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Ann M Rothstein PhD

TitleProfessor
InstitutionUniversity of Massachusetts Medical School
DepartmentMedicine
AddressUniversity of Massachusetts Medical School
364 Plantation Street, LRB
Worcester MA 01605
Phone508-856-8089
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    Other Positions
    InstitutionUMMS - School of Medicine
    DepartmentMedicine
    DivisionRheumatology

    InstitutionUMMS - School of Medicine
    DepartmentMicrobiology and Physiological Systems

    InstitutionUMMS - Graduate School of Biomedical Sciences
    DepartmentImmunology and Virology

    InstitutionUMMS - Graduate School of Biomedical Sciences
    DepartmentMD/PhD Program


    Collapse Biography 
    Collapse education and training
    Washington University, Saint Louis, MO, United StatesBAPhysiology
    University of Pennsylvania Pereleman School of Medicine, Philadelphia, PA, United StatesPHDTechnology
    Collapse awards and honors
    2011Distinguished Lecture, American Assoc Immuologists
    2012Distinguished Innovator, Lupus Research Institute

    Collapse Overview 
    Collapse overview


    Research



    rothsteinMy 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; (e) identify specific inhibitors of the TLR9/7 activation pathways; and (f) explore mechanisms of cross-regulation between cytocolic and endosomal nucleic acids.



    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 triggers of disease and antigen-independent amplification loops.  These studies have led to the identification of a unique profibrotic CD8 T cell subset that is involved in pulmonary fibrosis.



    Collapse Rotation Projects

    Rotation position open to work on topics related to the molecular mechanisms involved in theactivation and differentiation of both murine and human autoreactive Bcells.  The lab is particularlyinterested in innate sensors of cell damage, including members of the Toll-likereceptor and Pyhin receptor gene families.



    Collapse Post Docs

    Postdoctoral Research Associate Position available to work on topics related to the molecular mechanisms involved in theactivation and differentiation of both murine and human autoreactive Bcells.  The lab is particularlyinterested in innate sensors of cell damage, including members of the Toll-likereceptor and Pyhin receptor gene families.




    Collapse Bibliographic 
    Collapse selected publications
    Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
    List All   |   Timeline
    1. Bossaller L, Christ A, Pelka K, Nündel K, Chiang PI, Pang C, Mishra N, Busto P, Bonegio RG, Schmidt RE, Latz E, Marshak-Rothstein A. TLR9 Deficiency Leads to Accelerated Renal Disease and Myeloid Lineage Abnormalities in Pristane-Induced Murine Lupus. J Immunol. 2016 Aug 15; 197(4):1044-53. PMID: 27354219.
      View in: PubMed
    2. Gratz IK, Rosenblum MD, Maurano MM, Paw JS, Truong HA, Marshak-Rothstein A, Abbas AK. Cutting edge: Self-antigen controls the balance between effector and regulatory T cells in peripheral tissues. J Immunol. 2014 Feb 15; 192(4):1351-5. PMID: 24442443.
      View in: PubMed
    3. Bossaller L, Rathinam VA, Bonegio R, Chiang PI, Busto P, Wespiser AR, Caffrey DR, Li QZ, Mohan C, Fitzgerald KA, Latz E, Marshak-Rothstein A. Overexpression of membrane-bound fas ligand (CD95L) exacerbates autoimmune disease and renal pathology in pristane-induced lupus. J Immunol. 2013 Sep 1; 191(5):2104-14. PMID: 23918976.
      View in: PubMed
    4. Nündel K, Busto P, Debatis M, Marshak-Rothstein A. The role of Bruton's tyrosine kinase in the development and BCR/TLR-dependent activation of AM14 rheumatoid factor B cells. J Leukoc Biol. 2013 Nov; 94(5):865-75. PMID: 23804807.
      View in: PubMed
    5. Bossaller L, Chiang PI, Schmidt-Lauber C, Ganesan S, Kaiser WJ, Rathinam VA, Mocarski ES, Subramanian D, Green DR, Silverman N, Fitzgerald KA, Marshak-Rothstein A, Latz E. Cutting edge: FAS (CD95) mediates noncanonical IL-1ß and IL-18 maturation via caspase-8 in an RIP3-independent manner. J Immunol. 2012 Dec 15; 189(12):5508-12. PMID: 23144495.
      View in: PubMed
    6. Rosenblum MD, Gratz IK, Paw JS, Lee K, Marshak-Rothstein A, Abbas AK. Response to self antigen imprints regulatory memory in tissues. Nature. 2011 Nov 27; 480(7378):538-42. PMID: 22121024.
      View in: PubMed
    7. Green NM, Marshak-Rothstein A. Toll-like receptor driven B cell activation in the induction of systemic autoimmunity. Semin Immunol. 2011 Apr; 23(2):106-12. PMID: 21306913.
      View in: PubMed
    8. Gregory MS, Hackett CG, Abernathy EF, Lee KS, Saff RR, Hohlbaum AM, Moody KS, Hobson MW, Jones A, Kolovou P, Karray S, Giani A, John SW, Chen DF, Marshak-Rothstein A, Ksander BR. Opposing roles for membrane bound and soluble Fas ligand in glaucoma-associated retinal ganglion cell death. PLoS One. 2011 Mar 29; 6(3):e17659. PMID: 21479271.
      View in: PubMed
    9. Avalos AM, Uccellini MB, Lenert P, Viglianti GA, Marshak-Rothstein A. Fc?RIIB regulation of BCR/TLR-dependent autoreactive B-cell responses. Eur J Immunol. 2010 Oct; 40(10):2692-8. PMID: 20809520.
      View in: PubMed
    10. Avalos AM, Kiefer K, Tian J, Christensen S, Shlomchik M, Coyle AJ, Marshak-Rothstein A. RAGE-independent autoreactive B cell activation in response to chromatin and HMGB1/DNA immune complexes. Autoimmunity. 2010 Feb; 43(1):103-10. PMID: 20014975.
      View in: PubMed
    11. Green NM, Laws A, Kiefer K, Busconi L, Kim YM, Brinkmann MM, Trail EH, Yasuda K, Christensen SR, Shlomchik MJ, Vogel S, Connor JH, Ploegh H, Eilat D, Rifkin IR, van Seventer JM, Marshak-Rothstein A. Murine B cell response to TLR7 ligands depends on an IFN-beta feedback loop. J Immunol. 2009 Aug 1; 183(3):1569-76. PMID: 19587008.
      View in: PubMed
    12. Uccellini MB, Avalos AM, Marshak-Rothstein A, Viglianti GA. Toll-like receptor-dependent immune complex activation of B cells and dendritic cells. Methods Mol Biol. 2009; 517:363-80. PMID: 19378022.
      View in: PubMed
    13. Busconi L, Bauer JW, Tumang JR, Laws A, Perkins-Mesires K, Tabor AS, Lau C, Corley RB, Rothstein TL, Lund FE, Behrens TW, Marshak-Rothstein A. Functional outcome of B cell activation by chromatin immune complex engagement of the B cell receptor and TLR9. J Immunol. 2007 Dec 1; 179(11):7397-405. PMID: 18025183.
      View in: PubMed
    14. Marshak-Rothstein A, Rifkin IR. Immunologically active autoantigens: the role of toll-like receptors in the development of chronic inflammatory disease. Annu Rev Immunol. 2007; 25:419-41. PMID: 17378763.
      View in: PubMed
    15. Marshak-Rothstein A. Toll-like receptors in systemic autoimmune disease. Nat Rev Immunol. 2006 Nov; 6(11):823-35. PMID: 17063184.
      View in: PubMed
    16. Lau CM, Broughton C, Tabor AS, Akira S, Flavell RA, Mamula MJ, Christensen SR, Shlomchik MJ, Viglianti GA, Rifkin IR, Marshak-Rothstein A. RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement. J Exp Med. 2005 Nov 7; 202(9):1171-7. PMID: 16260486.
      View in: PubMed
    17. Saff RR, Spanjaard ES, Hohlbaum AM, Marshak-Rothstein A. Activation-induced cell death limits effector function of CD4 tumor-specific T cells. J Immunol. 2004 Jun 1; 172(11):6598-606. PMID: 15153474.
      View in: PubMed
    18. Leadbetter EA, Rifkin IR, Hohlbaum AM, Beaudette BC, Shlomchik MJ, Marshak-Rothstein A. Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature. 2002 Apr 11; 416(6881):603-7. PMID: 11948342.
      View in: PubMed
    19. Hohlbaum AM, Moe S, Marshak-Rothstein A. Opposing effects of transmembrane and soluble Fas ligand expression on inflammation and tumor cell survival. J Exp Med. 2000 Apr 3; 191(7):1209-20. PMID: 10748238.
      View in: PubMed
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