Lupus nephritis occurs in a majority of patients with systemic lupus erythematosus (SLE, lupus), and is a leading cause of morbidity and mortality. CD4+ and CD8+ T effector cells contribute to the inflammatory response in lupus nephritis in mice and in humans with their renal infiltration correlating with tissue damage and disease severity. Yet, there is limited knowledge of the phenotypic characteristics of the T cells that contribute to local tissue injury in lupus. In a like manner, autoreactive B cells with maturation to autoantibody- producing plasma cells promote renal injury in lupus, with initiation of immune complex glomerulonephritis, a sentinel finding of lupus in mice and humans. More recent data reveal that a subset of B cells, marked by expression of CD11c and the transcription factor T-bet, drives pathogenic autoantibody production and subsequent tissue injury in murine lupus nephritis, with data emerging that phenotypically similar cells arise in normal humans and circulate in the blood of patients with SLE. Renal-infiltrating B cells and plasma cells are a common finding in lupus nephritis in mice and humans, although such cells have not been well characterized. Changes in the local microenvironment likely affect the phenotype and function of renal-infiltrating T and B cells in lupus. The kidney microenvironment becomes hypoxic as a common denominator following a variety of insults, an appropriately physiologic response analogous to that which occurs to ensure proper lymphocyte effector function during hypoxic stress, such as in areas of pathogen replication or in and around tumors. We have shown in preliminary studies that this response in the murine lupus kidney results in transcriptional and phenotypic changes in tissue-infiltrating T and B cells, changes associated with their enhanced effector capability. We now propose in this innovative grant to explore the hypothesis that hypoxic stress necessarily shapes the phenotypes of renal-infiltrating T and B cells in lupus, with programming for activation and effector function, a hypothesis we will explore in murine lupus using in vitro and in vivo studies, including genetic and pharmacologic manipulation of hypoxia-induced effector pathways.
Patients with systemic lupus erythematosus (SLE, lupus) commonly have injury to their kidneys, called lupus nephritis. We and others have found that lymphocytes enter the kidney in lupus nephritis, and likely contribute to the injury that occurs therein. We now propose to determine the factors that contribute to the damage caused by kidney lymphocytes, and how we can modify them genetically and therapeutically to potentially prevent lupus nephritis in animal models of SLE, studies that are applicable to treatment of lupus in humans.
