Dr. Gravallese is the Theodore Bevier Bayles Professor of Medicine and Chief of the Division of Rheumatology, Inflammation and Immunity at Brigham and Women’s Hospital. The Gravallese laboratory is devoted to understanding the pathogenesis of systemic rheumatic diseases, including rheumatoid arthritis, spondyloarthritis and systemic lupus erythematosus. We study the onset, progression, persistence, and regulation of the inflammatory processes in these diseases using human tissues, murine models of disease and cutting-edge technologies, with the goal of contributing to the development of new clinical interventions. Our mission is to discover fundamental mechanisms of inflammation in these diseases, as well as to dissect the impact of inflammation on bone, a field known as osteoimmunology. 

Projects in the laboratory address the role of innate immune mechanisms in these diseases. We have identified a role for cytosolic DNA sensing pathways in the generation of arthritic inflammation. Innate immune pattern recognition receptors sense nucleic acid from microbial organisms and orchestrate production of cytokines to resolve infection, but these pathways can also recognize self-nucleic acid, resulting in autoimmunity. Cytosolic nucleic acid sensors can detect DNA within the cell cytosol. Utilizing a murine model in which there is accrual of cytosolic DNA due to deficiency in the enzyme DNase II, we have studied the impact of excess DNA on inflammatory arthritis and the production of anti-nuclear antibodies. DNA within the cytosol can activate three distinct pathways, each of which contributes differentially to the development of autoimmune disease manifestations. The cGAS (cyclic GMP-AMP synthase)-STING (STimulator of INterferon Genes) pathway is essential for the development of arthritis in the DNase II deficient mouse, while the Absent in Melanoma 2 (AIM2) pathway contributes to arthritis development through production of IL-1 and IL-18. The endosomal TLR pathways do not contribute to arthritis severity, but instead, deficiency of these pathways completely abrogates the development of anti-nuclear antibodies in the setting of DNaseII deficiency. We are currently addressing the role of these cytosolic DNA sensing pathways in several autoimmune diseases. In addition, projects in the laboratory address the specific role of the cGAS-STING and AIM2 pathways in bone.

Other projects in the laboratory involve dissecting the role of IL-17 family members in inflammatory arthritis. IL-17A is a key inflammatory cytokine in certain rheumatic diseases including spondyloarthritis (SpA) and psoriatic arthritis. While studying IL-17A biology and the role of IL-17A in the immunopathology of SpA, we became interested in additional IL-17 family members and are identifying their roles in these rheumatic diseases and in the associated bone pathology. Finally, our laboratory has an interest in the role of clonal hematopoiesis in rheumatic diseases, with a particular interest in the role of one factor, the epigenetic regulator of hematopoietic fate Ten-Eleven Translocase 2 (TET2). We are studying the potential role of TET2 in arthritis, bone, and the vasculature.