Dysfunction of polyubiquitin binding by ABIN1 as a basis for lupus nephritis (930.3)

It is estimated that at least five million people worldwide have a form of systemic lupus erythematosus (SLE). Lupus Nephritis (LN) occurs in about 50% of SLE patients and represents a major source of morbidity and mortality. Recent genome‐wide association studies have linked mutations in the A20‐binding inhibitor of NF‐κB (ABIN1) gene to increased risk of developing LN. The molecular signalling events involved in the pathogenesis of LN in SLE patients are not well defined, but ABIN1 has been shown to have a role. We aim to describe the specific role for ABIN1 in the development of SLE and LN using ubiquitin binding deficient mutants in both humans (ABIN1[D472N]) and the orthologous mutation in transgenic mice (ABIN1[D485N]). Urinary protein loss measured by ELISA and gross pathological findings in sectioned kidneys of transgenic animals expressing ABIN1[D485N] mutation depict progressive nephritis which is apparent at 3 months and severe at 5‐6 months of age. Immune deposits in the kidneys were detected via immunofluorescence in the ABIN1[D485N] mice but were not seen in wild type mice. These data dramatically exhibit the importance of ABIN1 function in the maintenance of normal immune activity relative to the kidney. Furthermore, we illustrate the immunoprotective function of ABIN1 in kidney cells themselves. RT‐PCR, western blot and ELISA depict exaggerated immunostimulatory and inflammatory responses of cultured kidney cells expressing ABIN1[D472N] (including podocytes, tubular cells and mesangial cells) to TNF‐α and IL‐1β when compared to wild type ABIN1. Increased production of cytokines and chemokines suggests an increased propensity to recruit immune cells to target tissue which may lead to the inflammatory states characteristic of LN. Collectively, we have shown in both in vivo and in vitro models that ABIN1‐mediated inhibition of NF‐κB signalling is required in the kidney for the prevention of LN. Grant Funding Source : National Institutes of Health