2001 Kidney, Biomarkers
2008 Biomarkers, Human Lupus Biology
2014 Central Nervous System, New Treatments
TWEAK/Fn14 pathway in the pathogenesis & treatment of neuropsychiatric SLE
The study and what it means to patients
We are testing if drugs that block the protein called TWEAK which mediates inflammation in the body can protect against central nervous system problems in lupus.
It is common for patients with lupus to have neuropsychiatric symptoms that result from damage to the central nervous system. However, we do not fully understand how these symptoms develop in lupus. We are zeroing in on an inflammatory mediator called TWEAK that is found in high levels in fluid around the brain and spinal cord in lupus patients with active neuropsychiatric symptoms. We are using mice that develop a lupus-like disease to explore if TWEAK acts on brain cells to promotes the development of neuropsychiatric symptoms. In addition, we will test whether drug inhibitors of TWEAK reduce or prevent neuropsychiatric symptoms in lupus mice.
The TNF-family member cytokine TWEAK has pleotropic effects, including enhancement of the inflammatory milieu and context dependent effects on cell survival and apoptosis. The only confirmed TWEAK receptor, Fn14, is expressed on astrocytes, microglia, endothelial cells, and neurons. Furthermore, TWEAK promotes the release of inflammatory cytokines that are known to play a role in neuropsychiatric SLE (NPSLE). Recently, we found that Fn14 deficient MRL-lpr/lpr lupus prone mice displayed significantly attenuated depressive-like behavior and improved cognition, while human NPSLE is associated with high TWEAK levels in the CSF. We will determine the role of TWEAK/Fn14 signaling in NPSLE and its utility as a biomarker and novel therapeutic target by studying TWEAK and Fn14 expression over time in lupus-prone mice, assessing the potential of TWEAK to replicate NPSLE-like deficits, and determining the efficacy of anti-TWEAK antibodies in treating neurobehavioral abnormalities in MRL-lpr/lpr mice. Furthermore, we will characterize the effects of TWEAK on the blood brain barrier (BBB) by assessing the effect of TWEAK on BBB permeability in brain microvascular endothelial cells in vitro, measuring the effect of TWEAK on the functional and anatomical integrity of the BBB in vivo, and elucidating the mechanism of TWEAK effects on the BBB.
LRI Class of 2008 Consortium Grant with Chandra Mohan, MD, PhD, at the University of Texas, Southwestern, in Dallas.
Lupus nephritis is common in people with lupus, and can cause irreversible kidney damage. The need for biomarkers (“early predictors”) to detect problems and monitor treatment effectiveness is urgent.
Working collaboratively under a consortium grant from the Lupus Research Institute, Drs. Chaim Putterman and Chandra Mohan have been investigating biomarkers to develop non-invasive tests to diagnose and monitor kidney damage from lupus. Their animal study identified four proteins that show up in urine in increasing quantities as kidney damage progresses. Each of these proteins is either present in humans or has a human equivalent. Based on the success in these studies, the researchers currently are studying whether an increase in the levels of these proteins also indicates an increase in disease among lupus patients.
“With LRI funding, we are now conducting tests in humans, using the urine of people with lupus to determine the value of these proteins as biomarkers or indicators of disease severity,” commented Dr. Putterman. “If we can predict flares when patients’ symptoms suddenly worsen and monitor their response to treatment, we can better manage their disease.”
LRI Class of 2001
Dr. Putterman and his team won an LRI grant to unravel the mystery as to why some people with lupus develop kidney disease and others do not.
In work he did previous to the LRI grant, Dr. Putterman found evidence that antibodies that recognize both DNA and kidney-specific antigens could contribute to kidney damage in lupus. The LRI grant was to identify kidney antigens that cross-react with anti-DNA auto-antibodies in lupus.
“Antibodies against DNA are commonly found in the blood of people with lupus. Inflammation of the kidneys, which affects many lupus patients, is believed to result from damage by these antibodies to the specialized kidney cells involved in removing waste materials from the blood. The answers as to why and how the DNA antibodies actually damage the kidney cells have been unclear.
Our work has been focused on identifying the target of the DNA antibodies in the kidney. We are also interested in how subtle differences in the structure or amount of the target in the kidney between individuals may explain why some lupus patients are more susceptible than others to kidney disease. With a grant from the LRI, we have used mouse models that have allowed us to make exciting progress in finding answers to some of these questions. We have also started to extend our initial findings to human lupus.”
Dr. Putterman has found that mice and humans with lupus carry anti-DNA autoantibodies that cross-react with a-actinin, a protein that may be important for kidney function.
“Using a DNA antibody that triggers lupus-like kidney disease in mice, we identified as the target of the antibody a kidney protein called alpha-actinin. Lupus mice had high titers (levels) of antibodies to alpha-actinin in their serum. Furthermore, the kidneys from sick lupus mice were found to have increased amounts of the antibodies that bound alpha-actinin. The finding that alpha-actinin was a possible target for anti-DNA antibodies confirmed previous work by another research team, Eilat and colleagues, who found that anti-DNA antibodies that can damage the kidney also bound to alpha-actinin.
Extending these findings to human lupus, we have found that human DNA antibodies from patients with active disease also bind to alphaactinin, as well as to other, as yet unidentified kidney proteins.
Our current experiments are focused on isolating the additional targets of these damaging antibodies. The results will help us learn more about whether there are inherited differences among people in the genes directing the production of these protein targets, and whether these differences correlate with the risk of kidney damage.”
With the help of two collaborating groups, Dr. Putterman is investigating whether the presence of antibodies to a-actinin is diagnostic of lupus and prognostic of disease severity in people. If subsequent larger clinical studies confirm the usefulness of a-actinin antibodies as a biomarker in lupus diagnosis and prognosis, Putterman plans to register patents for these antibodies as diagnostic tools.
“Our studies, along with those from many other laboratories intensively studying lupus, may be able to answer why individual lupus patients are susceptible to kidney injury. Our LRI-funded research program will hopefully also lead to improved methods of monitoring patients, and open up possibilities for development of new treatments.”
Dr. Putterman has been invited to present his LRI-funded research at national and international conferences.
His research findings also have been published extensively.
In 2010 Dr. Putterman reported: “All members of my group (now 6 scientists—MD and PhD post-docs) are working on lupus research related to my 2001 and 2008 LRI projects.”
Generated by LRI 2001 grant
a-Actinin is a cross-reactive target for pathogenic anti-DNA antibodies in renal tissue. Deocharan B, Qing X, Lichauco J, Putterman C. J Immunol 168:3072-3078, 2002.
a-Actinin: A target for pathogenic anti-DNA antibodies in lupus nephritis? Mason LJ, Ravirajan CT, Putterman C, Isenberg DA. Arthritis Rheum 50:866-870, 2004.
Human lupus anti-DNA/anti-a-actinin antibodies bind to mesangial cells and induce renal disease. Zhao Z, Weinstein E, Tuzova M, Davidson A, Mundel P, Marambio P, Putterman C. Arthritis Rheum 52:522-530, 2005.
Association of α-actinin binding anti-dsDNA antibodies with lupus nephritis. Renaudineau Y, Croquefer S, Jousse S, Devauchelle V, Guéguen P, Hanrotel C, Gilburd B, Renaudineau E, Saraux A, Shoenfeld Y, Putterman C, and Youinou P. Arthritis Rheum 54:2523-2532, 2006.
Target antigen localization and expression as determinants of the renal pathogenicity of anti-DNA antibodies: The role of a-actinin. Zhao Z, Deocharan B, Scherrer, PE, Ozelius LJ, Putterman C. J Immunol 176:7704-7714, 2006.
Generated by LRI 2008 grant
Urine proteome scans uncover total urine protease as a potential marker of lupus nephritis. Wu T, Fu Y, Brekken D, Che C, Oei HB, Zhou XJ, Ahn C, Putterman C, Mohan C. J Immunol 184: 2183-2193, 2010.
Urinary neutrophil gelatinase associated lipocalin (NGAL) as a novel biomarker for disease activity in lupus nephritis. Rubinstein T, Pitashny M, Levine B, Schwartz N, Schwartzman J, Weinstein E, Pego-Regiosa JM, Lu TYT, Isenberg D, Rahman A, Putterman C. Rheumatology (Oxford) 49:960-971 (doi:10.1093/rheumatology/kep468), 2010.
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