Professor of Medicine
756 BRB II/III
421 Curie Boulevard
Philadelphia, PA 19104-6160
Email : firstname.lastname@example.org
746-747 BRB II/III
421 Curie Boulevard
Philadelphia, PA 19104-6160
Vivian Ji, B.S.
Patricia Y. Tsao, MD, Ph.D. (Lab Manager)
Recent Peer Reviewed Publications
1. Garchow BG, Encinas OB, Leung YT, Tsao PY, Eisenberg RA, Caricchio R, Obad S, Petri A, Kauppinen S, Kiriakidou M., Silencing of microR6-21 in vivo ameliorates autoimmune splenomegaly in lupus mice. EMBO Mol Med. 3(10), 605-15, 2011.
2. Meng W, Yunk L, Wang LS, Maganty A, Xue E, Cohen PL, Eisenberg RA, Weigert MG, Mancini SJ, Prak ET. Selection of individual VH genes occurs at the pro-B to pre-B cell transition.
J Immunol. 187(4), 1835-44. 2011. Epub 2011 Jul 11.
3. Tsao PY, Arora V, Ji MQ, Wright AC, Eisenberg RA. KRN/I-Ag7 mouse arthritis is independent of complement C3. J Clin Immunol. 31(5), 857-63. Epub 2011 Jul 6.
4. Hayder M, Poupot M, Baron M, Nigon D, Turrin CO, Caminade AM, Majoral JP, Eisenberg RA, Fourniť JJ, Cantagrel A, Poupot R, Davignon JL. A phosphorus-based dendrimer targets inflammation and osteoclastogenesis in experimental arthritis. Sci Transl Med. 3(81), 2011.
5. Luning Prak ET, Monestier M, Eisenberg RA. B cell receptor editing in tolerance and autoimmunity. Ann N Y Acad Sci. 1217, 96-121. Epub 2011 Jan 5. Review.
Much of the work from our laboratory and others' have demonstrated the key role that B cells play in the pathogenesis of SLE. Not only are B cells responsible for the production of autoantibodies, but they also express the genetic abnormalities that cause the disease; they regulate T cells and other B cells; they secrete cytokines; and they present autoantigens. Removal of B cells from an SLE-mouse strain, either by germ-line genetic manipulation or by treatment with anti-IgM antibodies from birth, suppresses nearly all manifestations of the syndrome. We are now extending these approaches in two major directions:
1. Depletion of B cells from adult mice with active disease. Surprisingly, this is not currently possible in a specific manner. We are developing new approaches with mAb and novel mAb against B-cell markers to create a system in which we can intervene late in the course of disease and deplete all B cells in vivo. Important issues to resolve include the phenotype and lifespan of those cells that are actually producing autoantibodies.
2. Depletion of B cells in humans with SLE. We have initiated a phase I study with Rituxanâ (anti-human CD20, a pan B cell marker) to determine the effect of depleting B cells on SLE. We are beginning to plan a phase II efficacy trial. In conjunction, we are investigating the immunological changes that B-cell depletion causes in these patients, and we are utilizing human/SCID mouse chimeras to model the effectiveness of therapy.
Phillip L. Cohen, MD
Michael A. Maldonado, MD
Daniel A. Albert, MD
1. Fossati L, Sobel ES, Iwamoto M, Cohen PL, Eisenberg RA, and Izui S. The Yaa genemediated acceleration of murine lupus: Yaa- T cells from nonautoimmune mice collaborate with Yaa+ B cells to product lupus autoantibodies in vivo. Eur J Immunology 25:3412-3417, 1995.
2. Retter MW, Eisenberg RA, Cohen PL, and Clark SH. Sm and DNA binding by dual reactive B cells requires distinct VH, V kappa, and VH CDR3 structures. J. Immunol 155(4):2248-57, 1995.
3. Reap EA, Piecyk ML, Oliver A., Sobel ES, Waldschmidt T, Cohen PL, and Eisenberg RA. Phenotypic abnormalities of splenic and bone marrow B cells. Clin Immunol Immunopath 78:21-29, 1996.
4. Retter MW, Cohen PL, Eisenberg RA, and Clarke SH. Both Sm and DNA are Selecting Antigens in the Anti-Sm B Cell Response in Response in Autoimmune MLR/lpr Mice. J Immunology 156:1296-1306, 1996.
5. Kakkanaiah VN, Sobel ES, MacDonald GC, Cheek RL, Cohen PL, and Eisenberg RA. B-Cell Genotype Determine the Fine Specificity of Autoantibody in lpr Mice, J. Immunology, 159:1026-1035, 1997.
6. Eisenberg RA. Mechanisms of Systemic Autoimmunity in Murine Models of SLE. Immunologic Research 17/1&2:41-47, 1998. Sobel ES, Kakkanaiah VN, Schiffenbauer J, Reap EA, Cohen PL, and Eisenberg RA. Novel Immunoregulatory B Cell Pathways Revealed by lpr - + Mixed Chimeras. J Immunology 160:1497-1503, 1998.
The transfer of splenic T cells from one strain of mouse to another that differs only at MHC Class II results in a chronic graft-versus-host reaction which resembles systemic lupus erythematosus, both in its spectrum of autoantibodies and in its immunopathological manifestations. We are studying the specificity of interactions of T cells and B cells and the mechanism of loss of tolerance in this syndrome by utilizing a panel of transgenic and congenic mouse strains. We have shown that the donor T cells interact specifically with the recipient B cells to induce them to produce autoantibodies, and that the MHC Class II recognized on these B cells determines which autoantibodies are made. We have also found a rather surprising role for the recipient T cells, although the mechanism of this requirement is not yet clear. The use of immunoglobulin transgenic mice has demonstrated that the extensive somatic gene rearrangements and mutations of immunoglobulin genes that are engendered by this syndrome and the phenotypic and biochemical changes that accompany this. In future studies, we will determine the differentiative stage at which B cells can lose tolerance and the alterations in gene expression that characterize this ('gene-chip' technology).
Terri M. Laufer, MD
Jan Erikson, Ph.D., the Wistar Institute
Martin Weigert, Ph.D., Princeton University
Terri Finkel, MD, Ph.D., CHOP
1. Eisenberg RA and Cohen PL. Class II major histocompatibility antigens and the etiology of systemic lupus erythematosus. Clin Immunol Immunopathol 29:1-6, 1983.
2. Morris SC, Cheek RL, Cohen PL, and Eisenberg RA. Autoantibodies in chronic GVH result from cognate T-B interactions. J Exp Med 171:503-517, 1990.
3. Morris SC, Cheek RL, Cohen PL, and Eisenberg RA. Allotype-specific immunoregulation of autoantibody production by host B cells in chronic GVH. J Immunol 144:916-922, 1990.
4. Morris SC, Cohen PL, and Eisenberg RA. Experimental induction of systemic lupus erythematosus by recognition of foreign Ia. Clin Immunol Immunopathol 57:263-73, 1990.
5. Bradley DS, Jennette JC, Cohen PL, and Eisenberg RA. Chronic graft versus host disease-associated autoimmune manifestations are independently regulated by different MHC class II loci. J Immunol 152:1960-69, 1994.
6. Chen F, Maldonado MA, Madaio M, and Eisenberg RA. The roles of host (endogenous) T cells in Chronic Graft-versus-Host Autoimmune Disease. J Immunology 161:5880-5885, 1998.
7. Feuerstein N, Chen F, Madaio M, Maldonado M, and Eisenberg RA. Induction of Autoimmunity I a Transgenic Model of B Cell Receptor Peripheral Tolerance: Changes in Coreceptors and B Cell Receptor-Induced Tyrosine-Phosphoproteins. J Immunology 163(10)5287-5297, 1999.
8. Feurstein N, Shivers D, Eisenberg RA, and Finkel TH. Chromic GVH prevents anergy in bone marrow self reactive B cells: A selective increase in post endoplasmic reticulum processing and trafficking of autoreactive IgM recpetors to the cell surface. Submitted for publication.
9. Sekiguchi DR, Jainandunsing SM, Fields ML, Maldonado MA, Madaio MP, Erikson J, Weigert M and Eisenberg RA. Chronic graft-versus-host in immunoglobulin knock-in transgenic mice abrogates B-cell tolerance in anti-double- stranded DNA B cells. J Immunol. In press.
The MRL/lpr mouse strain develops a severe systemic lupus erythematosus-like syndrome that is dependent on the expression of the lpr (mutant Fas receptor) gene as well as undefined background genes in the MRL strain. We are studying the immunoregulation of this syndrome. We have found that the specificity of autoantibodies produced in the MLR/lpr mouse depends on the expression of the MRL background genes in the B cells that actually make the autoantibodies and, perhaps, in the T cells that provide help as well. In addition, studies of germ-free MRL/lpr mice show that there is no effect of the environment on the production of this disease. That is, it is entirely genetically determined. Future studies will look more closely at the role and the specificity of the T cells involved and the mechanism of loss of B cell tolerance.
Phil Cohen, MD
Michael Maldonado, M.D. (Medicine)
1. Mitsuda T, Eisenberg RA, and Cohen PL. The murine Sm-D autoantigen: multiple genes, genetic polymorphism, evolutionary conservation, and lack of intervening sequences in the coding region. J Autoimmunity 5:277-287, 1992.
2. Halpern MD, Fisher CL, Cohen PL, and Eisenberg RA. Influence of the Ig H chain locus on autoantibody production in autoimmune mice. J Immunol 149:3735-3740, 1992.
3. Treadwell EL, Cohen P, Williams D, O'Brien K, Volkman A, and Eisenberg RA. MRL mice produce anti-Su autoantibody, a specific marker for systemic lupus erythematosus. J Immunol 150:695-699, 1993.
4. Bloom DD, Davignon J-L, Retter MW, Shlomchik MJ, Pisetsky DS, Cohen PL, Eisenberg RA, and Clarke SH.V-region analysis of anti-Sm hybridomas from MRL/Mp-lpr/lpr mice. J Immunol 150:1591-1610, 1993.
5. Bloom DD, Davignon J-L, Cohen PL, Eisenberg RA, and Clarke SH. Overlap of the anti-Sm and anti-DNA responses of MRL/Mp-lpr/lpr mice. J Immunol 150:1579-1590, 1993.
6. Cohen PL, Creech E, Nakul-Aquaronne D, McDaniel R, Rapoport RG, Sobel ES, and Eisenberg RA. Antigen nonspecific effect of major histocompatibility complex haplotype on autoantibody levels in systemic lupus erythematosus-prone lpr mice. J Clin Invest 91:2761-2768, 1993.
7. Halpern, MD, Craven SY, Cohen PL, and Eisenberg RA. Regulation of anti-Sm autoantibodies by the immunoglobulin heavy chain locus. J Immunol 151:7268-7272, 1993.
8. Maldonado MA, Kakkanaiah V, MacDonald GC, Chen F, Reap EA, Balish E, Farkas WR, Jennette JC, Madaio MP, Kotzin BL, Cohen PL, and Eisenberg RA. The role of environmental antigens in the spontaneous development of autoimmunity in MRL-lpr mice. J Immunology 162(11):6322-30, 1999.
9. Freed JH, Marrs A, VanderWall , Cohen PL, Eisenberg RA. MHC class II- bound self peptides from autoimmune MRL/1pr mice reveal potential T cell epitopes for autoantibody production in murine systemic lupus erythematosus. J Immunol. 2000 May 1; 164(9): 4697-705.
10. Miwa T, Maldonado MA, Sun X, Luo HY, Cai D, Werth VP, Madaio MP, Eisenberg RA, and Song W-C. Deficiency of decay-accelerating factor (DAF CD55) exacerbates autoimmune disease in MRL/lpr mice. Sumitted for publication.
The Fas/Fas ligand system plays an important role in deleting inappropriate T cells and B cells, particularly the autoreactive ones. Mice that have mutations in one or the other of these genes show marked lymphoproliferative disease and the production of autoantibodies. We are studying the in vivo cellular specificity of the interactions of Fas and Fas ligand in the establishment of tolerance in both T cells and B cells. Evidence so far indicates that the expression of Fas ligand by different subsets of T cells plays distinct roles in immunoregulation.
Michael Maldonado, M.D. (Medicine)
1. Sobel ES, Katagiri T, Katagiri K, Morris SC, Cohen PL, and Eisenberg RA. An intrinsic B-cell defect is required for the production of autoantibodies in the lpr model of murine systemic autoimmunity. J Exp Med 173:1441-1449, 1991.
2. Sobel ES, Cohen PL, and Eisenberg RA. Lpr T cells are necessary for autoantibody production in lpr mice. J Immunol 150:4160-4167, 1993.
3. Sobel ES, Kakkanaiah VN, Cohen PL, and Eisenberg RA. Correction of gld autoimmunity by normal bone marrow suggests gld is mutation of the fas ligand. Inter Immunol 5:1275-1278, 1993.
4. Sobel ES, Kakkanaiah VN, Kakkanaiah M, Cheek RL, Cohen PL, and Eisenberg RA. Collaboration for autoantibody production in lpr mice is cognate and MHC-restricted. J Immunol 152:6011-6016, 1994.
5. Sobel ES, Kakkanaiah VN, Kakkanaiah M, Cohen PL, and Eisenberg RA. Co-infusion of normal bone marrow partially corrects the gld T-cell defect: Evidence for an intrinsic and extrinsic role for Fas ligand. J. Immunol 154:459-464,1995.
6. MacDonald GC, Kakkanaiah VN, Sobel ES, Cohen PL, and Eisenberg RA. In vivo depletion of Thy-1-positive cells originating from normal bone marrow abrogates the suppression of gld disease in normal-gld mixed-bone marrow
7. chimeras. J Immunol 154:444-449,1995.
8. Kakkanaiah VN, MacDonald GC, Cohen PL, and Eisenberg RA. Suppression and reversal of gld disease by parabiosis with normal mice. Clin Immunol Immunopath 78:6-13, 1996.
9. Weintraub JP, Eisenberg RA, and Cohen PL. Upregulation of Fas and the Costimulatory Molecules B7-1 and B7-2 on Peripheral Lymphocytes in Autoimmune B6/gld Mice. J Immunology 159:4117-4126, 1997.
10. Weintraub JP, Godfrey V, Wolthusen PA, Cheek RL, Eisenberg RA, and Cohen PL. Immunological and Pathological Consequences of Mutations in Both Fas and Fas Ligand. Cellular Immunology 186:8-17, 1998
11. Maldonado MA, MacDonald GC, Kakkanaiah VN, Fecho K, Dransfield M, Sekiguchi D, Cohen PL, and Eisenberg RA. Differential Control of Autoantibodies and Lymphoproliferation by Fas Ligand Expression on CD4+ and CD8+ T Cells in Vivo. J Immunology 3139-3142, 1999.