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Systemic Autoimmunity Branch
Our main goal is to unravel the fundamental mechanisms that lead to the development and perpetuation of systemic autoimmune disorders, particularly systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), and their associated organ damage.
SLE is a systemic syndrome of unclear etiology that affects primarily women of childbearing age. Patients with lupus also develop accelerated atherosclerosis and coronary artery disease not fully explained by traditional risk factors, which frequently lead to death in this group of patients. Patients with RA and other inflammatory joint diseases and autoimmune disorders also have increased risks for cardiovascular disease. However, the mechanisms leading to this increased vascular risk are unknown.
MPO-DNA colocalization in kidney sections from proteinuric
NZM mice with DNA stained blue and mouse IgG red.
Part of our work is focused on determining how and why premature vascular damage occurs in SLE and RA. Lupus patients show evidence of increased endothelial cell apoptosis, which correlates with tissue factor generation and vasomotor dysfunction, a predictor of future development of atherosclerosis. We have also found that patients with lupus have impaired vascular repair, and that this phenomenon is mediated by type I Interferons. Using human and murine models, we are characterizing the molecular pathways by which type I Interferons promote vascular damage and interfere with vascular repair, plaque formation and thrombotic events in lupus.. We are also studying the role of specific cytokines and immune cells in the development of vascular damage in RA.
Another area of interest is how innate immunity mediates the development of organ damage in lupus and, potentially, in other autoimmune diseases. We have recently characterized an abnormal neutrophil subset that appears to be pathogenic in lupus, synthesizes type I interferons, promotes vascular damage, and interferes with vascular repair. We have found that this subset is more prone to form neutrophil extracellular traps (NETS), which are structures made of processed chromatin bound to granular and selected cytoplasmic proteins. We are determining the relevance of aberrant NET formation in the induction of autoimmune responses in SLE, RA and other autoimmune disorders, as well as their potential role in the development of vascular complications.
By identifying mechanisms of tissue damage in SLE and RA, we hope to address if specific pharmacologic interventions that block identified pathways can mitigate these complications in these and other autoimmune disorders.
Marder W, Khalatbari S, Myles JD, Hench R, Lustig S, Yalavarthi S, Parameswaran A, Brook RD, Kaplan MJ. The Peroxisome Proliferator Activated Receptor-γ Pioglitazone Improves Vascular Function and Decreases Disease Activity in Patients With Rheumatoid Arthritis. J Am Heart Assoc. 2013 Nov 19;2(6):e000441. doi: 10.1161/JAHA.113.000441.
Kahlenberg JM, Yalavarthi S, Zhao W, Hodgin JB, Reed TJ, Tsuji NM, Kaplan MJ. An essential role for caspase-1 in the induction of murine lupus and its associated vascular damage. Arthritis Rheum. 2013 Oct 14. doi: 10.1002/art.38225.
Knight JS, Zhao W, Luo W, Subramanian V, O'Dell AA, Yalavarthi S, Hodgin JB, Eitzman DT, Thompson PR, Kaplan MJ. Peptidylarginine deiminase inhibition is immunomodulatory and vasculoprotective in murine lupus. J Clin Invest. 2013 Jul 1;123(7):2981-93. doi: 10.1172/JCI67390. Epub 2013 Jun 3.
Khandpur R, Carmona-Rivera C, Vivekanandan-Giri A, Gizinski A, Yalavarthi S, Knight JS, Friday S, Li S, Patel RM, Subramanian V, Thompson P, Chen P, Fox DA, Pennathur S, Kaplan MJ. NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis. Sci Transl Med. 2013 Mar 27;5(178):178ra40.
Thacker SG, Zhao W, Smith CK, Luo W, Wang H, Vivekanandan-Giri A, Rabquer BJ, Koch AE, Pennathur S, Davidson A, Eitzman DT, Kaplan MJ. Type I interferons modulate vascular function, repair, thrombosis, and plaque progression in murine models of lupus and atherosclerosis. Arthritis Rheum. 2012 Sep;64(9):2975-85. doi: 10.1002/art.34504.
Kahlenberg JM, Thacker SG, Berthier CC, Cohen CD, Kretzler M, Kaplan MJ. Inflammasome activation of IL-18 results in endothelial progenitor cell dysfunction in systemic lupus erythematosus. J Immunol. 2011 Dec 1;187(11):6143-56.
Marder W, Khalatbari S, Myles JD, Hench R, Yalavarthi S, Lustig S, Brook R, Kaplan MJ. Interleukin 17 as a novel predictor of vascular function in rheumatoid arthritis. Ann Rheum Dis. 2011 Sep;70(9):1550-5.
Villanueva E, Yalavarthi S, Berthier CC, Hodgin JB, Khandpur R, Lin AM, Rubin CJ, Zhao W, Olsen SH, Klinker M, Shealy D, Denny MF, Plumas J, Chaperot L, Kretzler M, Bruce AT, Kaplan MJ. Netting neutrophils induce endothelial damage, infiltrate tissues, and expose immunostimulatory molecules in systemic lupus erythematosus. J Immunol. 2011 Jul 1;187(1):538-52.
Lin AM, Rubin CJ, Khandpur R, Wang JY, Riblett M, Yalavarthi S, Villanueva EC, Shah P, Kaplan MJ, Bruce AT. Mast cells and neutrophils release IL-17 through extracellular trap formation in psoriasis. J Immunol. 2011 Jul 1;187(1):490-500. doi: 10.4049/jimmunol.1100123See extended list of publications
Updated December 5, 2013