The Laboratory of Ellen M. Gravallese M.D.
Email: egravallese@bwh.harvard.edu
Call: 617-525-1000
Overview
The Gravallese Laboratory is devoted to understanding the pathogenesis of inflammatory arthritis. Our mission is to discover fundamental mechanisms of inflammation in these diseases and to dissect the impact of inflammation on bone. We study the onset, progression, persistence, and regulation of systemic autoimmune diseases using human tissues, murine models of disease, ssRNA-sequencing and spatial transcriptomics in order to contribute to the development of new clinical interventions for rheumatic disease. A new paradigm in the pathogenesis of autoimmune disease is the aberrant control of the innate immune system. We are focusing on cytosolic DNA sensing as an agent of the innate immune system as we have identified that these pathways play an important role in specific disease manifestations and in bone.
Research Projects
Innate immunity and rheumatic disease
We have identified an important role for cytosolic DNA sensor pathways in the generation of arthritic inflammation and its subsequent impact on bone. Innate immune pattern recognition receptors sense nucleic acid from microbial organisms and orchestrate production of cytokines to resolve infection. While Toll-like receptors (TLRs) have long been known to detect nucleic acid, cytosolic nucleic acid sensors are also important in this regard. Utilizing an animal model in which there is accrual of cytosolic DNA due to deficiency in the enzyme DNase II, we demonstrated that excess DNA leads to severe inflammatory arthritis that resembles RA, including the production of autoantibodies.
Activation of DNA sensor pathways occurs in several distinct modules, which each contribute differentially to the development of autoimmunity. The Stimulator of INterferon Genes (STING) pathway is essential for the development of arthritis, while the Absent in Melanoma 2 (AIM2) pathway contributes but is not sufficient for the arthritis development, due to specific production of active IL-18. Blocking the endosomal TLR pathway did not affect arthritis severity but completely abrogated the development of ANAs in the DNaseII KO setting.
We have also determined that these cytosolic DNA sensors are activated in osteoclast precursor cells and mature osteoclasts, leading us to investigate the role of the STING pathway in bone. We identified the unique finding that the DNaseII deficient mice exhibit striking bone formation in the spleens and long bones, and that the bone accrual phenotype requires STING. Our current work, highlighted below, furthers the specific role of these pathways in bone homeostasis and inflammation.
Baum R, Sharma S, Carpenter S, Li QZ, Busto P, Fitzgerald KA, MarshakRothstein A, Gravallese EM. Cutting edge: AIM2 and endosomal TLRs differentially regulate arthritis and autoantibody production in DNase II-deficient mice. J Immunol. 2015 Feb 1;194(3):873-7.
Baum R, Sharma S, Organ JM, Jakobs C, Hornung V, Burr DB, Marshak-Rothstein A, Fitzgerald KA, Gravallese EM. STING contributes to abnormal bone formation induced by deficiency of DNase II in Mice. Arthritis Rheumatol. 2017 Feb;69(2):460-471
MacLauchlan S, Kushwaha P, Tai A, Chen S, Manning C, Swarnkar G, Abu-Amer Y, Fitzgerald KA, Sharma S, and Gravallese EM. STING-dependent interferon signatures restrict osteoclast differentiation and bone loss in mice. Proc Natl Acad Sci USA 2023 Apr 11;120(15):e2210409120.
Macrophages and their subsets in rheumatoid arthritis
Recent work in the laboratory is addressing the role of macrophage subsets and trained immunity in the pathogenesis of rheumatic diseases. SPP1 macrophages have been identified as both a disease-promoting and disease protective cell type, depending upon the setting. We have identified an enrichment of SPP1+ synovial tissue macrophages (STMs) in RA compared to healthy synovium, correlating with clinical parameters. These cells also demonstrate distinct glycolytic gene signatures. Importantly, we demonstrate SPP1+ macrophage clusters are enriched in the synovium in individuals at risk for RA (IAR), suggesting they represent an early disease-specific myeloid subset. Despite the known inflammatory and bone remodeling functions of SPP1 and the presence of SPP1+ STMs in RA synovial tissue, there are no studies examining their exact function in the RA, or the metabolic regulators of these cells. This project delves into an understanding of this and other macrophage subsets in rheumatoid arthritis pathogenesis.