Mariana Kaplan, M.D.
Associate Professor of Internal Medicine,
Division of Rheumatology

makaplan@umich.edu


Research interests:

mechanisms of endothelial damage in autoimmune diseases; role of innate immunity in autoimmune diseases; type I interferons in the pathogenesis of lupus; dendritic cells and autoimmunity.


Research Description:

Systemic lupus erythematosus (SLE) is an autoimmune disease of unclear etiology that affects multiple organs and 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.

Our laboratory is interested in 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 due to type I IFNs. We are now characterizing how type I IFNs promote vascular damage in lupus, both in human and animal models.

Other mechanisms that promote end-organ damage (kidney, blood vessels), including aberrant neutrophils, are a focus of this laboratory. Our lab has characterized an abnormal neutrophil subset that appears to be pathogenic in lupus and we are currently characterizing the mechanisms that drive the abnormal phenotype and function of these cells.

My laboratory is studying the interactions of autoreactive lupus T cells with different autologous APCs (in particular dendritic cells), and whether phenotypic/functional differences of lupus APCs could explain some of the severe immunological abnormalities found in these patients. We have determined that lupus myeloid dendritic cells have distinct phenotypic and functional abnormalities and we are further characterizing the role of these changes in abnormal T cell function in SLE.

Increased in vitro apoptosis and altered expression of cell surface receptors and ligands involved in programmed cell death, have been reported in PBMC from SLE patients It has been proposed that dysregulation of apoptosis may play a major role in the pathogenesis of SLE. Our lab has found that monocytes from lupus patients undergo accelerated apoptosis. This process is mediated, at least in part, by an autoreactive T cell subset that kills autologous APCs in the absence of nominal antigen. We have recently described the apoptotic pathways involved in this process and we propose that APC apoptosis could be relevant to the generation of an autoimmune response by increasing the apoptotic load (and the source of autoantigens), and by decreasing normal cell clearance mechanisms. Indeed, our in vivo studies support the role of macrophage apoptosis in the induction of autoimmunity as we have recently found that accelerated macrophage apoptosis accelerates autoimmunity features in lupus-prone mice. We are interested in determining the autoantigen specificities in T cell-mediated APC apoptosis in SLE. We propose that characterizing the apoptotic ligands involved in APC apoptosis could lead into the development of novel therapeutic interventions designed to abrogate or block the onset and/or severity of this disease.

Representative publications:

Kaplan MJ, Ray D, Mo R-R, Yung RL, Richardson BC. TRAIL(Apo2 Ligand) and TWEAK (Apo3 Ligand) mediate CD4+ T cell killing of antigen-presenting macrophages. Journal of Immunology 2000;164:2897-2904.

Kaplan MJ, Lewis EE, Shelden EA, Somers E, Pavlic R, McCune WJ, Richardson BC. The apoptotic ligands TRAIL, TWEAK and FasL mediate monocyte death induced by autologous lupus T cells. Journal of Immunology 2002; 169: 6020-9

Rajagopalan S, Somers S, 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; 301;3677-83.

Kaplan MJ, Lu Q, Wu A, Attwood J, Richardson B. Demethylation of promoter regulatory elements contributes to perforin overexpression in CD4+ lupus T cells. Journal of Immunology 2004; 172: 3652-61.

Kaplan MJ. Apoptosis in systemic lupus erythematosus. Clinical Immunology 2004; 112: 210-8.

Denny M, Chandaroy P , Killen P, Caricchio R, Lewis E, Richardson B, Lee KD, Gavalchin J, Kaplan MJ. Accelerated macrophage apoptosis induces autoantibody formation and organ damage in systemic lupus erythematosus. Journal of Immunology 2006;176; 2095-104.

Ding D, Mehta H, McCune WJ, Kaplan MJ. Aberrant phenotype and function of myeloid dendritic cells in systemic lupus erythematosus 2006 Journal of Immunology 2006; 177:5878-5889.

Denny M, Thacker S, Mehta H, Somers E, Dodick, T, Kelley L, Barrat F, McCune W, Kaplan MJ. Interferon-alpha induces abnormal vascular repair in systemic lupus erythematosus: a potential link to premature atherosclerosis. Blood 2007; 110: 2907-15.

Monrad SU, Killen P, Anderson M, Bradke A, Kaplan MJ. Role of aldosterone blockade in lupus nephritis. Arthritis Research and Therapy 2008; 10:R5.

Monrad S, Rea KM, Thacker S, and Kaplan MJ. Myeloid dendritic cells exhibit decreased C-type lectin receptor and phagocytosis in systemic lupus erythematosus. Arthritis Research & Therapy 2008;R14.

Zhao W, Thacker S, Hodgin J, Zhang H, Wang J, Park J, Randolph A, Somers E, Pennathur S, Kretzler M, Brosius F, Kaplan MJ. The Peroxisome Proliferator-Activated Receptor-Gamma agonist Pioglitazone improves cardiometabolic risk and renal inflammation in murine lupus. Journal of Immunology 2009 doi:10.4049/jimmunol.0804341 (e-published ahead of print).