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Lupus

An essential part of the Yale Lupus Program is ongoing clinical and translational research, with the goal of better understanding lupus and advancing treatment. Patients at the Center have access to novel therapies and the opportunity to participate in clinical research studies should they choose to do so. A cadre of highly recognized scientists at Yale is involved in investigating the possible causes and new treatments of lupus using animal models, biological samples, and clinical data from lupus patients. These investigators include Drs. Rick Bucala, Joe Craft, Eric Meffre, Insoo Kang, Fotios Koumpouras and Mark Mamula. Collectively, the expertise of these investigators ranges from innate immunity to B and T cell immunity in lupus. These investigators closely interact and actively participate in The Yale Rheumatic Diseases Research Core Center (YRDRCC) to further promote lupus-related research at Yale. Our collaborative, multidisciplinary endeavors work to promote a better understanding of the etiology and pathogenesis of lupus, for the purpose of advancing new, effective therapies.

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Researchers

  • Waldemar Von Zedtwitz Professor of Medicine (Rheumatology) and Professor of Pathology and of Epidemiology (Microbial Diseases); Chief, Rheumatology, Allergy, & Immunology

    Richard Bucala, MD, PhD, is a Professor of Medicine, Pathology, and Epidemiology & Public Health.  He studies the mechanisms by which protective immune responses lead to immunopathology, focusing on MIF-family cytokines and their genetics, which his group first cloned and characterized experimentally.  Currently, his laboratory is leading multidisciplinary efforts to develop immunotherapies tailored to an individual’s genetic makeup. An anti-MIF antibody developed by the group is undergoing clinical testing in oncology, and an anti-MIF receptor antibody, recently FDA approved, is under evaluation in SLE. Dr. Bucala also is credited with the discovery of the fibrocyte, which is being targeted therapeutically in different fibrosing disorders.  He is a co-founder of Cytokine Networks and of MIFCOR, a biotechnology startup begun as a student-advised project.  Dr. Bucala was elected to the American Society for Clinical Investigation and the Association of American Physicians. He is the Editor-in-Chief of Arthritis & Rheumatology and has served on numerous advisory boards for the NIH, the pharmaceutical industry, academia, and private foundations.

  • Paul B. Beeson Professor of Medicine (Rheumatology) and Professor of Immunobiology; Paul B. Beeson Professor of Medicine; Program Director, Investigative Medicine

    Dr. Joseph Craft is Paul B. Beeson Professor of Medicine and Professor of Immunobiology at the Yale School of Medicine, and past chief of the Section of Rheumatology at Yale. He received his degrees in chemistry as a Phi Beta Kappa graduate of University of North Carolina at Chapel Hill and in medicine as an Alpha Omega Alpha graduate of the University of North Carolina School of Medicine. Dr. Craft did postgraduate training in internal medicine and in rheumatology and immunology at Yale, and has been on the faculty at that institution since 1985. At Yale, he teaches undergraduate, graduate, and medical students. He directs a research laboratory devoted to understanding the immune response to pathogens and vaccines, and dissecting and treating autoimmune diseases, such as systemic lupus erythematosus, with a primary focus upon the differentiation, metabolism, and function and regulation of T cells that promote B cell maturation in secondary lymphoid organs. His research has been continually supported by the National Institutes of Health since 1985, and he is a two-time R37 (MERIT) Awardee. He has been a primary mentor for over 20 postdoctoral fellows and for 21 PhD and MD/PhD graduate students, including 7 graduate students currently in his lab. Dr. Craft is Director of the Investigative Medicine Program at Yale, a unique program designed to provide Ph.D. training for physicians, and in his capacity as Director of the program and its Director of Graduate Studies, has supervised training of over 50 Investigative Medicine PhD students. Dr. Craft is recipient of the Bohmfalk Teaching Prize at Yale School of Medicine for outstanding teaching in the basic sciences. He is an elected Fellow of the American Association for the Advancement of Science, and an elected member of the American Society for Clinical Investigation and the Kunkel Society. Dr. Craft also is a member of the Board of Lupus Therapeutics of the Lupus Research Alliance, devoted to initiating novel therapeutic trials in lupus, and past Chair of the Board of Scientific Counselors at the National Institute of Arthritis, Musculoskeletal, and Skin Diseases (NIAMS). He is former chair of the Immunological Sciences (now HAI) and current member of the Arthritis, Connective Tissue and Skin Diseases (ACTS) standing study sections at NIH, past chair of the Scientific Advisory Board of the Alliance for Lupus Research, and a former Pew Scholar in the Biomedical Sciences and Kirkland Scholar. He is co-founder of L2Diagnostics, a company in New Haven, CT, formed in partnership with Yale University and devoted to discovery of new diagnostics and therapeutic targets for immunological and infectious diseases, and is currently a member of its Board of Directors.

  • Associate Professor of Medicine (Rheumatology); Director of Allergy & Immunology, Internal Medicine

    Dr. Insoo Kang is Associate Professor of Medicine (Rheumatology) at Yale University School of Medicine. He completed his post-graduate training in rheumatology and at Yale. He has been on the faculty at Yale School of Medicine since 1999. He is a physician scientist with a research interest in understanding the human immune system using biological samples and clinical data. In particular, Dr. Kang has defined subsets of T cells with distinct cellular characteristics based on the expression of cytokine receptors on T cells in health and disease as well as the interactions of such cell subsets with monocytes and other immune cells.

  • Assistant Professor of Medicine (Rheumatology); Grand Rounds Course Director, Rheumatology; Director Yale Lupus Program; Fellowship Program Director, Rheumatology

    Dr. Fotios Koumpouras is Assistant Professor of Medicine and Director of the Yale Lupus Program. Dr. Koumpouras is a native of New York City and is a graduate of the Stuyvesant School at 16yrs of age. He completed his college education at State University of New York with honors in Chemistry and Biology, and was a member of the research team at the Wadsworth Center New York State Department of Health investigating cyclin E as a prognostic marker for breast cancer. In addition, he was part of the effort at the Albany Medical College to bio-engineer erythrocytes in search for a new blood substitute. Dr. Koumpouras attended St. George's University School of Medicine and was elected into Iota Epsilon Alpha, the international medical honor society, and graduated first in his class, completed post-graduate training in internal medicine and was Chief Medical Resident at Stony Brook University. He completed a clinical rheumatology fellowship program, as well as a program in Investigative Rheumatology, at Yale University School of Medicine. He was awarded the Physician Scientist Development Award from the American College of Rheumatology, and was co-PI for the ILAR project geared to improve access for rheumatologic services in East Africa.

    Dr. Koumpouras worked closely with Dr. Susan Manzi from 2007-2015 at the University of Pittsburgh and Allegheny Clinic, and was an integral member of the clinical research team. He was involved in both investigator initiated and pharmaceutical clinical trials for SLE and was principal site investigator for the ITN trial of Abatacept and Cyclophosphamide for Lupus Nephritis. He was also principal site investigator for the Double-Blind Randomized Placebo-Controlled Trial of the Effect of Vitamin D3 on the Interferon Signature in Patients with Systemic Lupus Erythematosus. Furthermore, he was site co-PI for the SLICC clinical research program, which resulted in improved criteria for the diagnostic assessment of SLE. He was co-investigator of the Safety and Effectiveness of Belimumab in Systemic Lupus Erythematosus Registry (SABLE) clinical trial. Dr. Koumpouras was the site PI for BLISS 99 and co-PI for HGS 1006, the clinical trials that lead to approval of Benlysta for the treatment of systemic lupus.  Presently Dr. Koumpouras is the principle investigator for over 7 active clinical trials in SLE at Yale and developed and is principle investigator of the Yale Rheumatology BioRepository.

    Dr. Koumpouras is board certified in both internal medicine and rheumatology. He is an active member of the American College of Rheumatology, the Arthritis Foundation, and the Lupus Foundation.  He is an committee member for the ACR RheumPAC, often going to Washington to advocate for arthritis in congress.  In addition to SLE, Dr. Koumpouras has an interest in lupus biomarkers, new lupus therapeutics, clinical trial management and execution, rheumatology education, diagnostic and treatment dilemmas, and adolescent arthritis.

  • Professor of Medicine (Rheumatology)

    Dr. Mamula’s received degrees from UCLA, the University of Notre Dame and the University of Oklahoma.  Dr. Mamula’s central research interests are in investigating the early events involved with breaking immune tolerance to self proteins, both in autoimmune disease and in tumor biology.  Overall, it is the goal of Dr. Mamula's laboratory to understand the mechanisms that may shift this balance toward the initiation of anti-self immune responses.  Seminal work from the Mamula lab elucidated the biochemical forms of autoantigens capable of breaking immunologic tolerance to intracellular autoantigens in systemic lupus erythematosus (SLE), and type 1 diabetes (T1D).  Simply put, Dr. Mamula examines posttranslational protein modifications that alter cellular biology and immunity.  These studies have now been applied to the development of novel therapeutic approaches in developing anti-tumor vaccines in breast cancer and colon cancer.  In addition, studies from the Mamula laboratory first demonstrated the ability of B cells to present autoantigens in the triggering of T cell autoimmunity and in the phenomenon of epitope spreading in lupus autoimmunity.  This work preceded more recent studies illustrating the how B cells transfer autoantigens to other antigen presenting cells, including dendritic cells and macrophages. 

  • Associate Professor of Immunobiology and of Medicine (Immunology)

    My work focuses on the etiology of autoimmune diseases affecting millions of individuals in the world by identifying molecules and pathways involved in the establishment of B-cell tolerance through the investigation of rare patients with primary immunodeficiency (PID), enrolled at Yale and through an international network.

    Patients with PID provide opportunities to study the impact of specific gene defects on the regulation of B-cell tolerance and the removal of developing autoreactive B cells in humans. Using a RT-PCR based strategy that allows us to assess the frequency of autoreactive B cells, we found that alterations in B-cell receptor (BCR) signaling in patients lacking functional BTK or CD19, or mutations in molecules mediating TLR signaling such as TACI, IRAK4, MyD88 as well as in adenosine deaminase (ADA) and activation-induced cytidine deaminase (AID) all result in a defective central checkpoint and a failure to counterselect developing autoreactive B cells in the bone marrow. Interestingly, successful gene therapy in ADA-deficient patients results in the restoration of early B-cell tolerance checkpoints, revealing that appropriate regiments could correct B-cell selection impairments characteristic of many patients with autoimmune conditions. Our investigations also revealed that central B-cell tolerance defects are primary to many autoimmune diseases including rheumatoid arthritis, type 1 diabetes and systemic lupus erythematosus and can result from genetic polymorphisms such as the R620W PTPN22 risk allele associated with all these diseases and that was reported to alter BCR signaling important for the regulation of this checkpoint.

    In contrast, most patients with multiple sclerosis only suffer from specific defects of their peripheral B-cell tolerance checkpoint that likely result from abnormal regulatory T cells, which normally control this second B-cell selection step in the periphery. Regardless of which early B-cell tolerance checkpoint is defective in patients with autoimmune diseases, all these patients are characterized by the accumulation of autoreactive clones in their mature naïve B cell compartment, which may contribute to the development of autoimmunity by increasing the frequency of B cells presenting self-antigens. Understanding the etiology of autoimmunity is the first step toward effective treatment, therapy and ultimately, cure.