Harold W. Jockers Professor of Medicine
Research Interests
- Faculty
- Immunity, Innate
- Lyme Disease
- Rheumatology
- Tick-Borne Diseases
- Lyme Neuroborreliosis
Inflammation and Innate Immunity
The Section of Rheumatology’s research laboratories explore the role of innate immunity and inflammatory pathways in initiating and perpetuating autoimmunity in different rheumatologic diseases, with a goal of identifying pathologic mechanisms and better therapies. Investigations of disease models in the laboratory and of human subjects are pursued; these encompass molecular profiling and genetic studies, and novel therapeutic interventions. Our experimental approaches integrate across laboratories to take advantage of Department strengths in immune profiling, bioinformatics, core instrumentation (see more here and here) and human clinical investigation.
Ongoing programs include:
Lyme disease
Ixodes tick-transmitted infection with the Lyme disease spirochete can result in acute and chronic arthritis with features similar to other forms of noninfectious inflammatory arthritidies. The molecular pathogenesis of Lyme disease and its associated arthritis are major areas of study, and encompass tick-host interactions, mouse models of disease, and human clinical investigation. State-of-the-art genomic, proteomic and imaging approaches are employed to better understand spirochete evasion of host defenses and to develop new diagnostics for Lyme disease. Emerging tick-borne infections of particular risk to rheumatic disease patients on immunosuppressive agents, including those caused by the red blood cell parasite Babesia microti and a newly recognized relapsing fever spirochete Borrelia miyamotoi, are also major areas of interests.
Researcher
MIF-allele specific immunotherapy
Common genetic polymorphisms in the innate cytokine macrophage migration inhibitory factor (MIF) are associated with autoimmune disease susceptibility and clinical severity, and efforts are underway to develop therapies tailored to an individual’s allele-dependent disease manifestations, whether due to SLE, rheumatoid arthritis, or the inflammatory complications of infections such as tuberculosis or malaria. An anti-MIF antibody from the laboratory has advanced into phase II human clinical testing and small molecule MIF modulators are under development for autoimmunity and for tissue protection. The function of new MIF-like genes and orthologues are under study for their role in immune evasion. Separate studies focus on the role of fibrocytes in autoimmune fibrosing conditions such as scleroderma interstitial lung disease, and results have contributed to novel a fibrocyte-directed therapeutic currently in phase II clinical evaluation.
Researcher
Waldemar Von Zedtwitz Professor of Medicine (Rheumatology) and Professor of Pathology and of Epidemiology (Microbial Diseases); Chief, Rheumatology, Allergy, & Immunology; Affiliated Faculty, Yale Institute for Global Health; Rheumatologist in Chief, Rheumatology, YNHH
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 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. Dr. Bucala licensed anti-MIF toward the development of Imalumab and his work 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.
Innate immune pathways in autoimmunity and aging
The role of the innate response to nucleic acid-containing immune complexes in perpetuating autoimmunity in SLE and elucidating the inflammasome pathways necessary for this pathologic response is an important objective of investigation. These pathways contribute to lupus interferon signatures and may be key targets for new therapies. Separately, delineating the role of immunosenescence in “inflamm-aging” and the increased prevalence of autoimmunity with age is an objective of the Kang laboratory. The group has discovered a significant, age-related decline in IL-7-dependent CD8 T cell responses and is investigating the underlying mechanism for this phenomenon.
Researcher
Professor; Director of Allergy & Immunology, Internal Medicine
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.
Microbiota and autoimmunity
The host response to commensal bacteria and its role in both initiating and promoting autoimmune phenomena in lupus and the antiphospholipid syndrome is under study in both animal models and human subjects. The Kriegel lab is examining the role of the microbiota as agents of molecular mimicry in inflammatory and autoimmune pathways. Identifying and countering such universal triggers is leading to new insights in disease pathogenesis and prompt novel approaches toward disease prevention and treatment.
Innate recognition in aging and autoimmunity
The impact of clinical or pharmacologic immunosuppression on innate immune recognition pathways, especially Toll-like receptors and inflammasomes, in human subjects is being studied by state-of-the-art immune profiling and bioinformatics approaches of individual leukocyte subsets. The increased proinflammatory milieu of aging is associated with elevated levels of cytokines, and chronic but low-grade inflammation may contribute to age-associated frailty, morbidity and mortality. Large human cohort studies have uncovered an age-related dysregulation of innate immune pathways as well as important individual variations in immune status with implications for autoimmunity and the response to infection and vaccination.
Researcher
Professor of Medicine and Professor of Epidemiology (Microbial Diseases); Associate Dean for Scientific Affairs, Dept Clinical: Internal Medicine
Ruth R. Montgomery is a cellular immunologist with particular expertise in use of novel technology for human translational studies. Her research employs systems wide studies to identify individual differences in immune responses that lead to divergent outcomes to infection. Her group focuses on effects of aging on innate immunity and individual variation influencing susceptibility to West Nile, dengue, Zika and COVID-19 viruses, and inflammatory profiling of patients with sickle cell disease. She has overseen studies of immune responsiveness in human cohorts with successful enrollment of >2000 healthy individuals. Dr. Montgomery’s work is notable for her use of primary human cells to demonstrate immune related mechanisms and illuminate potential avenues for therapeutic interventions. She launched the CyTOF facility at Yale in 2013, was co-chair of the University Provost’s ITS Advisory Committee (ITSAC), and serves as Associate Dean for Scientific Affairs.