Dissecting the Transition from Autoreactivity to Disease in Lupus Nephritis

In lupus, the immune system produces autoantibodies that mistakenly target a person’s own proteins or genomic material, including their DNA. When these DNA-targeting autoantibodies bind or attach to the DNA, they form a complex that can move into the kidneys, causing kidney inflammation and impaired function, which may lead to lupus nephritis (LN). LN is the most common organ-threatening complication of lupus. Despite standard-of-care treatment, many people with LN progress to end-stage kidney disease. While anti-DNA autoantibodies increase the risk of LN, the presence of these autoantibodies alone does not mean LN will necessarily develop, showing that other factors may be involved. Dr. Reizis will study animal models and kidney tissue samples from biopsies of people with LN to uncover the other factors that play a role in the development of LN.

The factors involved in the progression from pre-clinical autoimmunity (before symptoms appear) to overt nephritis (when symptoms have appeared) are not well understood. Genetics play a role, as do environmental factors, infections, and the growth of bacteria in the gut. Dr. Reizis will explore these factors in a mouse that models lupus and has anti-DNA autoantibodies but does not exhibit overt nephritis. He will test genetic factors (like gene alterations that cause increased inflammation), microbial exposure, as well as environmental factors such as exposure to ultraviolet light. He will then analyze immune cells in the kidney of the mouse model and kidney biopsy samples from people with and without overt nephritis to understand what differences in the cells’ features, location, and interactions may contribute to the development of LN.

What this study means for people with lupus

Dr. Reizis is studying a major unmet need in lupus management- understanding why some patients with anti-DNA autoantibodies progress to clinical nephritis while others do not. By pinpointing factors contributing to the development of LN, Dr. Reizis’ study could improve how we monitor and predict the progression to nephritis in individuals with SLE, potentially informing personalized treatment strategies.

Lupus nephritis is the most common organ-threatening manifestation of systemic lupus erythematosus (SLE), affecting ~50% of SLE patients with a significant bias to patients of non-European ancestry. Autoantibodies are necessary but not sufficient for the development of nephritis; thus, elevated titers of anti-dsDNA IgG increase the risk for but do not necessarily result in LN. Moreover, glomerular injury caused by autoantibodies alone appear insufficient for clinical nephritis, which is thus precipitated by additional, poorly defined inflammatory stimuli. The overall goal of this project is to model the preclinical autoantibody-mediated chronic glomerular pathology, and analyze the factors that may precipitate its transition to overt nephritis. We hypothesize that additional factors, such as microbial products and/or immune responses driving T cell activation, cooperate with anti-dsDNA antibodies to precipitate histological and clinical nephritis. To test this hypothesis, we will be using DNASE1L3-deficient mice, which model monogenic SLE caused by DNASE1L3 gene mutations in human patients. Our analysis of these DNASE1L3 knockout (D1L3KO) mice in standard specific pathogen-free conditions revealed a prominent anti-dsDNA response and immune complex deposition in the glomeruli, but no overt nephritis. Furthermore, kidneys of these mice manifest a distinct immune microenvironment characterized by the accumulation of T helper cells expressing the inhibitory receptor PD-1, and of macrophages expressing its ligand PD-L1. In Aim 1, we will systematically study factors and pathways that may convert anti-dsDNA autoreactivity into kidney inflammation in D1L3KO mice. We will test whether the predisposing genetic factors, recreation of natural microbial exposures, or relevant environmental insults such as UV irradiation can precipitate overt nephritis in these mice. We will also block the PD-1/PD-L1 signaling pathway and test its effect on the transition to nephritis. In Aim 2, we will analyze the in situ immune cell microenvironment in subclinical versus overt nephritis. In particular, we will use high-dimensional immunochemistry (CODEX) to characterize the phenotypes, localization and interactions of immune cells in subclinical nephritis in D1L3KO mice compared to overt nephritis in other models. The results will be extended to an correlated with the CODEX analysis of kidney biopsies from SLE patients with limited or overt nephritis. We anticipate that the results would provide novel insights into immune mechanisms of nephritis in SLE, and may inform better strategies for its prediction, monitoring and ultimately treatment.