The Mary Kirkland Center supports HSS investigators who engage in novel - and clinically relevant - basic and clinical research that is specifically directed toward lupus. Research projects address disease susceptibility, alterations in immune function, mechanisms of target organ damage, epidemiology, clinical features, and new therapies for lupus.
Dr. Jane E. Salmon, a Kirkland Center Investigator, previously discovered that genetic variations in the Fc receptor genes confer susceptibility to kidney disease in some SLE patients. An interest in defining the genetic and environmental factors that trigger SLE continues at HSS. Dr. Luminita Pricop, a recipient of a Kirkland Pilot Research Grant, has hypothesized that polymorphisms in the promoter of the human FcγRIIB gene may lead to altered expression and function of FcγRIIB in lupus, impairing B cell and monocyte function in disease. Her hypothesis is based upon the finding of single nucleotide polymorphisms (SNPs) in the promoter of the FcγRIIB gene, including one that is over-expressed in lupus when compared to controls, and that in combination, appear to alter gene expression. These findings have the potential to shed new light on FcR expression and function in SLE. Dr. Mary K. Crow, a Kirkland Center Investigator, has initiated a new line of investigation designed to explore the novel hypothesis that the genetic predisposition to SLE rests, at least in part, in repetitive genetic elements that alter the expression of nearby genes and activate the immune system. The capacity of these genome derived sequences, as well as small RNA molecules, to signal cell activation is being investigated.
HSS has a long history of contributing important observations regarding regulation of the immune response in health and in systemic autoimmune diseases. Dr. Eric Meffre, a recipient of a Kirkland Pilot Research Grant, is investigating the generation of the B lymphocyte repertoire in patients with lupus, rheumatoid arthritis, and scleroderma. By using the sophisticated single cell polymerase chain reaction technology, Dr. Meffre is identifying the points in the B cell maturation pathway at which the B cells from autoimmune disease patients fail to be appropriately deleted. Alterations in the mechanisms of B cell maturation can result in persistence of cells that ultimately produce pathogenic autoantibodies. Dr. Theresa Lu has recently been recruited to HSS to study the mechanisms that account for expansion of the lymphoid system in the setting of immune responses -- conditions which can be exaggerated and altered in lupus. Understanding the soluble mediators that control development of these lymphoid structures may provide new ideas for development of agents that could modulate excessive immune activity. Once the cells and structures of the lupus immune system are in place, development of autoimmunity will depend on activation of those cells by self antigens.
Dr. Crow is working to discover how the cells of the lupus immune system, in contrast to those of healthy individuals, direct their activity toward components of one's own cells. One class of molecules, cytokines, is likely to contribute to this altered immune system activity in lupus. Through the analysis of microarray gene expression data, Dr. Crow observed that genes that are regulated by a type of cytokine, the type I interferons, are overexpressed in SLE cells. With her colleague Dr. Kyriakos Kirou, she showed that increased expression of interferon-alpha-induced genes defines a subset of SLE patients that are characterized by production of autoantibodies specific for RNA-binding proteins and increased disease activity. These observations support further study of interferon-induced genes as useful biomarkers of disease activity and stimulate studies of the pathophysiologic relationship of interferon and immune complexes containing RNA and RNA-binding proteins. Importantly, as interferons are known to be important activators of several immune functions, these data support development of new therapeutics that target members of the type I interferon cytokine family.
Dr. Lionel Ivashkiv, a recipient of a Kirkland Pilot Research Grant, has studied how the interferons and other cytokines work together to alter the intracellular signaling pathways of inflammatory cells. Once interferon is produced, it primes its target cells to be more responsive to subsequent exposure to additional cytokines, contributing to excessive immune activation and production of inflammatory mediators. Understanding the molecular components -- including the so-called Jak-STAT pathway, used by cytokines to activate cells -- can suggest new approaches to modification of excessive immune system activity.
Once the T and B lymphocytes of the immune system have been activated and directed to produce autoantibodies that target self-antigens, immune complexes form and trigger inflammatory pathways. In lupus, the effects of inflammatory mediators on target organs such as kidney, blood vessels, and placenta have important clinical consequences. Nephritis, premature atherosclerosis, and recurrent fetal loss in pregnancy can result from uncontrolled generation of inflammation in lupus.
Dr. Salmon has studied mechanisms of tissue damage in each of these end organs. Recent work performed with her colleague Dr. Guillermina Girardi, a recipient of a Kirkland Pilot Research Grant, has examined a murine model of anti-phospholipid antibody-induced fetal loss and has clearly demonstrated a previously unexpected role for the complement system in this outcome. These results have shifted the previous paradigm regarding mechanisms of fetal loss in lupus. In contrast to the presumption that thrombosis is the major event that damages placental, and subsequently fetal, tissue, Drs. Salmon and Girardi demonstrated that inflammation is the important mechanism of damage in the mouse model. To test whether these observations in an experimental system can be extended to human patients, Dr. Salmon has recently embarked on a major multicenter study to document the elements of complement system activation in pregnant lupus patients who have pregnancy complications. As inhibition of the complement cascade in the mouse model blocks fetal loss and growth retardation, Dr. Salmon and colleagues are working to define therapeutics that might modulate complement activation in lupus patients. One such therapy, heparin, has now been shown by Drs. Salmon and Girardi to inhibit anti-phospholipid antibody-induced fetal damage because it is a complement inhibitor, even at doses that do not therapeutically anticoagulate.
Drs. Salmon, Crow, Paget, and Lockshin have collaborated with NewYork-Presbyterian Hospital cardiologist, Dr. Mary Roman, to investigate the prevalence and correlates of premature atherosclerosis in patients with lupus. They have found that 37% of SLE patients - but only 15% of age-matched controls - have evidence of atherosclerotic plaques in their blood vessels. A longer duration of lupus disease and greater degree of organ damage related to lupus were among the most significant factors associated with premature atherosclerosis. To understand the underlying lupus-related mechanisms that account for this serious complication, Drs. Crow and Salmon are studying the genes that are activated in the lupus patients with carotid plaque. Identifying the molecular mechanisms that account for blood vessel damage in SLE may allow more aggressive and targeted therapies to prevent one of the most significant causes of morbidity and mortality in lupus patients.
Dr. Lockshin is pursuing the recent discovery that certain anti-DNA antibodies - the classic lupus autoantibodies - cross-react with receptors in the brain that contribute to learning and memory. In one stroke, this discovery has changed the way we think about CNS lupus and has suggested new ideas for treatment in a critical area where existing treatments have been ineffective. The basic scientific work was done by Drs. Betty Diamond and Bruce Volpe at Albert Einstein College of Medicine, but the extension of this work into patients with SLE has been carried forward by Dr. Lockshin in collaboration with Dr. Melanie Harrison (as well as Drs. Diamond and Volpe). Together, they have moved quickly to assess the association between the presence of the cross-reactive antibodies and CNS lupus, using both cognitive testing and brain imaging approaches.
One of the most important goals of the Kirkland Center is to contribute to the development of new therapies for patients with lupus. The basic research conducted by Kirkland Center investigators helps to identify the molecular pathways and their components that are most responsible for the dysregulation of the immune system and damage to organs that result in lupus disease. Current studies of the interferon pathway and the complement system in lupus, as well as work on the genes activated in premature atherosclerosis that is seen in some lupus patients, are providing the rationale and preliminary data that drive development of new therapies.
In addition to discovering the most promising molecules to target therapeutically, Kirkland Center investigators participate in experimental trials of new therapeutic approaches in lupus patients.
The Kirkland Center supports research infrastructure through its funding for purchase and maintenance of major equipment and its support of the operation of Core Facilities. Kirkland Center funds were used for development of the new HSS state-of-the-art Transgenic Animal Facility and for purchase of new lasers and computer software that allow multi-color sorting of cell populations, as well as single cell sorting. The Kirkland Center also provides new equipment for the laboratories of new faculty members.