Rheumatoid arthritis (RA) is the most common autoimmune disease which affects 2.5 million people in US, many of which are VA military personnel. One in four veterans has arthritis (25.6%), compared to one in five civilians. RA is a chronic, disabling autoimmune disease in which the body attacks its own tissues. As RA progresses, performing simple daily activities can become increasingly difficult for patients suffering from the disease. There is no cure for RA and up to 50% of patients do not respond to anti-TNF therapies as circulating Th17/IL-17 levels are highly elevated subsequent to TNF blockade. For this subset of RA patients, disruption of a novel pathway that impairs the synergy between TNF and IL-17 cascades may provide an alternative treatment. Effective therapies can benefit all active and retired military and VA members with RA, as well as their families and friends who may suffer from RA. Findings that lead to new therapy will benefit the VA personnel by reducing the cost for medical and surgical care; in addition to the secondary RA complications including depression, cardiovascular disease and psychosocial stress. Consequently, effective RA therapy will improve the pain & the life quality of the retired veterans. We discovered that toll like receptor (TLR)5 is highly elevated in RA compared to normal macrophages, and its expression closely correlates with RA disease activity score (DAS28). We also demonstrated that TLR5 natural ligands are present in RA synovial fluid. Ligation of TLR5 to its natural ligands, transforms RA peripheral blood (PB) nave cells into classical M1 macrophages (M?s) which produce high levels of TNF, IL-6 and IL-1?. In addition, IL-6 and IL-1? produced from TLR5 driven M1 M?s can differentiate the nave T cells into inflammatory RA Th17 cells that secrete IL-17. In mice, systemic and local injection of a TLR5 agonist exacerbates joint swelling. The objective of this proposal is to understand the cellular and molecular mechanisms of TLR5 function and to evaluate whether TLR5 antibody (Ab) can be utilized as a promising strategy for RA therapy. We hypothesize that ligation of joint TLR5 triggers differentiation of proinflammatory M?s and T cells which can ultimately expand the RA inflammatory process to the erosive phase. We further postulate that a novel TLR5 Ab generated by our lab may be an alternative treatment strategy for non-responders as it negates the interaction of effector myeloid and lymphoid cells in RA. To test our hypothesis, we will examine the contribution of RA M? and T cell cross talk with endothelial cells on bone neovascularization. Subsequently, to establish the preclinical stage efficacy, TLR5 Ab therapy will be compared to the currently available treatments in RA cells and preclinical models. Successful completion of this project will identify a novel mechanism that links the function of effector myeloid cells to lymphoid cells as well as establishing a novel treatment strategy for RA patients that do not respond to the current therapies.
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 RA patients annually. There is no cure for RA and up to 50% of the RA patients do not respond to current therapies. Therefore we aim to find a novel therapy that can slow or reverse RA progression. To resolve the critical barrier in RA treatment, we have identified a receptor which plays a central role in promoting joint inflammation and bone erosion. To investigate whether this identified receptor may be a novel target for RA therapy; a potent blocking antibody was engineered against this receptor. The goal of this proposal is to understand the identified receptor's mechanism of function and to evaluate whether the antibody engineered against this receptor can be utilized as a promising strategy for RA therapy.
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| 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 |
