Lupus

Richard Bucala, MD, PhD, is Chief, Section of Rheumatology, Allergy & Immunology and the Waldemar Von Zedtwitz Endowed Professor of Medicine, Pathology, and Epidemiology & Public Health. He studies the regulation of the immune system with a focus on how protective responses can lead to immunopathology and disease. His laboratory’s main emphasis is MIF-family cytokines, their role in genetic susceptibility to disease, and their therapeutic targeting for different clinical conditions. The Bucala group is credited with the molecular cloning of MIF and discovery of its critical role in regulating glucocorticoid immunosuppression, which opened novel approaches to therapy in autoimmune inflammatory conditions. His lab also identified the MIF receptor and discovered common polymorphisms in the MIF gene, which show global population stratification. Depending on the nature of the immune or invasive provocation, variant MIF alleles protect from disease or contribute to immunopathology in autoimmunity and in different infections and chronic conditions. His laboratory developed biochips for application to genetic epidemiology studies of malaria and tuberculosis in resource-limited settings and his research is leading efforts to develop MIF-based therapies tailored to an individual’s genetic makeup. The laboratory has developed new therapies such as the anti-MIF antibody (Imalumab) and contributed to the FDA-approved anti-MIF receptor antibody (Milatuzumab). Research partnerships in structure-based drug design have led to novel small molecule MIF modulators for use in autoimmune, oncologic, and infectious diseases. The function of the MIF-like genes expressed by the parasites responsible for malaria, leishmaniasis, and helminthic infection also are under investigation. As these proteins were discovered to uniquely suppress immunologic memory, they offer new targets for vaccination against these infections. Dr. Bucala further is credited with the discovery of the circulating fibrocyte, which is being targeted therapeutically in different fibrosing disorders. He co-founded two biotechnology companies, including the startup MIFCOR begun as a student-advised project. He attends in the Yale New Haven Health System in-patient service and is the past Editor-in-Chief of Arthritis & Rheumatology. Dr. Bucala was elected to the American Society for Clinical Investigation and the Association of American Physicians and has served on advisory boards for the UN, the federal government, the pharmaceutical industry, academia, and private foundations.

Dr. Joe Craft, Paul B. Beeson Professor of Medicine and Professor of Immunobiology at Yale, is a graduate of the University of North Carolina School of Medicine. He did postgraduate training in internal medicine, rheumatology and immunology at Yale, and directs a laboratory devoted to understanding of systemic lupus erythematosus (SLE, lupus) and host responses to viral pathogens. Dr. Craft is a two-time NIH MERIT Awardee, recipient of the Yale Bohmfalk Basic Science Teaching Prize, and an elected Fellow of American Association for Advancement of Science. He directs the Yale Investigative Medicine MD to PhD Program and is Director of the Colton Center for Autoimmunity at Yale. Dr. Craft is chair of the Board of Lupus Therapeutics of the Lupus Research Alliance (LRA), past chair of the Board of Scientific Counselors at NIAMS and of the Scientific Advisory Board of the Alliance for Lupus Research (now LRA). He chaired the Immunological Sciences (now Hypersensitivity, Autoimmune and Immune-mediated Diseases) Study Section of NIH and is a former Pew Scholar in the Biomedical Sciences and a 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.

Dr. Insoo Kang is Professor of Medicine (Rheumatology, Allergy & Immunology) at Yale University School of Medicine. He completed his post-graduate training in rheumatology and immunology research 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.

My expertise is in the diagnosis and clinical care of systemic lupus erythematosus (SLE) as well as in the conduct of clinical trials.  My initial research interests have evolved from laboratory-based investigation (Proc Natl Acad Sci USA. 1997; 94:7566-7571) to an academic clinical career focused on SLE and rheumatology education.   My early professional experience as medical director of Dr. Manzi’s Lupus Center of Excellence at the University of Pittsburgh put me at the center of managing multidisciplinary clinical services while engaging in clinical research and clinical trials. One of these lead to a new therapy for SLE in 2011.  As Director of the Yale Lupus Program, I lead a dedicated team focused on SLE care, research, and wellness.  An off-shoot of the lupus program was the development the Yale rheumatology-dermatology clinic, which I founded.  Also, I created a biobank from a well characterized cohort of patients with SLE that produced collaborative research in cardiac lupus, pathogenies of lupus, inflammasome biology, and others.  Under my leadership, Yale is now part of every major clinical trial in SLE. I often provide advice for new SLE trials.  I was asked to be part of the Executive Health Yale Medicine Program based on my expertise and reputation.   In 2019 I became Training Program Director and recently was elected to serve on the American College of Rheumatology Education grant study section and on the Committee on Training and Workforce issues where we hope to develop a resource for those transitioning into the role of Program Director.  I leverage my skills as an academic clinician and disease subspecialist to develop outstanding next generation rheumatologists.

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.

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.

Dr. Seth obtained his BA and MA from Harvard University in 1998 and began his MD/PhD training at Rockefeller-Cornell before transferring with his research mentor to complete his degrees at University of Texas Southwestern in 2007. He came to Yale for residency in Internal Medicine and joined the Section of rheumatology for his fellowship in 2010. Dr. Seth has considerable success in his training years including Thomas Temple Hoope’s Prize for best undergraduate thesis at Harvard, and a patent from his Master’s work, with publication of 6 manuscripts, including a first author paper in the top-ranked Journal of Cell Biology on actin assembly. Dr. Seth received numerous undergraduate and graduate research fellowships and was the recipient of an ACR REF Scientist Development Award in 2013, with funding through 2016. He has been mentored by Dr. Craft as he hones his skills in genetic analysis of cell development, and function of Tfh cells in immunity and autoimmunity.