The goal of Dr. Salmon’s research is to identify predictors and determinants of disease phenotype in systemic lupus erythematosus (SLE) and related diseases, and to thereby identify targets for therapy. In SLE and other autoimmune diseases, autoantibodies and immune complexes initiate inflammation and organ damage through receptors for IgG and complement activation products. The laboratory investigates downstream mediators and effector mechanisms of tissue injury. Their basic, translational and clinical studies have led to a paradigm shift in the understanding of mechanisms of pregnancy loss, cardiovascular disease and nephritis in patients with SLE. This work to define pathogenic mechanisms in SLE is likely to translate to non-autoimmune patients.
Dr. Salmon’s laboratory defined structure-function relationships among human receptors for IgG, key effectors in immune-complex diseases and showed that allelic variants were risk factors for nephritis. She led the first case-control study to define prevalence and clinical correlates of pre-clinical atherosclerosis in SLE and found accelerated and premature disease, independent of traditional cardiovascular risk factors, rather related to inflammation.
Building on her discovery that innate immune pathways, complement, neutrophils and TNF-α, are critical effectors of pregnancy complications in mouse models, she led an NIH-funded, multi-center 11 year prospective longitudinal study of 700 pregnant patients to identify predictors of pregnancy outcomes in patients with lupus and/or anti-phospholipid syndrome. She has now embarked on the first interventional trial of biologic therapy to protect pregnancies at high risk for preeclampsia, an approach likely to have broad public health implications.
The antiphospholipid syndrome (APS) is characterized by thrombosis and pregnancy loss that occur in the presence of antiphospholipid (aPL) antibodies. APS is a leading cause of pregnancy loss and pregnancy-related morbidity. The pathogenesis of fetal loss and growth restriction in APS is incompletely understood, and treatment is suboptimal. Currently, therapy for pregnant women with APS is focused on preventing thrombosis, but anticoagulation is only partially successful in averting miscarriage and carries risks for fetus and mother. The Salmon laboratory identified the critical role of inflammation as a mediator of placental insufficiency, in general, and defined new treatment targets.
We proposed that complement activation is a central mechanism of pregnancy loss in APS, and demonstrated that this novel hypothesis was valid in an experimental animal model of aPL antibody-induced fetal death. We found that inhibition of the complement cascade in vivo blocks fetal loss and growth restriction associated aPL antibodies and, using genetically manipulated mice, blocking antibodies and small molecules, identified specific complement components and the downstream mediator, TNF-alpha, as key effectors of placental damage. We are using similar approaches to characterize mediators of preeclampsia in antibody-independent experimental models. Identification of the drivers of placental insufficiency will provide the basis for new therapies to improve outcomes in pregnant women with SLE, APS and, potentially, in pregnancy loss and preeclampsia in non-autoimmune patients.
To translate to patients the discovery in mouse models that innate immune pathways, complement, neutrophils and TNF-α, are critical effectors of pregnancy complications, Dr. Salmon led the PROMISSE (Predictors of pRegnancy Outcome: bioMarkers In antiphospholipid antibody Syndrome and Systemic lupus Erythematosus) Study, an NIH-funded, multi-center 11 year prospective longitudinal study of pregnant patients. The goal of PROMISSE was to identify predictors of pregnancy outcomes in patients with lupus and/or aPL. We have recruited over 700 pregnant patients, enrolled at nine major clinical centers, and obtain detailed medical and obstetrical information during the course of their pregnancies, and serial blood specimens for biomarkers. Demographic, socioeconomic and potential circulating inflammatory mediators, complement activation products and biomarkers of placental dysfunction are analyzed every month of pregnancy to establish a pregnancy risk profile, and we continue to mine the data and sample collection. In addition, we are analyzing RNA obtained through pregnancy to compare temporal changes in gene expression during the course of complicated and uncomplicated pregnancies and to understand immune regulation in pregnancy and identify predictors of poor outcomes. The identification of markers in aPL and SLE patients may prove generally applicable to anticipate complications during pregnancy in disease-free women.
Characterization of clinically applicable surrogate markers that predict severe pregnancy complications have enabled us to design an interventional trial. And now, we have embarked on the first interventional trial of biologic therapy to protect pregnancies at high risk for preeclampsia, an approach likely to have broad public health implications.
Autopsy and observational data suggest that SLE is associated with premature atherosclerosis and myocardial infarction. The prevailing hypothesis has been that accelerated atherosclerosis is attributable to an increased frequency of conventional risk factors in SLE patients, such as hypertension and hyperlipidemia, which may be provoked or potentiated by therapeutic use of corticosteroids. However, data are accumulating that suggest that the inflammatory process per se may be important in the initiation and progression of atherosclerosis.
We performed the first case-control study to assess the presence, magnitude, and determinants of atherosclerosis in SLE and its correlates in a population-based sample of 200 SLE patients and 200 matched disease-free controls. Although SLE patients and controls were comparable in traditional cardiovascular disease risk factors, atherosclerosis, detected by carotid ultrasound, was more prevalent in SLE patients (37 vs. 15%, p<0.001). The excess in atherosclerosis was most pronounced in the youngest patients (5.6-fold increase in SLE patients less than 40 years of age). We identified the presence of SLE as the most important independent correlate of atherosclerosis other than age. Clinical features and autoantibody specificities differentiated SLE patients with and without plaque. Our case control study of patients with rheumatoid arthritis revealed increased and accelerated atherosclerosis, comparable to that of SLE. This work supports the possibility that chronic inflammation per se predisposes to premature cardiovascular disease and suggests that therapies directed at inflammation might prevent atherosclerosis. Ongoing work examining endothelial cell gene expression and assessing levels of potential biomarkers in the circulation will test this hypothesis and elucidate mechanisms of accelerated atherosclerosis in patients with SLE and other autoimmune diseases.
Immune complex deposition activates neutrophils, increases vascular permeability and leads to organ damage in SLE and RA. Dr. Salmon’s laboratory has been exploring novel approaches to attenuate tissue injury initiated by immune complexes and downstream mediators they drive. The bioactive lipid sphingosine-1-phosphate (S1P), acting via S1P receptor 1 (S1P1), is a key regulator of endothelial cell barrier function. We found that S1P1 signaling in endothelial cells prevents loss of barrier integrity induced by activated neutrophils and attenuates animal models of acute inflammatory injury mediated by immune complexes. Current studies will determine whether the S1P-S1P receptor axis can be targeted to prevent organ damage in experimental models of SLE and rheumatoid arthritis. In parallel, we will assess S1P-S1P receptor expression in tissue from patients.
Lupus nephritis often results in progressive renal dysfunction. The inactive Rhomboid 2 (iRhom2) is a newly identified key regulator of A disintegrin and metalloprotease 17 (ADAM17), whose substrates, such as TNF-α and heparin-binding epidermal growth factor (HB-EGF), have been implicated in the pathogenesis of chronic kidney disease. We demonstrate that deficiency of iRhom2 protects the lupus-prone mice from developing severe kidney damage without altering autoantibody production, by simultaneously blocking the HB-EGF/EGFR and the TNF-α signaling in the kidney tissues. Kidneys from lupus nephritis patients showed increased iRhom2 and HB-EGF expression which associates with severe irreversible damage. Studies are ongoing to explore this novel target for selective and simultaneous dual inhibition of two major pathological pathways in the effector arm of lupus nephritis.
Jane E. Salmon, MD
Xiaoping Qing, MD, PhD
Nathalie Burg, MD
Postdoctoral Research Fellows:
Coline Haxaire, PhD
Marta Guerra, BS
Julia Porada-Davis, BA