Research / Clinical Summary

Gregg Silverman, MD Professor IR, Medicine Tumor Growth, Invasion & Metastasis Program Contact by Email Visit the Website

Our research group has been interested in the immunobiologic implications for the usage of particular antibody genes by different sets of B lymphocytes, and understanding how different B cell antigen receptor encounters lead to lymphocyte activation, proliferation or apoptotic deletion.

Of special interest are certain natural microbial toxins that we have demonstrated can act as superantigens affecting large sets of B cells, defined by their antibody variable region gene usage. We have characterized how in vivo encounters with a model B-cell superantigen, staphylococcal protein A, can result in targeted activation induced cell death. We have identified the exact intrinsic pathway of apoptosis and demonstrated the requirement for a single pro-death Bcl-2 family member, Bim.

Parallel studies are in progress to assess similarities and differences for CD20 mediated B cell deletion occurring after therapeutic treatments with rituxan. These studies are relevant to understanding and developing better therapeutic agents for the selective targeting and deletion of malignant B-cell populations in models of lymphoma and leukemia. In other studies we are developing antibody-based therapies to interfere with inflammatory responses from the innate immune system. These agents may have applications in a range of inflammatory diseases, including autoimmune diseases or graft vs. host disease that may develop after bone marrow transplantation.

Selected Publications:
Goodyear CS, Corr M, Sugiyama F, Boyle D, Silverman GJ. Cutting edge: Bim is required for superantigen mediated B-cell death. Cutting edge: J Immunol 2007 178:2636-40.

Silverman GJ. Anti-CD20 therapy and autoimmune disease: therapeutic opportunities and evolving insights.Front Biosci. 2007 12:2194-206.

Silverman GJ. Targeting of B cells in SLE - Rationale and Therapeutic Opportunities. Bull Hosp Jt Dis. 2006 64(1-2):51-6.

Enzler T, Bonizzi G, Silverman GJ, Otero DC, Widhopf GF, Anzelon-Mills A, Rickert RC, Karin M. Alternative and classical NF-kappa B signaling retain autoreactive B cells in the splenic marginal zone and result in lupus-like disease. Immunity. 2006 25(3):403-15.

Silverman GJ. Therapeutic B cell depletion and regeneration in rheumatoid arthritis: emerging patterns and paradigms.Arthritis Rheum. 2006 54(8):2356-67.

Silverman GJ, Goodyear CS. Confounding B-cell defences: lessons from a staphylococcal superantigen. Nat Rev Immunol. 2006 6(6):465-75.

Feral CC, Rose DM, Han J, Fox N, Silverman GJ, Kaushansky K, Ginsberg MH. Blocking the alpha 4 integrin-paxillin interaction selectively impairs mononuclear leukocyte recruitment to an inflammatory site. J Clin Invest. 2006 116(3):715-23.

Goodyear CS, Sugiyama F, Silverman GJ. Temporal and dose-dependent relationships between in vivo B cell receptor-targeted proliferation and deletion-induced by a microbial B cell toxin. J Immunol. 2006 176(4):2262-71.

Silverman GJ. Anti-CD20 therapy in systemic lupus erythematosus: a step closer to the clinic. Arthritis Rheum. 2005 52(2):371-7.

Silverman GJ, Goodyear CS, Siegel DL. On the mechanism of staphylococcal protein A immunomodulation. Transfusion. 2005 45(2):274-80.

Goodyear CS, Silverman GJ. B cell superantigens: a microbe's answer to innate-like B cells and natural antibodies. Springer Semin Immunopathol. 2005 26(4):463-84.

Chang MK, Binder CJ, Miller YI, Subbanagounder G, Silverman GJ, Berliner JA, Witztum JL. Apoptotic cells with oxidation-specific epitopes are immunogenic and proinflammatory. J Exp Med. 2004 200(11):1359-70.

Goodyear CS, and Silverman GJ. Staphylococcal toxin induced preferential and prolonged in vivo deletion of innate-like B lymphocytes. Proc Natl Acad Sci. 2004 101(31): 11392-11397.

Goodyear CS, Narita M, Silverman GJ. In vivo VL targeted apoptotic supra-clonal B-cell deletion by a microbial toxin. Journal of Immunology, 2004 172: 2870-2877.

Shaw PX, Goodyear CS, Chang M-K, Witzum JL, Silverman GJ. The autoreactivity of anti-phosphorylcholine antibodies for apoptotoc cells and atherosclerosis-associated determinants. The Journal of Immunology, 2003 170: 6151-6157.

Binder CJ, Horkko S, Dewan A, Chang MK, Kieu E.P., Goodyear CS, Shaw PX, Palinski W, Witztum JL, Silverman GJ. Pneumococcal vaccination decreases atherosclerotic lesion formation: molecular mimicry between Streptococcus pneumoniae and oxidized LDL. Nature Medicine, 2003 9 (6):736-743.

Goodyear CS and Silverman G.J. : Death by a B-cell superantigen: In vivo VH targeted apoptotic supra-clonal B-cell deletion by a staphylococcal toxin. Journal of Experimental Medicine, 2003 197 (9): 1125-1139.

Silverman GJ, Cary S, Aguilar S, Dwyer D, Luo L, Wagenknecht R, Curtiss VE. A B-cell superantigen induced persistent “hole” in the B-1 repertoire. Journal of Experimental Medicine, 2000 192(1):87-98.