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.

Learn more here: Linda Bockenstedt, MD.

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.

Learn more here: Richard Bucala, MD, PhD.

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.

Learn more here: Insoo Kang, MD.

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.

Learn more here: Martin Kriegel, MD, PhD.

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.

Learn more here: Ruth Montgomery, PhD.