Dissecting the immune landscape in lupus nephritis

About half of patients with lupus develop lupus nephritis, or lupus kidney disease. This complication is the leading cause of illness and death in patients with lupus. However, researchers don’t know which cells are injuring the kidneys. That’s what Dr. Hacohen’s project aims to determine. In a previous study, his lab analyzed the kidneys of patients with lupus kidney disease and discovered 21 types of immune cells, most of which are absent from healthy kidneys. With the Distinguished Innovator Award, they will extend this work and examine tissue biopsies from newly diagnosed patients to ascertain which of the 21 immune cell types are present in patients with the most or least severe kidney injury. This analysis will allow his team to determine which types are related to kidney damage, function, and response to therapy. The results will provide new targets for treatments, as well as new tools to predict whether patients will respond to treatment and to provide insight into their future kidney health.

What this study means for people with lupus:

Dr. Hacohen’s research seeks to determine which cells cause kidney damage in lupus. Identifying these cells could lead to new treatments that prevent this damage.

Lupus nephritis (LN) is the principal source of morbidity and mortality among patients with systemic lupus erythematosus, and is characterized histologically by immune cells infiltrating glomeruli, tubulointerstitial space, and archetypal changes in tissue architecture. Currently, the histological classification of LN kidney biopsies drives therapeutic decision-making. Despite advances in immunosuppressive regimens, many patients still develop impaired renal function or fail to achieve complete renal remission. The failure to control disease likely reflects an incomplete understanding of immunologic mechanisms driving LN. Furthermore, the ability to study relevant immunologic mechanisms has been hindered by limited knowledge of the immune cell types/states and pathways shared between murine models and human lupus nephritis. Thus, there is an urgent need for a high-resolution analysis of immune responses in kidneys of patients and animals that develop lupus nephritis. To address this need, in our recent analysis, as part of an NIH-funded consortium (NIH/AMP-PEARL), we used single cell RNA sequencing (scRNA-seq) to discover 21 immune cell types/states that are enriched in lupus compared to healthy kidneys. These cells represent functional states of cells that are relevant to human lupus nephritis. However, due to limitations in cohort size and sample availability, we did not determine the spatial localization of the cells types/states within different compartments of the kidney or their relation to damaged areas of the tissue, and most importantly, did not have the power to associate these cell type/states with clinical outcomes. To localize the identified cellular subsets and associate with clinical outcome, we propose to develop a panel of antibodies against markers that discriminate each cell subset (based on cell-specific gene signatures that we found by scRNA-seq), to spatially localize these markers within patient kidney biopsies, and to link cell subsets with tissue damage and, critically, with clinical outcomes. We will also determine the utility of existing mouse lupus models to deepen analysis of our findings (as well as other immune mechanisms relevant to human disease), by profiling cells from the kidneys of established mouse lupus models and comparing the cell types/states to those found in our NIH/AMP studies of human lupus kidneys. The results of these studies will: 1) generate new hypotheses for how immune cells work together to cause tissue damage in LN patient kidneys, leading to new drug targets and better predictors of disease; 2) guide us in the use and improvement of mouse models to understand human lupus nephritis, a critical need in the field of lupus biology. Overall, our proposal represents a powerful and novel unbiased approach to understanding lupus nephritis in both mouse models and patients with disease.