OC 19.1 - Vascular Injury Derived Exosomes Accelerate Renal Damage in Lupus Prone Mice

Background: Microvascular damage is an emerging contributing factor to lupus nephritis (LN) leading to end stage renal disease [1,2]. We have demonstrated that apoptotic exosomes derived from vascular injury (ApoExo) trigger the production of SLE-associated antibodies and LG3/perlecan autoantibodies (anti-LG3) in wild-type mice. ApoExo infusion induces anti-LG3 production and tertiary lymphoid structure (TLS) formation in a murine vascular allograft model [3]. We identified anti-LG3 in humans and demonstrated that they trigger microvascular rarefaction and renal fibrosis in lupus prone mice. We hypothesize that ApoExo induce an autoimmune response that accelerates the development of lupus nephritis.

Aims: Evaluate the impact of ApoExo infusion in accelerating LN by evaluating 1)humoral response 2)renal infiltrate 3)interstitial damage and 4)dysfunction in lupus prone mice.

Methods: 20 weeks old NZB/WF1 mice were infused with ApoExo or vehicle every second day for 3 weeks. Circulating anti-LG3 and ApoExo levels were measured by ELISA and hs-FCM respectively. Kidneys were collected and renal histology and 3D in vivo micro-computed tomography (MicroCT) analyses were performed.

Results: NZB/WF1 mice infused with ApoExo show higher levels of circulating anti-LG3 compared with the vehicle group (p=0.0034). Preliminary MicroCT data demonstrated a 35% microvascular involution associated with LN development. In addition, ApoExo infused NZB/WF1 mice demonstrate significant renal inflammatory infiltration compared to mice infused with vehicle. ApoExo triggered the recruitment to the renal interstitium of CD3+, CD20+, and AID+ lymphocytes into nodules reminiscent of TLS (p=0.0342). Finally, heightened renal tubular damage (p=0.010) and decreased kidney function (p=0.013) were observed in ApoExo infused NZB/WF1 mice compared to the ones infused with vehicle.

Conclusion(s): ApoExo infusion increases renal nodular lymphocyte infiltration, autoantibody production and renal lesions in lupus prone mice. This project is, to our knowledge, the first to evaluate the contribution of vascular injury derived extracellular vesicles to LN.

Funding: CIHR, CRSNG and KFoC