Ann Marshak-Rothstein, Ph.D.

Professor of Microbiology

B.A.     Washington University
Ph.D.   University of Pennsylvania School of Medicine

lab-pic-2

My laboratory is primarily interested in factors regulating T and B lymphocyte activation, function, longevity, and apoptosis, especially in animal models of systemic autoimmune disease. Particular attention has focused on the kinds of antigen that can activate potentially autoreactive B cells. Previous studies have shown that relatively low affinity autoreactive B cells can be very efficiently activated by autoantigens that have the capacity to engage both the B cell receptor and either Toll-like receptor 9 (TLR9) or TLR7. These antigens include natural chromatin, defined dsDNA fragments, and RNA-associated macromolecular complexes. Studies are underway to: (a) further characterize the nature of the autoantigens that fit this criteria; (b) compare gene expression profiles of B cells activated by either conventional foreign ligands or autoantigens; (c) evaluate the early signaling events that distinguish activation by autoantigens from activation by conventional foreign antigens; (d) compare the functional properties of B cells activated by BCR/TLR9 or BCR/TLR7 co-engagement; and (e) identify specific inhibitors of the TLR9/7 activation pathways.

A second major interest involves the regulatory functions of Fas-ligand. Fas-ligand was originally identified as a pro-apoptotic transmembrane protein critically involved in the regulation of T cells by activation induced cell death. However, under certain conditions, Fas-ligand can also induce a strong pro-inflammatory response. Fas-ligand can be cleaved by a membrane metalloproteinase to yield a soluble product that had been reported to serve as a neutrophil chemokine. However, we have found that transmembrane Fas-ligand is the most potent pro-inflammatory form of the molecule and that it can trigger the rapid expression and release of a number of inflammatory chemokines. Studies are underway to: (a) evaluate the role of Fas/FasL interactions on T cell persistence in vivo; (b) explore the mechanisms by which Fas-deficient tumor specific T cells can mediate tumor regression; (c) develop the technology to specifically target naturally formed FasL microvesicles to tumor populations; (d) distinguish the Fas signaling cascades that trigger apoptosis as opposed to inflammatory cytokine release; and (e) determine the functional phenotype of mice genetically targeted to express only a membrane form of Fas-ligand.
A third topic of investigation involves animal models of pseudo-GVHD in which TCR transgenic T cells are specifically targeted to either MHC class II+ cells or to the vascular endothelium. The model is designed such that target antigen expression can be turned on or off to allow for the evaluation of antigen-dependent and antigen-independent pathologies.

Representative Publications:

  1. Hohlbaum, A. M., S. Moe, and A. Marshak-Rothstein. 2000. Opposing effects of transmembrane and soluble Fas-ligand expression on inflammation and tumor cell survival. J. Exp. Med. 191:1209-19.
  2. Hohlbaum, A.M., M.S. Gregory, S-T. Ju, and A. Marshak-Rothstein. 2001.Fas ligand engagement of resident peritoneal macrophages in vivo induces apoptosis and the production of neutrophil chemotactic factors. J. Immunol. 167:6217-24.
  3. Leadbetter, E.A., I.R. Rifkin, A.M. Hohlbaum, B. Beaudette, M.J. Shlomchik, and A. Marshak-Rothstein. 2002. Chromatin/IgG Complexes Activate B Cells by Dual Engagement of sIgM and Toll-like Receptors. Nature 416:603-607.
  4. Viglianti, G.A., C.M. Lau, T.M. Hanley, B.A. Miko, M.J. Shlomchik, and A. Marshak-Rothstein. 2003. Activation of autoreactive B cells by CpG dsDNA. Immunity. 19:837-47.
  5. Saff, R.R., E.S. Spanjaard, A.M. Hohlbaum, and A. Marshak-Rothstein. 2004. Activation-induced cell death limits effector function of CD4 tumor-specific cells. J. Immunol. 172:6598-606.
  6. Lau, C.M., C. Broughton, A.S. Tabor, S. Akira, R.A. Flavell, M.J. Mamula, S.R. Christensen, M.J. Shlomchik, G.A. Viglianti, I.R. Rifkin, and A.Marshak-Rothstein. 2005. RNA-Associated Autoantigens Activate B Cells by Combined BCR/Toll-like Receptor 7 Engagement. J. Exp. Med. 202:1171-1177.
  7. Beaudette-Zlatanova, B.C., T. Ling, M.J. Shlomchik, A. Marshak-Rothstein, and I.R. Rifkin. 2006. B Cells and Dendritic Cell from V Kappa 8 Light Chain Transgenic Mice Activate MRL-lpr/gld CD4+ T Cells. J. Immunol. 177:45-52.
  8. Marshak-Rothstein, A. 2006. Tolling for Autoimmunity-Prime Time for TLR7. Immunity 25:397-399.
  9. Marshak-Rothstein, A. 2006. Toll-like Receptors in Systemic Autoimmune Disease. Nat. Rev. Immunol. 6:823-835 Review.
  10. Marshak-Rothstein, A. and I.R. Rifkin. 2007. Immunologically Active Autoantigens: The Role of Toll-like Receptors in the Development of Chronic Inflammatory Disease. Annu. Rev. Immunol. 25:419-441.
  11. Tian, J., A.M. Avalos, S.Y. Mao, B. Chen, K. Senthil, H. Wu, P. Parroche, S. Drabic, D. Golenbock, C. Sirois, J. Hua, L.L. An, L. Audoly, G. LaRosa, A. Bierhaus, P. Naworth, A. Marshak-Rothstein, M.K. Crow, K.A. Fitzgerald, E. Latz, P.A. Kiener, and A.J. Coyle. 2007. Toll-like Receptor 9-dependent Activation by DNA-containing Immune Complexes is Mediated by HMGB1 and RAGE. Nat. Immunol. 8:487-496.
  12. Busconi, L, J.W. Bauer, J.R. Tumang, A. Laws, K. Perkins-Mesires, A.S. Tabor, C. Lau, R.B. Corley, T.L. Rothstein, F.E. Lund, T.W. Behrens, and A. Marshak-Rothstein. 2007. Functional outcome of B Cell Activation by Chromatin Immune Complex Engagement of the B cell Receptor and TLR9. J. Immunol. 179:7397-7405.

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Primary teaching affiliate
of BU School of Medicine