<0.001). Circulating anti‐dsDNA autoantibodies, characteristic of human SLE, were also measured. Anti‐dsDNA IgG was higher in SLE mice as compared to controls (13.1±2.2 kU/mL vs. 522±291 kU/mL, p=0.09). Bortezomib‐treated SLE mice had lower levels of anti‐dsDNA IgG (522±291 vs. 12.0±2.7 kU/mL, p=0.08). To assess the impact of antibody depletion on vascular function, carotid rings were suspended in organ chamber baths and endothelium‐dependent and endothelium‐independent concentration responses (10−8 to10−4M) to acetylcholine (ACh) and sodium nitroprusside (SNP) were assessed in vessels pre‐contracted with the thromboxane mimetic U46619 (0.4 μg/mL). ACh‐mediated relaxation was impaired in SLE‐vehicle mice as previously reported by our laboratory; however, relaxation was improved in bortezomib‐treated SLE mice compared to vehicle‐treated SLE mice (Figure; *, p<0.05 vs. all other groups; #, p<0.05 SLE‐vehicle vs. control groups and SLE‐bortezomib vs. control groups). Bortezomib treatment did not significantly alter SNP‐mediated relaxation in any treatment group. Taken together, these data suggest that autoantibodies play an important mechanistic role in the development of endothelial‐dependent vascular dysfunction.

Support or Funding Information

Research supported by: VA Merit Award BX002604‐01A2 to MJR and NIH NHLBI PO1HL051971 and P20GM104357 to UMMC‐Department of Physiology and Biophysics. EBT is supported by NIH NHLBI F32HL137393.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.