Associate Professor of Internal Medicine,
Division of Rheumatology
Role of innate immunity in autoimmune diseases and organ damage. Neutrophils and dendritic cells in autoimmune diseases; Mechanisms of endothelial damage in systemic lupus erythematosus and other autoimmune diseases.
Systemic Lupus Erythematosus (SLE) is a multisystemic autoimmune disease of unclear etiology that affects primarily women of childbearing age. Patients with lupus also develop accelerated atherosclerosis and coronary artery disease of unclear etiology, which now represents an important cause of death in this population.
The Kaplan Laboratory is studying the mechanisms by which premature vascular damage occurs in SLE. We have described that 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. The Kaplan Laboratory is currently characterizing the molecular pathways by which type I Interferons promote vascular damage and interfere with vascular repair in lupus, using human and murine models. Current pathways investigated include the inflammasome as well as PPAR-gamma.
Another area of interest of this laboratory 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 are currently characterizing the mechanisms that drive the abnormal phenotype and function of these cells and their role in autoantigen exposure and stimulation of innate and adaptive immunity. Recently, we have described that the formation of neutrophil extracellular traps (NETS) is enhanced in low density granulocytes from SLE patients and that this phenomenon is associated to vascular damage, autoantibody production and type I IFN synthesis. Current work is focusing on establish the pathways leading to enhanced NET formation in SLE as well as the in vivo implications that this phenomenon has in lupus pathogenesis.
In addition, the Kaplan Laboratory is examining mechanisms of tissue damage in SLE and whether specific pharmacologic interventions can abrogate/ameliorate these complications in lupus and, potentially, in other autoimmune diseases.
Radic M, Kaplan MJ. Jumbled NETs promote vasculitis. Arthritis & Rheumatism 2012 Jul 6. doi: 10.1002/art.34615. [Epub ahead print].
Knight JS, Kaplan MJ. Lupus neutrophils: ‘NET’ gain in understanding lupus pathogenesis. Current Opinion in Rheumatology 2012 May 19 doi: 10.1097/BOR.0b013e3283546703.[Epub ahead of print].
Somers EC, Zhao W, Lewis, EE, Wang L, Wing JJ, Baskaram S, Kazerooni E, McCune WJ, Kaplan MJ. Type I interferons are associated with subclinical markers of cardiovascular disease in a cohort of systemic lupus erythematosus patients. PLoS One 2012; 7(5):e37000. PMC3351452.
Thacker S, Zhao W, Smith C, Luo W, Wang H, Vivekanandan-Giri A, Rabquer B, Koch AE, Pennathur S, Davidson A, Eitzman D, Kaplan MJ. Type I interferons modulate endothelial function, repair, thrombosis and plaque severity in murine models of lupus and atherosclerosis. Arthritis & Rheumatism 2012 May 1. doi: 10.1002/art.34504. [Epub ahead of print].
Kaplan MJ. Neutrophils in the pathogenesis and manifestations of SLE. Nature Reviews in Rheumatology 2011 Sep 27; 27(7):691-9. PMC3243068.
Kahlenberg JM, Thacker SG, Berthier CC, Cohen C, Kretzler M and Kaplan MJ. Inflammasome activation of IL-18 results in endothelial progenitor cell dysfunction in systemic lupus erythematosus. Journal of Immunology 2011; 187:6143-56. PMC3221936.
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. Journal of Immunology 2011; 187(1):538-52. PMC3119769.
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. Journal of Immunology 2011; 187(1):490-500. PMC3119764.
Marder W, Khalatbari S, Myles J, Yalavarthi S, Hench R, Lustig S, Brook R, Kaplan MJ. Interleukin-17 as a novel predictor of vascular function in rheumatoid arthritis. Annals of the Rheumatic Diseases 2011; 70:1550-5. PMC3151670.
Kahlenberg JM and Kaplan MJ. The interplay of inflammation and cardiovascular disease in lupus. Arthritis Research & Therapy 2011; 13:203. PMC3157642.
Thacker SG, Berthier CC, Mattinzoli D, Rastaldi MP, Kretzler M, and Kaplan MJ. The detrimental effects of interferon-α on vasculogenesis in lupus are mediated by repression of IL-1 pathways: potential role in atherogenesis and renal vascular rarefaction. Journal of Immunology 2010; 185:4457-69. PMC2978924.
Denny MF, Yalavarthi S, Zhao W, Thacker SG, Anderson M, Sandy AR, McCune WJ, and Kaplan MJ. A distinct subset of proinflammatory neutrophils isolated from patients with systemic lupus erythematosus induces vascular damage and synthesizes type I Interferons. Journal of Immunology 2010; 184:3824-97. PMC2929645.
Thacker SG, Duquaine D, Park J, and Kaplan MJ. Lupus-prone New Zealand Black/New Zealand White F1 mice display endothelial dysfunction and abnormal phenotype and function of endothelial progenitor cells. Lupus 2010; 19:288-99. PMC3151666.
Zhao W, Thacker SG, Hodgin JB, Zhang H, Wang JH, Park JL, Randolph A, Somers EC, Pennathur S, Kretzler M, Brosius FC, and Kaplan MJ. The PPAR-gamma agonist pioglitazone improves cardiometabolic risk in systemic lupus erythematosus. Journal of Immunology 2009; 183:2729-40. PMC2765333.
Monrad S, Rea KM, Thacker S, Kaplan MJ. Myeloid dendritic cells display downregulation of C-type lectin receptors and aberrant lectin in systemic lupus erythematosus. Arthritis Research & Therapy 2008; 10:R114. PMC2592801.
Monrad SU, Killen P, Anderson M, Bradke A, and Kaplan MJ. The role of aldosterone blockade in murine lupus nephritis. Arthritis Research and Therapy 2008; 10:R5. PMC2374470.
Denny MF, Thacker S, Mehta H, Somers EC, Dodick T, McCune WJ, and Kaplan MJ. Interferon-alpha promotes abnormal vasculogenesis in lupus: a potential pathway for premature atherosclerosis. Blood 2007; 110:2907-15. PMC2018671.
Ding D, Mehta H, McCune WJ, and Kaplan MJ. Aberrant phenotype and function of myeloid dendritic cells in systemic lupus erythematosus. Journal of Immunology 2006; 177:5878-89. PMID 17056512.
Denny M, Chandaroy P , Killen P, Caricchio R, Lewis E, Richardson B, Lee KD, Gavalchin J, and Kaplan MJ. Accelerated macrophage apoptosis induces autoantibody formation and organ damage in systemic lupus erythematosus. Journal of Immunology 2006; 176:2095-104. PMID 16455965.
Rajagopalan S, Somers EC, Brook R, Kehrer C, Pfenninger D, Lewis E, Chakrabarti A, Richardson BC, Shelden E, McCune WJ, and Kaplan MJ. Endothelial cell apoptosis in systemic lupus erythematosus: a common pathway for abnormal vascular function and thrombosis propensity.Blood 2004; 103:3677-83. PMID 14726373.