Jane E. Salmon, MD
Research Description
Inflammatory Effector Mechanisms Laboratory
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 (Fc0R) and complement activation products. These mechanisms are currently studied in three projects.
The role of complement activation in antiphospholipid antibody-induced pregnancy loss and thrombosis
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 a prospective observational study. The goals of our study are (1) to determine whether there is a unique pattern of complement activation in patients with aPL-associated fetal loss and (2) to generate substantial and convincing clinical data to launch a clinical trial of complement inhibitors for aPL-associated recurrent fetal loss. We are recruiting over 400 pregnant patients, enrolled at 6 major clinical centers, and grouped and analyzed according to the presence or absence of aPL and preexisting SLE. We will 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.
Accelerated Cardiovascular Disease in Systemic Lupus Erythematosus and Rheumatoid Arthritis: Prevalence and Responsible Mechanisms
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 will test this hypothesis and examine the mechanisms of accelerated atheroscelerosis in patients with SLE and other autoimmune diseases.
The Role of Receptors for Immunoglobulin G in Autoimmune Diseases
Fc0R are receptors on the surface of cells that bind the Fc portion of immunoglobulin G, thereby linking the humoral and cellular components of the immune system. Several critical observations by this laboratory have underscored the importance of Fc0R to host defense and the pathogenesis of inflammatory disease. (1) Fc0R-dependent mononuclear phagocyte function is abnormal in human immune complex disease; (2) Inherited variants of Fc0R structure strongly influence receptor function: alleles of Fc0RIIA and Fc0RIIIA alter the ability of the receptors to bind human IgG and impact the risk of renal disease in SLE and of serious bacterial infection; and (3) Fc0R alleles are abnormally distributed in human autoimmune diseases. The overall goals of ongoing studies are to understand structure-function relationships among Fc0R and to further define the role of Fc0R in the pathogenesis of autoantibody-mediated diseases.
Laboratory Personnel:
Visiting Senior Scientist:
Gloria Koo, PhD
Associate Scientist:
Guillermina Girardi, PhD
Postdoctoral Research Fellows:
Xiaoping Qing, MD, PhD
Shari Gelber, MD, PhD
Danieli Andrade, MD
Milena Vukelic, MD
Diana Goldenberg, MD, MPH
Research Associates:
Marta Guerra, BS
Patricia Redecha, BS
Randi Eisner, MSW
Michelle Perna, BA
Laarni Quimson, BA
Joan Rho, BA
Emily Miller, BA
Appointments
Collette Kean Research Chair, Hospital for Special Surgery
Senior Scientist, Hospital for Special Surgery
Attending Physician, Hospital for Special Surgery
Co-Director, The Mary Kirkland Center for Lupus Research, Hospital for Special Surgery
Professor of Medicine, Weill Medical College of Cornell University
Professor of Medicine in Obstetrics and Gynecology, Weill Medical College of Cornell University
Jane E. Salmon, MD is the author of the following articles on HSS.edu:
For Professionals
Selected Publications
Lynch AM, Murphy JR, Byers T, Gibbs RS, Neville MC, Giclas PC, Salmon JE, Holers MV. Alternative Complement Pathway Activation Fragment Bb in Early Pregnancy as a predictor of preeclampsia. Am J Obstet Gynecol 198:385.e1-9, 2008.
Belostocki K, Pricop L, Redecha PB, Aydin A, Leff L, Harrison MJ, Salmon JE. Infliximab treatment shifts the balance between stimulatory and inhibitory Fc#RII isoforms on neutrophils in rheumatoid arthritis patients. Arthritis Rheum 58: 384-388, 2008.
Pieretti J, Roman MJ, Devereux RB, Lockshin MD, Crow MK, Paget SA, Schwartz JE, Sammaritano L, Levine DM, Salmon JE. Systemic lupus erythematosus predicts increased left ventricular mass. Circulation 116: 419-26, 2007.
Roman MJ, Crow MK, Lockshin MD, Devereux RB, Paget SA, Sammaritano, L, Levine DM, Davis A, Salmon JE. Rate and determinants of progression of atherosclerosis in systemic lupus erythematosus. Arthritis Rheum 56: 3412-19, 2007.
Roman MJ, Salmon JE. Cardiovascular manifestations of rheumatologic diseases. Circulation 116 :2346-2355, 2007.
Girardi G., Yarilin D, Thurman JM, Holers VM, Salmon JE. Complement activation induces dysregulation of angiogenic factors and causes fetal rejection and growth restriction. J Exp Med 203: 2165-2175, 2006.
Roman M, Moeller E, Davis A, Paget SA, Crow MK, Lockshin MD, Sammaritano L, Devereux RB, Schwartz JE, Levine DM, Salmon JE. Preclinical carotid atherosclerosis in patients with rheumatoid arthritis: prevalence and associated factors. Ann Intern Med 144: 249-256, 2006.
Berman J, Girardi G, Salmon JE. TNF-a is a critical effector and a target for therapy in antiphosphospholipid antibody-induced pregnancy loss. J Immunol 174: 485-490, 2004.
Girardi G, Redecha PB, Salmon JE. Heparin prevents antiphospholipid antibody-induced fetal loss by inhibiting complement activation. Nat Med 10:1222-6, 2004.
Roman, MJ, Shanker B-A, Davis A, Lockshin MD, Sammaritano L, Simantov R, Crow MK, Schwartz JE, Paget SA, Devereux RB, Salmon JE. Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus. New Engl J Med 349: 2399-406, 2003.
Girardi G, Berman J, Redecha P, Spruce L, Thurman JM, Kraus D, Hollmann TJ, Casali P, Caroll MC, Wetsel RA, Lambris JD, Holers VM and Salmon JE. Complement C5a receptors and neutrophils mediate fetal injury in the antiphophospholipid syndrome. J Clin Invest 112: 1644-54, 2003.
Holers VM, Girardi G, Mo L, Guthridge JM, Molina H, Pierangeli SS, Espinola R, Xiaowei LE, Mao D, Vialpando CG, Salmon JE. Complement C3 activation is required for anti-phospholipid antibody-induced fetal loss. J Exp Med 195:211-220, 2002.
Salmon JE, Pricop L: Human receptors for immunoglobulin G: Key elements in the pathogenesis of rheumatic disease. Arthritis Rheum 44: 739-750, 2001.
Salmon JE, Millard SS, Schachter LA, Arnett FC, Ginzler EM, Gourley MF, Ramsey-Goldman R, Kimberly RP: Fc#RIIA alleles are heritable risk factors for lupus nephritis in African Americans. J Clin Invest 97: 1348-1354, 1996.
For more publications, please see the
PubMed listing.
Clinical Trials
