Chaim Putterman, M.D.
Chaim Putterman, MD – Summary of Research Program and Goals
Systemic lupus erythematosus (SLE) is a prototypical systemic autoimmune disease, characterized by the presence of numerous autoantibodies and involvement of multiple organ systems. Inflammation of the kidneys, or lupus nephritis, appears in up to 50% of lupus patients during the course of their disease. Despite medical treatment, morbidity and mortality from renal disease are all too common in lupus patients, with reports of 5-year renal survival ranging from 46-95%. Overall increases in the incidence of lupus and in the number of deaths from the disease reported in the United States are additional reasons for significant concern for clinicians and researchers alike. Unfortunately, major strides forward in understanding lupus and the advent of newer “biologic” therapies in the field of Rheumatology have yet to translate into measurable benefits for the majority of patients with SLE. Current treatments, while effective, only control disease activity but are not curative. Furthermore, therapeutic modalities that are employed at this time for the treatment of patients with lupus are non-specific – and commonly affect normal cells that are essential for the defense against foreign pathogens, in addition to suppressing the disease-relevant autoreactive B cells. Nevertheless, early diagnosis and prompt treatment can still significantly improve long-term prognosis.
Anti-double stranded (ds) DNA antibodies are a serologic hallmark of patients with SLE. In recent years it has been increasingly clear that not only are anti-dsDNA antibodies an important diagnostic marker for lupus, but that these autoantibodies are also instrumental in the pathogenesis of lupus nephritis. The mechanisms by which anti-dsDNA antibodies induce renal injury, however, are not completely understood. It has been suggested that anti-dsDNA antibodies bind DNA in the circulation followed by non-specific deposition of these immune complexes in the kidney, or that in-situ immune complexes are formed in the kidney by binding of anti-dsDNA antibodies to nuclear antigens deposited on the glomerular basement membrane. Alternatively, some anti-dsDNA antibodies may cause injury by penetrating into living cells and affecting metabolic pathways. Finally, we and others have generated evidence that strongly suggests that at least some anti-dsDNA antibodies are pathogenic not by virtue of their affinity for DNA, but rather by direct cross-reactivity with renal antigen.
One major long-term goal of the laboratory is to study the renal pathogenicity of anti-dsDNA antibodies. We are determining the cross-reactive kidney antigen bound by anti-DNA antibodies in human lupus and in mouse models of the disease to understand what determines the nephritogenic potential of these antibodies. We made significant progress in defining one renal antigen bound by cross-reactive anti-DNA antibodies. We discovered that a-actinin is a major cross-reactive target for the anti-dsDNA antibody response in murine lupus, and that both human monoclonal and polyclonal anti-dsDNA antibodies bind to a-actinin as well. In current studies, we are investigating if a-actinin can serve not only as a target but also as an antigenic trigger for anti-DNA antibodies, whether anti-a-actinin antibodies are associated with specific disease features (analysis of patient cohorts), and what might be the mechanism by which these antibodies induce damage in kidney cells (proteomic and microarray approaches). Understanding the renal pathogenicity of cross-reactive anti-dsDNA antibodies by identifying the target antigen for these antibodies in the kidney would improve our understanding of a key manifestation of lupus, and would facilitate the development of serological tools to better predict the onset and severity of renal involvement in patients with SLE. Furthermore, identification of the triggering and/or target antigen in lupus will allow us to develop novel approaches to the treatment of lupus, by blocking the effects of anti-DNA antibodies on target organs or by specifically tolerizing pathogenic B cells.
Members of the TNF-superfamily of ligands are centrally involved in normal immune responses, and in the pathogenesis of autoimmune disorders. In a second group of related projects in the laboratory, we are investigating the role of a relatively new member of the TNF superfamily (TWEAK) and its receptor Fn14 in the pathogenesis of lupus, specifically lupus nephritis. We have shown that TWEAK induces a pro-inflammatory profile of cytokines and chemokines in kidney epithelial and mesangial cells, and thus contributes to the influx of inflammatory cells observed in the early stages of lupus nephritis. Modulation of the TWEAK/Fn14 pathway in SLE may be an important target for novel therapies for this disease. Furthermore, we are exploring the role of TWEAK as a biomarker for disease activity in lupus nephritis. Indeed, such as serum or urinary biomarker would have tremendous value for patient care, allowing early and accurate diagnosis and more precise management, without the need for an invasive kidney biopsy.
- Putterman C, Ulmansky R, Rasooly L, Tadmor B, Ben-Bassat H, Naparstek Y. Down-regulation of surface antigens recognized by SLE antibodies on embryonal cells following differentiation and exposure to corticosteroids. Eur J Immunol 28:1656-1662, 1998.
- Putterman C, Diamond B. Immunization with a peptide dsDNA surrogate induces autoantibody production and kidney immunoglobulin deposition. J Exp Med 188:29-38, 1998.
- Putterman C, Deocharan B, Diamond B. Molecular analysis of the autoantibody response in peptide-induced autoimmunity. J Immunol 164:2542-2549, 2000
- Deocharan B, Qing X, Lichauco J, Putterman C. a-Actinin is a cross-reactive target for pathogenic anti-DNA antibodies in renal tissue. J Immunol 168:3072-3078, 2002.
- Beger E, Deocharan B, Edelman M, Erblich B, Gu Y, Putterman C. A peptide DNA surrogate accelerates autoimmune manifestations and nephritis in lupus-prone mice. J Immunol 168:3617-3626, 2002.
- Deocharan B, Marambio P, Edelman M, Putterman C. Differential effects of interleukin-4 in peptide induced autoimmunity. Clin Immunol 108:80-88, 2003.
- Zhao Z, Weinstein E, Tuzova M, Davidson A, Mundel P, Marambio P, Putterman C. Human lupus anti-DNA/anti-a-actinin antibodies bind to mesangial cells and induce renal disease. Arthritis Rheum 52:522-530, 2005.
- Li Q, Xie C, Mackay M, Aranow C, Putterman C, Mohan C. Glomerular proteome assays: A novel approach to study glomerular-reactive autoantibodies in lupus. J Clin Invest 115:3428-3439, 2005.
- Campbell S, Burkly LC, Gao HX, Berman JW, Su L, Browning B, Zheng T, Schiffer L, Michaelson JS, Putterman C. Pro-inflammatory effects of TWEAK/Fn14 interactions in glomerular mesangial cells. J Immunol 176: 1889–1898, 2006.
- Qing X, Zavadil J, Crosby M, Gilkeson G, Bottinger E, Putterman C. Nephritogenic anti-DNA antibodies regulate gene expression in glomerular mesangial cells: A possible mechanism for renal pathogenicity in lupus nephritis. Arthritis Rheum 54:2198-2210, 2006.
- Zhao Z, Deocharan B, Scherrer, PE, Ozelius LJ, Putterman C. Target antigen localization and expression as determinants of the renal pathogenicity of anti-DNA antibodies: The role of a-actinin. J Immunol 176:7704-7714, 2006.
- Schwartz N, Su L, Burkly LC, Mackay M, Aranow C, Kollaros M, Michaelson JS, Putterman C. Urinary TWEAK and the activity of lupus nephritis. J Autoimmunity 27:242-250, 2006.
- Pitashny M, Schwartz N, Qing X, Hojaili B, Aranow C, Mackay M, Putterman C. Urinary Lipocalin-2 as a potential biomarker for human lupus nephritis. Arthritis Rheum 56:1894-1903, 2007.
- Deocharan B, Zhou Z, Antar K, Siconolfi-Baez L, Angeletti RH, Hardin J, Putterman C. a-actinin immunization elicits anti-chromatin autoimmunity in non-autoimmune mice. J Immunol 179: 1313-1321, 2007.
- Zhao Z, Burkly LC, Eisenberg R, Choudhury A, Campbell S, Michaleson JS, Putterman C. Blocking TWEAK/Fn14 interactions improves nephritis in the chronic graft versus host (cGVH) model of SLE. J Immunol 179:7949-7958, 2007.
- Qing X, Pitashny M, Thomas DB, Barrat FJ, Hogarth M, Putterman C. Pathogenic anti-DNA antibodies modulate gene expression in mesangial cells: Involvement of HMGB1 in anti-DNA antibody induced renal injury. Immunology Lett 121:61-73, 2008
- Gao HX, Campbell SR, Burkly LC, Jakubowski A, Jarchum I, Banas B, Saleem M, Mathieson PW, Berman JW, Michaelson JS, Putterman C. TNF-like Weak Inducer of Apoptosis (TWEAK) induces potent inflammatory and proliferative effects in human kidney cells. Cytokine 46:24-35, 2009.
- Gao HX, Campbell SR, Cui MH, Zong P, Hwang JH, Gulinello M, Putterman C. Depression is an early disease manifestation in lupus-prone MRL/lpr mice. J Neuroimmunol 207:45-56, 2009.
- Molano A, Lakhani P, Burkly LC, Michaelson JS, Putterman C. TWEAK stimulation of resident kidney cells in the pathogenesis of graft versus host induced lupus nephritis Immunology Letters 125:119-128, 2009.
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