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

makaplan@umich.edu

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.

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.

Our laboratory is also interested in studying the mechanisms by which premature atherosclerosis 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 are now characterizing mechanisms of blood vessel repair in lupus and recently reported that revascularization of damaged vessels is impaired in these patients and that this phenomenon is due to the cytokine interferon-alpha. We are now characterizing how interferon alpha promotes abnormal vasculogenesis and atherosclerosis in SLE.

Other mechanisms that promote end-organ damage, including aberrant neutrophils are a focus of this laboratory.

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, Pfenninger D, Chakrabarti A, Kehrer C, Somers E, Pavlic R, Mukherjee D, Brook R, D'Alecy LG, Kaplan MJ. Increased asymmetric dimethylarginine and endothelin 1 levels in secondary Raynaud's phenomenon. Implications for vascular dysfunction and progression of disease. Arthritis Rheum 2003; 48: 1992-2000.

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

Rajagopalan S, Somers E, Brook R, Kehrer C, Pfenninger D, Lewis E, Chakrabarti A, Richardson BC,Shelden E, McCune WJ, 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. Apoptosis in systemic lupus erythematosus. Clinical Immunology 2004; 112: 210-8.

Denny MF, Chandaroy P, Killen PD, Caricchio R, Lewis EE, Richardson BC, Lee KD, Gavalchin J, Kaplan MJ. Accelerated macrophage apoptosis induces autoantibody formation and organ damage in systemic lupus erythematosus.J Immunol. 2006 Feb 15;176(4):2095-104.

Ding D, Mehta H, McCune WJ and Kaplan MJ. Aberrant myeloid dendritic cell phenotype and function in systemic lupus erythematosus. Journal of Immunology 2006 Nov 1;177(9):5878-89.

Denny MF, Thacker S, Mehta H, Somers EC, Dodick T, Barrat FJ, McCune WJ, Kaplan MJ. Interferon-{alpha} promotes abnormal vasculogenesis in lupus: a potential pathway for premature atherosclerosis. Blood. 2007 Jul 16; [Epub ahead of print]