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Research

Photo of Confocal Microscope

Systemic Autoimmunity Branch

Neutrophil extracellular traps (NETs) in neutrophils isolated from a patient with rheumatoid arthritis, following stimulation with recombinant IL-17A in vitro. Exuberant NET formation is observed, characterized by long strands of DNA (blue) decorated with the granular protein, neutrophil elastase (red).

Mariana Kaplan, M.D.
Chief, Systemic Autoimmunity Branch
Phone: 301-402-5884
E-mail: mariana.kaplan@nih.gov

Research overview

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.

NETs can be detected in affected kidneys of NZM mice, and cause endothelial dysfunction in vitro

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.


Selected Publications

Knight JS, Subramanian V, O'Dell AA, Yalavarthi S, Zhao W, Smith CK, Hodgin JB, Thompson PR, Kaplan MJ. Peptidylarginine deiminase inhibition disrupts NET formation and protects against kidney, skin and vascular disease in lupus-prone MRL/lpr mice. Ann Rheum Dis. 2014 Aug 7. PubMed Icon

Smith CK, Vivekanandan-Giri A, Tang C, Knight JS, Mathew A, Padilla RL, Gillespie BW, Carmona-Rivera C, Liu X, Subramanian V, Hasni S, Thompson PR, Heinecke JW, Saran R, Pennathur S, Kaplan MJ. Neutrophil extracellular trap-derived enzymes oxidize high-density lipoprotein: An additional proatherogenic mechanism in systemic lupus erythematosus. Arthritis Rheumatol. 2014 May 16. PubMed Icon

Carmona-Rivera C1, Zhao W, Yalavarthi S, Kaplan MJ. Neutrophil extracellular traps induce endothelial dysfunction in systemic lupus erythematosus through the activation of matrix metalloproteinase-2. Ann Rheum Dis. 2014 Feb 25. doi: 10.1136/annrheumdis-2013-204837 PubMed Icon

Palanichamy A, Bauer JW, Yalavarthi S, Meednu N, Barnard J, Owen T, Cistrone C, Bird A, Rabinovich A, Nevarez S, Knight JS, Dedrick R, Rosenberg A, Wei C, Rangel-Moreno J, Liesveld J, Sanz I, Baechler E, Kaplan MJ, Anolik JH. Neutrophil-mediated IFN activation in the bone marrow alters B cell development in human and murine systemic lupus erythematosus. J Immunol. 2014 Feb 1;192(3):906-18. doi: 10.4049/jimmunol.1302112. Epub 2013 Dec 30. PubMed Icon

Knight JS, Luo W, O'Dell AA, Yalavarthi S, Zhao W, Subramanian V, Guo C, Grenn RC, Thompson PR, Eitzman DT, Kaplan MJ. Peptidylarginine Deiminase Inhibition Reduces Vascular Damage and Modulates Innate Immune Responses in Murine Models of Atherosclerosis. Circ Res. 2014 Jan 14. [Epub ahead of print] PubMed Icon

Kahlenberg JM, Yalavarthi S, Zhao W, Hodgin JB, Reed TJ, Tsuji NM, Kaplan MJ.An essential role of caspase 1 in the induction of murine lupus and its associated vascular damage. Arthritis Rheumatol. 2014 Jan;66(1):152-62. doi: 10.1002/art.38225. PubMed Icon

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. PubMed Icon

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. PubMed Icon

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. PubMed Icon

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. PubMed Icon

See extended list of publications

 

Updated September 12, 2014