501 Anti-LG3 antibodies contribute to microvascular loss and fibrosis in lupus nephritis

Background Lupus nephritis (LN) is a common and serious manifestation of systemic lupus erythematosus (SLE) and 30% of cases, affected patients progress to end stage renal disease (ESRD). Microvascular damage is an emerging contributing factor to LN renal dysfunction leading to end stage renal disease. We have shown that vascular injury derived apoptotic exosomes can trigger SLE autoantibodies as well as autoantibodies targeting perlecan/LG3 (anti- LG3). We have also unraveled biomarkers and effector roles of anti-LG3 in kidney vascular damage in both native and transplanted kidneys. We hypothesize that anti-LG3 responses contribute to microvascular damage of importance in LN development. Methods Longitudinal bleeds were performed on SLE prone NZB/NZWF1 and control mice. Circulating Anti-LG3 IgG levels were measured by ELISA. 26 weeks old NZB/NZWF1 mice were infused with anti-LG3 or control IgG, every second day for 3 weeks. Kidneys were harvested at sacrifice for renal histology and immunohistochemistry analyses. PTC capillary loss was evaluated with MECA-32 staining and renal interstitial fibrosis aSMA and Collagen IV staining. Results Elevated levels of anti-LG3 are found in SLE prone mice, compared to control mice. Importantly, NZB/NZWF1 mice passively transferred with anti-LG3 exhibited significantly increased interstitial inflammation, PTC capillary loss, and renal interstitial fibrosis in the absence of glomerular abnormalities (crescents and proliferation), compared to mice transferred with control IgG. Conclusions These observations suggest that anti-LG3 antibodies are elevated in SLE and show a tropism specific for the interstitial microvasculature, contributing to microvascular loss and fibrosis. A better understanding of the impact of these novel biomarkers and effector will improve identification, prediction, and management of LN.

Abstract licence: CC BY-NC

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