Silva Markovic-Plese, M.D.

markovics@neurology.unc.edu 6109D Neuroscience Research Building Campus Box 7125 Chapel Hill, NC 27599-7025 919.966.5547/3701

Research

My research interests focus on molecular events involved in the initiation of autoimmune response in multiple sclerosis (MS) and mechanisms of action of immunomodulatory and neuroprotective therapies for this disabling disease.

Following our report on increased frequency of activated myelin-reactive T-cells in the peripheral blood and cerebrospinal fluid of MS patients, we continue to study activation requirements for T-cell subsets in the relapsing remitting (RR) MS. We have detected an unexpectedly high degree of T-cell receptor (TCR) degeneracy and molecular mimicry as a frequent phenomenon that may play a role in the initiation of autoimmune response in MS. Current project in the laboratory identified in a systematic fashion (using combinatorial peptide libraries) a range of stimulatory antigens for autoreactive CD4+ cells that are cross-reactive with viral antigens in MS. More recent studies are focusing on how ubiquitous viral infections modulate the antigen-presenting capacity of dendritic cells and central nervous system microglia via toll like receptor (TLR) signaling.

Studies of costimulatory requirements for autoreactive T-cell activation are another area of interest in our laboratory. We have identified a subset of autoreactive CD4+ cells that are CD28-costimulation independent, and undergo facilitated activation in the absence of this costimulatory signal. We are expanding our studies to involve alternative costimulatory pathways, including members of the TNF-R (CD30, CD40, 4-1BB, CD27, OX40) and TNF families (CD30L, CD40L, 4-1BBL, CD70 and OX40L). These studies will characterize dysregulation of costimulatory pathways affecting T-cell activation, differentiation, and long-term survival in autoimmune disease.

Our laboratory also studies mechanisms of anti-inflammatory and neuroprotective effects of statins. We have demonstrated dose-dependent proliferation inhibition, decrease in inducible MHC class II expression, decreased T-cell activation markers expression, and Th1 cytokine production. These multiple effects are likely mediated by the inhibition of isoprenoid synthesis that prevents posttranslational modification of multiple proteins involved in cell activation and TCR signaling.

Multiple Phase I-III clinical trails testing new immunomodulatory therapies are presently conducted at UNC MS Research Center. The investigator-initiated clinical trial measuring therapeutic effect of IFN beta in combination with atorvastatin involves a comprehensive gene expression analysis. Candidate genes involved in the anitinflammatory effects of statins are identified and further characterization of their effect is currently underway.

Publications

Zhang X, Tao Y, Troiani L, Markovic-Plese S (2011). Simvastatin Inhibits IFN Regulatory Factor 4 Expression and Th17 Cell Differentiation in CD4+ T Cells Derived from Patients with Multiple Sclerosis.
J Immunol. 187(6):3431-7.

Sha Y, Markovic-Plese S (2011). A role of IL-1R1 signaling in the differentiation of Th17 cells and the development of autoimmune diseases. Self Nonself. 2(1):35-42.

Meeker RB, Poulton W, Markovic-Plese S, Hall C, Robertson K (2011). Protein changes in CSF of HIV-infected patients: evidence for loss of neuroprotection. J Neurovirol. 17(3):258-73.

Ramgolam VS, Sha Y, Marcus KL, Choudhary N, Troiani L, Chopra M, Markovic-Plese S (2011). B cells as a therapeutic target for IFN-β in relapsing-remitting multiple sclerosis. J Immunol. 186(7):4518-26.

Ramgolam VS, DeGregorio SD, Rao GK, Collinge M, Subaran SS, Markovic-Plese S, Pardi R, Bender JR (2010). T cell LFA-1 engagement induces HuR-dependent cytokine mRNA stabilization through a Vav-1, Rac1/2, p38MAPK and MKK3 signaling cascade. PLoS One. 5(12):e14450.

Buie LK, Rasmussen CA, Porterfield EC, Ramgolam VS, Choi VW, Markovic-Plese S, Samulski RJ, Kaufman PL, Borrás T (2010). Self-complementary AAV virus (scAAV) safe and long-term gene transfer in the trabecular meshwork of living rats and monkeys. Invest Ophthalmol Vis Sci. 51(1):236-48.

Ramgolam VS, Sha Y, Jin J, Zhang X, Markovic-Plese S (2009). IFN-beta inhibits human Th17 cell differentiation. J Immunol. 183(8):5418-27.

Markovic-Plese S (2009). Degenerate T-cell receptor recognition, autoreactive cells, and the autoimmune response in multiple sclerosis. Neuroscientist. 15(3):225-31.

Zhang X, Jin J, Tang Y, Speer D, Sujkowska D, Markovic-Plese S (2009). IFN-beta1a inhibits the secretion of Th17-polarizing cytokines in human dendritic cells via TLR7 up-regulation. J Immunol. 182(6):3928-36.

Montes M, Zhang X, Berthelot L, Laplaud DA, Brouard S, Jin J, Rogan S, Armao D, Jewells V, Soulillou JP, Markovic-Plese S (2009). Oligoclonal myelin-reactive T-cell infiltrates derived from multiple sclerosis lesions are enriched in Th17 cells. Clin Immunol. 130(2):133-44.

Lindzen E, Jewells V, Bouldin T, Speer D, Royal W 3rd, Markovic-Plese S (2008). Progressive tumefactive inflammatory central nervous system demyelinating disease in an acquired immunodeficiency syndrome patient treated with highly active antiretroviral therapy. J Neurovirol. 14(6):569-73.

Zhang X, Jin J, Peng X, Ramgolam VS, Markovic-Plese S (2008). Simvastatin inhibits IL-17 secretion by targeting multiple IL-17-regulatory cytokines and by inhibiting the expression of IL-17 transcription factor RORC in CD4+ lymphocytes. J Immunol. 180(10):6988-96.

Zhang X, Tang Y, Sujkowska D, Wang J, Ramgolam V, Sospedra M, Adams J, Martin R, Pinilla C, Markovic-Plese S (2008). Degenerate TCR recognition and dual DR2 restriction of autoreactive T cells: implications for the initiation of the autoimmune response in multiple sclerosis. Eur J Immunol. 38(5):1297-309.

Markovic-Plese S, Singh AK, Singh I (2008). Therapeutic potential of statins in multiple sclerosis: immune modulation, neuroprotection and neurorepair. Future Neurol. 3(2):153.

Peng X, Jin J, Giri S, Montes M, Sujkowski D, Tang Y, Smrtka J, Vollmer T, Singh I, Markovic-Plese S (2006). Immunomodulatory effects of 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitors, potential therapy for relapsing remitting multiple sclerosis. J Neuroimmunol. 178(1-2):130-9

Markovic-Plese S, Hemmer B, Zhao Y, Simon R, Pinilla C, Martin R (2005). High level of cross-reactivity in influenza virus hemagglutinin-specific CD4+ T-cell response: implications for the initiation of autoimmune response in multiple sclerosis. J Neuroimmunol. 169(1-2):31-8.

Lindzen E, Gilani A, Markovic-Plese S, Mann D (2005). Acute disseminated encephalomyelitis after liver transplantation. Arch Neurol. 62(4):650-2.

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Affiliations

Department of Neurology
Department of Microbiology and Immunology
Neuroscience Center