The goal of our research is to identify determinants of disease phenotype in systemic lupus erythematosus (SLE) and related diseases, and to thereby identify targets for therapy. Our laboratory approach is to study effector function and mechanisms of tissue injury. In SLE and other autoimmune diseases, autoantibodies and immune complexes trigger inflammation and organ damage through receptors for Ig (FcgR) and complement activation products. Our work focuses on elucidating mechanisms of tissue injury in lupus and other autoimmune diseases. We study the initiators of damage and the downstream effectors to understand the basis of organ damage in SLE and the predictors and determinants of disease outcome in lupus patients with nephritis, pregnancy, and cardiovascular disease. Our current studies include the following projects:
The antiphospholipid syndrome (APS) is characterized by thrombosis and pregnancy loss that occur in the presence of antiphospholipid (aPL) antibodies. Over the last two decades, APS has emerged as 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.
We recently proposed that complement activation is a central mechanism of pregnancy loss in APS, and demonstrated that this novel hypothesis was valid in a mouse model of aPL antibody-induced fetal death. We have found that inhibition of the complement cascade in vivo blocks fetal loss and growth restriction associated aPL antibodies. We have identified complement component C5, and particularly its cleavage product C5a, as key mediators of fetal loss.
Ongoing studies are examining the initiators, inflammatory mediators, and the cellular effectors of aPL-induced fetal injury. Identification of complement components and downstream effectors that trigger aPL-associated injury will provide the basis for new therapies to improve outcomes in pregnant women with APS and, potentially, in pregnancy loss due to other immune mechanisms.
To translate our novel basic research observations on the role of complement in aPL-mediated pregnancy loss to patients, we have begun the PROMISSE (Predictors of pRegnancy Outcome: bioMarkers In antiphospholipid antibody Syndrome and Systemic lupus Erythematosus) Study, a prospective observational study. The goals of our study are:
We have recruited over 700 pregnant patients, enrolled at nine major clinical centers, and grouped and analyzed according to the presence or absence of aPL and preexisting SLE. We obtain detailed medical and obstetrical information during the course of their pregnancies, serial blood specimens for complement and cytokine assays, and RNA to elucidate temporal changes in gene expression during the course of complicated and uncomplicated pregnancies. These data will be analyzed to identify predictors of poor fetal outcome.
Characterization of clinically applicable surrogate markers that predict pregnancy complications will enable us to initiate an interventional trial of complement inhibition in patients at risk for aPL antibody-associated fetal loss. The identification of such surrogate markers in aPL and SLE patients may also prove generally applicable to anticipate complications during pregnancy in disease-free women.
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 (carotid plaque assessed by 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. These may define two disease patterns: one smoldering, prolonged disease that is accompanied by high damage score, limited production of autoantibodies confers vascular damage (atherosclerosis), and a second with more extensive autoimmunity and aggressive disease, often requiring cytotoxic therapy.
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.
Visiting Senior Scientist:
Gloria Koo, PhD
Postdoctoral Research Fellows:
Xiaoping Qing, MD, PhD
Shari Gelber, MD, PhD
Milena Vukelic, MD
Marta Guerra, BS
Elisabeth Cohn, BA
Aanam Aslam, BA
Tanya Pavri, BA
Daniel Maass, BA