Another Piece of the Puzzle of Podocyte B7-1 Expression: Lupus Nephritis

Abstract

Background/Aims: Lupus nephritis (LN) is a frequent complication and a major predictor of poor prognosis of systemic lupus erythematosus. Immune complex deposition and T cell infiltration are crucial events in LN pathogenesis. B7-1 (CD80), normally expressed by antigen-presenting cells, is one of the major co-stimulators of T-cell activation through the binding with its counter-receptors CD28 and cytotoxic T-lymphocyte antigen-4. Unexpectedly, B7-1 induction was described at the podocyte level in patients affected by different renal diseases, including LN. These observations suggested a novel exciting function for B7-1 as a biomarker of podocyte injury, and hence that B7-1 inhibitory drugs could serve as podocyte-targeted treatment of intractable renal diseases. However, subsequent studies hardly questioned the reliability of B7-1 detection assays and the therapeutic efficacy of B7-1 blockade in proteinuric patients, casting doubts on B7-1 expression by podocytes. Here, we thoroughly investigated whether B7-1 was indeed expressed by podocytes in LN, before even considering employing B7-1 blockade in patients with severe manifestations of LN and unfavourable prognosis. Methods: Applying different immunohistochemical assays with 4 primary antibodies, we analysed kidney biopsies from 42 LN patients at different stages of the disease, and from NZB/NZW mice, an LN model. Results: B7-1 was not induced in podocytes in human and murine LN; instead its expression was confined to infiltrating inflammatory cells. Conclusion: B7-1 is not expressed by podocytes in LN. A renoprotective effect of B7-1 blockade in LN patients cannot be ruled out but, if confirmed, cannot be the result of an effect on podocyte B7-1.

B7-1 mediates podocyte injury and glomerulosclerosis through communication with Hsp90ab1-LRP5-β-catenin pathway

“…Using RNAscope, B7-1 was found nearly in all types of glomerular diseases. This is inconsistent with previous studies, as they did not find B7-1 antigen protein expression in DN or others [ 23 , 24 ]. We thought the reason possibly lies that antigens decay quickly, while genes persist.…”

Role of Podocyte Injury in Glomerulosclerosis

“…It has been found that B7-1 was expressed on podocytes of lupus nephritis (LN) (Reiser et al 2004), and the expression of podocyte B7-1 in LN patients and LN mouse models is positively correlated with the degree of proteinuria. However, new evidence has stricken up a discordant tune (Baye et al 2016), leading to further mandatory studies of the application of B7-1 blockers in treating proteinuric patients (Novelli et al 2016a).…”

Podocyte Injury in Lupus Nephritis

“…Moreover B7-1 (CD80), which is usually expressed on B cells and APCs and induces T-cell co-stimulation, has also been detected on podocytes in several models of proteinuric kidney diseases, including LN [76]. However, recent studies have reported conflicting results suggesting that B7-1 is not expressed in mouse models of LN and in human LN [77,78]. Moreover, clinical trials in patients with LN failed to demonstrate a clear outcome benefit of abatacept, an inhibitor of B7-1/CD28 interaction [79,80].…”