In the United States, 2.5 million people have rheumatoid arthritis (RA). RA is a chronic inflammatory autoimmune disorder that starts in the young to middle adult years and may lead to complete joint destruction if untreated. There is no cure for RA at present and up to 40% of RA patients do not respond to anti-TNF agents or other biological treatments due to lack of efficacy or intolerability therefore novel treatment targets are urgently needed. Findings that lea to novel treatments can benefit all active and retired military and VA members with RA, as well as their families and friends who may suffer from RA. Effective and improved treatments through identification of cascades that modulate RA synovial inflammation and bone erosion will allow active duty members to remain longer in service and will also relieve joint pain and disability in retired Veterans. The quantity of RA synovial CD68+ macrophages is reduced in positive response to therapy concurrent with reduction in disease activity therefore the number of myeloid cells closely correlates with radiological bone damage, joint pain and inflammation. Yet, the mechanism that drives RA myeloid cell differentiation to proinflammatory macrophages or mature bone eroding osteoclasts is undefined. To address this vital issue, highly modulated genes were identified in RA compared to normal myeloid cells employing microarray analysis. In validation of the microarray data, we found that TLR7 is one of the most highly upregulated genes in RA synovial fluid and RA peripheral blood myeloid cells compared to normal peripheral blood myeloid cells. We discovered a novel TLR7 endogenous ligand in RA synovial fluid and documented that this ligand is strongly capable of transforming the newly recruited na?ve myeloid cells into inflammatory macrophage phenotype. We also found that the osteoclast maturation process is associated with increased TLR7 expression and that the enhanced response to TLR7 endogenous ligand can provoke differentiation of fully mature RA osteoclasts. Based on the supportive data, we hypothesize that the na?ve RA myeloid cells are remodeled to proinflammatory macrophages and mature osteoclasts through TLR7 ligation. Therefore disruption of TLR7 binding to its endogenous ligand will resolve RA and experimental arthritis by dysregulating the development of inflammatory macrophages and mature osteoclasts. We uncover for the first time, a novel TLR7 endogenous ligand, and propose to determine the origination and the underlying mechanism by which ligation of this endogenous ligand to TLR7 contributes to RA pathogenesis and how this cascade of events is interconnected to the inflammatory RA network. Finally we will document whether interruption in TLR7 ligation to its endogenous ligand can be used as a promising new therapeutic target in RA.
Rheumatoid arthritis (RA) is more prominent in women and has greater severity in Hispanics and Black populations. Recent wars have brought a new influx of Veterans who are younger and are most prone to developing autoimmune connective tissue diseases, especially RA. Our clinic at the Jesse Brown VA sees around 700-900 patients with RA and other autoimmune diseases annually. Majority of RA patients have prolonged morning stiffness that makes simple daily activities difficult. The disease tends to affect large and small joints and finally leads to bone and cartilage erosion. In this proposal we have characterized a novel gene that is greatly elevated in RA compared to normal specimen and found that activation of this specific gene contributes to joint inflammation and bone erosion. We propose to determine whether disruption of this gene's function could alleviate the pain and bone destruction in RA patients in order to allow the active duty members to remain in service longer as well as to resolve the pain and disability suffered by retired Veterans.
| Elshabrawy, Hatem A; Volin, Michael V; Essani, Abdul B et al. (2018) IL-11 facilitates a novel connection between RA joint fibroblasts and endothelial cells. Angiogenesis 21:215-228 |
| Kim, Seung-Jae; Chen, Zhenlong; Essani, Abdul B et al. (2017) Differential impact of obesity on the pathogenesis of RA or preclinical models is contingent on the disease status. Ann Rheum Dis 76:731-739 |
| Elshabrawy, Hatem A; Essani, Abdul E; Szekanecz, Zoltán et al. (2017) TLRs, future potential therapeutic targets for RA. Autoimmun Rev 16:103-113 |
| Kim, Seung-Jae; Chen, Zhenlong; Essani, Abdul B et al. (2016) Identification of a Novel Toll-like Receptor 7 Endogenous Ligand in Rheumatoid Arthritis Synovial Fluid That Can Provoke Arthritic Joint Inflammation. Arthritis Rheumatol 68:1099-110 |
| Elshabrawy, Hatem A; Chen, Zhenlong; Volin, Michael V et al. (2015) The pathogenic role of angiogenesis in rheumatoid arthritis. Angiogenesis 18:433-48 |
