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Leading the way to a cure

2013 TIL Grants

Target Identification in Lupus Grantees

Under our Target Identification in Lupus (TIL) grant program, investigators leverage a two-year, up-to-$400,000 award to remove the barriers to new treatments and a possible cure. All research funded under the TIL program is based on realizable goals for translation into therapeutic discovery programs — that is, research that can move quickly from the laboratory to the patient’s bedside. Researchers also have the opportunity to apply through a non-competitive progress report for a third year of funding for up-to-$200,000.

Betsy Barnes, PhD

UMDNJ-New Jersey Medical School<< view more >>
Targeting IRF5 activation for the treatment of lupus

While we still don’t understand all the underlying causes of lupus, we do know that it tends to run in families, suggesting a strong genetic component. Indeed, researchers have already identified several genes associated with the disease. One such gene encodes for the transcription factor interferon regulatory factor 5 (IRF5), which helps control the expression of several inflammatory molecules that contribute to the disease.

Dr. Barnes and her team found that people with lupus have significantly higher levels of IRF5 expressed in primary immune cells than healthy people, and that this higher expression is associated with known changes in the IRF5 gene that are linked to lupus risk. In addition, recent data suggests that IRF5 is continually activated in the blood cells of people with lupus but not in those without the disease.

With their ALR grant, the researchers plan to modify the activation status of IRF5 in the immune cells of lupus patients, thus altering the ability of IRF5 to trigger inflammatory responses that likely contribute to the disease.

What this study means for people with lupus: Results from these studies will not only contribute to a greater understanding of the actions of IRF5, but could aid in the development of new treatments that target the protein to prevent lupus and its symptoms.

Joseph Craft, MD

Yale University<< view more >>
Follicular Helper T Cells in SLE: Characterization and Therapeutic Targets

Patients with lupus develop autoantibodies (also called antinuclear antibodies, or ANA) that cause tissue inflammation in organs such as the kidneys. These autoantibodies are made by B lymphocytes. In order to produce the autoantibodies, however, B cells require help from other lymphocytes called T cells. The ongoing T cell/B cell interaction in the spleen, lymph nodes, and tonsils are critical for autoantibody production in lupus.

With their ALR grant, Dr. Craft and his team will begin to dissect the signals that permit such interactions and identify characteristics of these abnormally activated T cells in people with lupus They also plan to see if potential treatments now in clinical trials affect T cells that help B cells make autoantibodies.

What this study means for people with lupus: The goal of this work is to identify existing and new therapeutic targets for people with lupus.

Rujuan Dai, PhD

Virginia Polytechnic Institute and State University<< view more >>
Targeting the miR-182-96-183 Cluster to Ameliorate Lupus

The hallmark of lupus is the breakdown of tight immune regulation, leading to the production of large amounts of autoantibodies against "self." This results in the chronic inflammation that eventually damages multiple organs, including skin, joints, blood vessels, and kidneys. Due to the complexity of Lupus, the precise cause remains an enigma, with no cure. Thus, there is a pressing need for a new approach to understand and treat the disease.

Dr. Dai's project will examine the role of newly discovered microRNAs (miRNAs) in the development and treatment of lupus. These molecules have emerged as key to governing immune regulation. Disruption of miRNA development or function in immune cells leads to immune tolerance breakdown and autoimmunity in mice.

Dr. Dai and her group recently reported increased production of one cluster of miRNA molecules (miR-182-96-183) in 3 mouse lupus models. Importantly, this cluster targets genes that play critical roles in controlling immune function and preventing autoimmune dysfunction.

With their grant, the group will test the central hypothesis that the miR-182-96-183 cluster contributes to the development of autoimmune diseases like lupus, possibly by regulating FOXO gene expression, and that preventing or reducing production of these miRNA molecules could, in turn, reduce or prevent lupus-related inflammation and symptoms. In addition, they will develop transgenic mice that overproduce this miRNA cluster in immune cells so they can continue to investigate its underlying role in autoimmune diseases.

What this study means for people with lupus: This study will not only provide important insights into the contribution of miRNA to the underlying development of lupus, but the information it generates may eventually lead to the development of innovative miRNA-based therapeutic strategy for lupus treatment and/or prevention.

Syamal Datta, MBBS

Northwestern University<< view more >>
Peptide Vaccine Suppressing Autoantigen-Specific Response in Human Lupus

The cells and molecules, also called antibodies, of the immune system fight foreign organisms. Sometimes, however, these defenses can react against the body itself. Normally, this self-reactivity is kept in check by special regulatory T cells called Treg. In autoimmune diseases like lupus, however, such regulatory cells are lacking, leading to abnormal reactivity against cell components such as DNA and histone proteins that bind to DNA (nuclear autoantigens).

Dr. Datta and his team found that replacing diseased immune system cells with stem cells that can grow healthy immune system cells creates a new source of Treg cells to repair the deficiency. It also helps maintain patients in true immunological remission. The Treg cells generated after stem cell transplantation are potent in reducing the risk of relapse and other complications from the disease and the ongoing medical treatments. They are not found in patients who achieve apparent remission via conventional drug treatments.

However, stem cell therapy is a drastic measure with significant risks that should only be tried in those in whom nothing else works. To avoid such a risky procedure, Dr. Datta and his team have developed a natural, nontoxic vaccine therapy using certain peptides or small bits of proteins that generate similar Treg cells and cause immunologic remission of the disease in lupus-prone mice.

With this grant, Dr. Datta's group will use the peptides to induce similar, autoantigen-specific regulatory T cells in peripheral blood of lupus patients in cell cultures. They also plan to identify genes and protein expression profiles of the potent Treg cells to identify unique surface markers and define the mechanisms and molecular pathways involved in their generation, maintenance and regulatory activity in humans.

What this study means for people with lupus: The ability to compare genes and proteins expressed by Treg cells before and after a stem cell transplant offers a unique opportunity to understand these remission-inducing suppressor cells and address new issues critical for developing immune-regulating therapies for people with lupus. Results from this study would ultimately be able to be used to screen the best therapeutic peptide for maintaining lupus patients in true remission by inducing autoantigen-specific Treg cells, or by infusing Treg cells created in culture.

Anne Davidson, MBBS

The Feinstein Institute for Medical Research<< view more >>
Inhibition of interleukin trans-signaling in SLE

The protein interleukin-6 (IL-6) plays an important role the immune system and has been implicated in certain inflammatory cascades present in lupus. In an inflammatory cascade, one step in the inflammatory process triggers the next, with a cumulative effect. It would be beneficial if there were a way to reduce or eliminate interleukin -6's ability to cause harm in people with lupus.

There are two different ways interleukin -6 affects the cells of the human body. In classic interleukin -6 signaling, interleukin -6 binds to a receptor appearing on cells and then interleukin -6, its receptor, and a co-receptor, gp130 produce a signal inside the affected cell. The second way interleukin -6 affects the cells of the human body is called "interleukin -6 trans-signaling": here, interleukin -6 binds to a soluble form of its receptor and then with gp130 produces a signal inside a cell. While classic interleukin -6 signaling affects only a few of the cell types in the human body, interleukin -6 trans-signaling affects a much broader range of cells and, thus, contributes in very major ways to the development and persistence of disease.

Previously, therapies directed against interleukin -6 have shown benefit in some people with lupus, but have been accompanied by intolerable side effects. What if the targeting could be more specific? Focusing on interleukin -6 trans-signaling has already been shown to be effective in mouse models of other autoimmune diseases.

What this study means for people with lupus: Dr. Davidson will use a form of gp130 in a murine lupus model to look at the effects of targeting interleukin -6 trans-signaling on a range of lupus symptoms and on inflammation and kidney injury. The medication that might be used for this lupus therapy is already being developed for the treatment of other diseases. The success of these mouse studies might lead with little delay to this approach being studied in people with lupus.

Laurie Sue Davis, PhD

UT Southwestern Medical Center<< view more >>
TREM-1 in lupus nephritis

Two proteins appear to be influential in lupus-related kidney disease (lupus nephritis): TREM-1 and TREM-2. In lupus kidney disease, TREM-1 may encourage inflammation while TREM-2 may suppresses components of inflammation and thereby calm the inflammatory response. TREM-1 is over expressed in other autoimmune diseases.

Dr. Davis has previously shown elevated levels of a soluble form of TREM-1 (sTREM-1) in the blood of and biopsies taken from people with lupus kidney disease; and that that in a mouse model of lupus, blocking TREM-1 improved kidney inflammation.

In the current research, first, the expression of TREM-1 and TREM-2 in lupus will be compared with their expression in other types of kidney diseases and in people with no disease. Second, biopsy specimens will be used to profile how TREM-1 and TREM-2 are expressed differently in lupus and in other kidney diseases. Third, the researchers will investigate whether inhibiting TREM-1 activity reduce kidney disease in two different mouse models of lupus.

What this study means for people with lupus: Dr. Davis's two major long-term goals are, firstly to determine whether the soluble forms of TREM-1 and TREM-2 (sTREM-1 and sTREM-2) might provide a way of forecasting or predicting how lupus kidney disease may develop in individual people diagnosed with lupus. And secondly, can medicines inhibiting TREM-1 successfully prevent end stage renal disease in people with lupus.

Michael Denny, PhD

Temple University<< view more >>
Abnormal Neutrophil Development in SLE

We know that several parts of the immune system are involved in lupus. Dr. Denny and his team focus on the development and alteration of immune cells called neutrophils. These white blood cells are the most prevalent of all immune system cells and are crucial for responding to bacteria and fungi.

Dr. Denny and his team have identified an abnormal pool of neutrophils in people with lupus. They also developed a way to very quickly isolate these cells from blood samples for study. With this grant, they will try to understand whether these abnormal neutrophils arise from an alteration in cell development. In particular, they will look at the genetic level of the cell to identify alterations in genes that are critical for the proper development and maturation of neutrophils. Identifying the underlying mechanism responsible for the abnormalities is the first step in controlling the neutrophils involvement in disease or, possibly, eliminating them all together.

What this study means for people with lupus: Identifying the genetic causes of these neutrophil alterations could open the door to new therapies.

Betty Diamond, MD

The Feinstein Institute for Medical Research<< view more >>
Dendritic cell dysfunction as a path to SLE

Dendritic cells trigger reactions in the immune system. Dr. Diamond and her team previously showed that deleting a specific gene in dendritic cells leads to the development of lupus in animal models. With this grant, they will explore exactly how these abnormal dendritic cells change the response of immune system cells and cause lupus. This is particularly important research because the gene they’re examining has already been identified as one that increases risk of lupus.

What this study means for people with lupus: These studies will provide important new insights into how lupus develops and progresses, providing valuable information that could be used to develop new treatments or even identify ways to prevent the disease in high-risk individuals.

Shu Man Fu, MD, PhD

University of Virginia<< view more >>
Progressions and Biomarkers of Proliferative Lupus Nephritis

The majority of people with lupus will eventually develop kidney problems as the disease attacks the kidneys and its blood supply. Called "proliferative lupus nephritis," the condition often leads to end-stage renal disease that requires either chronic dialysis or kidney transplantation, both of which have a significant impact on the quality of life.

Dr. Fu's laboratory has identified three stages of lupus nephritis, acute, transitional, and chronic glomerulonephritis (GN), in an animal model. They also found that the gene expression of affected kidney cells is different and distinct for each stage. With their ALR grant, they want to confirm their findings and use laser capture microdissection techniques and gene array analyses to biopsy kidney specimens from lupus patients with proliferative GN. Then they can determine if the genetic changes they saw in the animal model can be applied to humans. They also want to see if the resulting proteins from these genetic aberrations appear as potential biomarkers in the urine, where they could be used to more accurately and easily stage the disease.

What this study means for people with lupus: Lupus nephritis is not only difficult to treat, it is also difficult to diagnose and track, requiring a kidney biopsy to identify the stage of the disease. Finding biomarkers that could be used to track the progression of the disease would not only help with its management, but is important in designing clinical trials for new drug development.

Michael Holers, MD

University of Colorado Denver, AMC and DC<< view more >>
The CR2:C3d receptor: ligand interaction as a therapeutic target in lupus

Two components of the immune system are CR2 and C3d. CR2 is a receptor of a type of white blood cell, lymphocytes. C3d is capable of binding to germs and other things the human body may attack. In a healthy person, CR2 and C3d are part of the apparatus through which the body creates antibodies. After C3d binds to germs, it attaches to CR2. Excessive activity of CR2 and C3d lead to the creation of antibodies harmful to people with lupus.

Recently, the Holers' lab has been able to develop a strategy and the tools that will allow the testing of novel inhibitors of both CR2 and C3d. These tools are monoclonal antibodies, one of which zeros in on CR2 and blocks its functioning, without directly affecting other closely related receptor interactions. The second tool is a monoclonal antibody that zeros in on the C3d fragment and blocks the interaction of C3d with CR2 and does so without affecting any other function of C3. C3d is a tiny fragment of C3.

Once these tools are in place, the researchers will use a mouse model of lupus to test the scientific hypothesis that disruption of the attachment of C3d and CR2 will reduce the way the mouse's germ fighting system attacks the mouse's own tissues, causing disease.

What this study means for people with lupus: Dr. Holers hopes the current research will lead to new, effective therapies that target the CR2-C3d interaction. It is hoped that the approach will permit limiting or eliminating the amplifying effect of the CR2-C3d interaction.

Caroline Jefferies, PhD

Royal College of Surgeons in Ireland<< view more >>
Ro52 and Siglec-E as therapeutic targets in SLE

Among the various immune system abnormalities that underlie lupus are proteins called interferons that immune system cells normally release during viral infection. However, in people with lupus, these interferons are released at other times, leading to abnormally high levels. They not only trigger inflammation, but are also involved in activating the immune system to produce autoantibodies that drive the pathology of this disease.

Thus, strategies that reduce interferon levels could also reduce lupus symptoms and slow or even halt the progression of the disease, possibly restoring the immune system to normal. Dr. Jefferies' lab focuses on identifying just such strategies. So far, they have found two molecules called Ro52 and Siglec-E, that stem the production of interferon.

With their ALR grant, they will see if activating these proteins can reduce lupus symptoms.

What this study means for people with lupus: This work could ultimately lead to the development of SLE treatments that target the Ro52 and Siglec-E molecules.

Mariana Kaplan, MD

University of Michigan<< view more >>
Lupus and the Inflammasome

People with lupus develop blood vessel damage that increases their risk of early heart attacks. This blood vessel damage is also thought to contribute to the severity of the kidney disease that occurs later in the disease. Dr. Kaplan's team has suggested that one mechanism leading to this accelerated blood vessel disease is related to an imbalance between cells that damage and those that repair the lining, or vasculature, of blood vessels. The researchers have previously reported that a molecule called interferon (IFN) alpha plays a crucial role in this process, promoting premature atherosclerosis and kidney damage progression.

They recently found that IFN-alpha suppresses a molecule called interleukin-1 (IL-1) beta and increases levels of another called IL-18. Both play a role in inflammatory processes. IFNalpha also activates the machinery that processes these two cytokines, called the inflammasome.

With their grant, Dr. Kaplan and her team will use human and animal systems to better understand how IFN-alpha interacts with the inflammasome machinery, triggering blood vessel damage. They will focus on a specific inflammasome component, caspase-1, exploring how IFN-alpha alters its role to impair blood vessel function and repair.

They will also investigate how IFN-alpha reduces production of IL-1 beta and the impact this has on blood vessel function in lupus cells.

What this study means for people with lupus: Identifying the inflammasome as an important mechanism of organ damage and blood vessel abnormalities in SLE could lead to the development of new therapies to prevent the devastating complications of the disease.

Michael Karin, PhD

The University of California, San Diego<< view more >>
New targets for treatment of glucocorticoid-resistant Lupus

Despite the introduction of newer medicines, glucocorticoids and other immunosuppressive drugs continue to be needed to treat lupus, especially lupus flares. Glucocorticoids interfere with activation of transcription factors required for production of type I interferons and induce death (through apoptosis) of plasmacytoid dendritic cells (involved in the production of these interferons) and other immune cells, including B lymphocytes. The high doses of glucocorticoid therapy that are usually needed to achieve this goal, can cause severe side-effects and that together with development of resistance to the medicine, limit its effectiveness.

Nucleic acid-containing immune complexes bind toll-like receptors 7 and 9, and the activation of these receptors appears to interfere with glucocorticoid-mediated inhibition of interferon-alpha production and apoptosis of plasmacytoid dendritic cells. So, inhibitors of toll-like receptors 7 and 9 might increase the efficacy of low-dose glucocorticoid treatment.

Dr. Karin and his team propose to investigate two signaling molecules through which engagement of TLR7/9 leads to induction of type I interferons, both in plasmacytoid dendritic cells and conventional dendritic cells. This process also appears to protect these cells from glucocorticoid-induced death, thereby interfering with the effectiveness of glucocorticoid therapy. The investigation will focus especially on IKKalpha and TRAF3, which play key roles in toll-like receptor 7 and 9-mediated induction of type I interferons.

What this study means for people with lupus: : If inhibition of either IKKalpha and/or TRAF3 interferes with type I interferon production in toll-like receptor 7 and 9-activated mouse and human dendritic cells, and affects the development of lupus-like disease in mice, then drugs that inhibit the activity of either molecule can be used to improve the effectiveness of glucocorticoid therapy. Such inhibitors may also be useful on their own.

Vicki Kelley, PhD

Brigham and Women's Hospital<< view more >>
Distinguishing CSF-1 and IL-34 As Therapeutic Targets for Lupus Nephritis

Kidney failure is a primary cause of disease and mortality in people with lupus. Macrophages, immune system cells that release inflammatory molecules, are major contributors to kidney disease. Dr. Kelley and her team discovered that a molecule critical in the development of macrophages and expressed by macrophages, called CSF-1, could be a good target for treatment. Using a mouse model of lupus nephritis, they found if they deleted CSF-1, they prevented lupus nephritis, while increasing its presence hastened nephritis.

CSF-1 also exists in humans, with higher levels in the kidney, blood, and urine correlating with greater kidney damage and disease activity. In addition, their preliminary data suggests that high levels of CSF-1 in the urine and blood may be a harbinger of lupus nephritis even before clinical signs of damage occur. Detection of CSF-1 could lead to earlier treatment, avoiding kidney damage altogether.

Recently, IL-34, a second molecule that binds to the CSF-1 receptor was discovered. Although IL-34 resembles CSF-1, they are not identical. However, Dr. Kelley’s work indicates that both are more prevalent in the kidney, blood and urine in a mouse model of lupus nephritis.

With this grant, Dr. Kelley and her group hope to better understand the role of CSF-1 and IL-34, particularly their different and shared roles in the development of lupus nephritis. Their goal is to determine if these molecules are distinct therapeutic targets and biomarkers for predicting and tracking lupus nephritis in patients.

What this study means for people with lupus: Pharmaceutical companies have already developed compounds to block CSF-1 and its related molecules, with clinical trials expected to begin soon. Dr. Kelley's studies could provide important information for the development and use of such drugs as they offer the promise of producing new treatments for lupus nephritis. This could lead to earlier treatment, avoiding kidney damage altogether.

Terri M. Laufer, MD

University of Pennsylvania<< view more >>
Follicular Helper T Cells: Altered Differentiation in Lupus

Systemic lupus erythematosus (SLE) is characterized by the presence of antibodies directed against the patient’s own cells and DNA. Although the disease is caused by damaged white blood cells, autoantibodies enable diagnosis and contribute to the organ damage that occurs.

Thus, identifying the pathways that lead to autoantibody formation could provide therapeutic targets for the treatment of lupus.

With this grant, Dr. Laufer and her team will focus on a type of helper T cell called T follicular helper cells (TFH), which direct the development of antibodies. TFH cells normally function to direct B cells to make antibodies against pathogens and vaccines. However, an increase in their number or function is associated with lupus, and their accelerated development or persistence is believed to drive the production of those dangerous autoantibodies. Indeed, people with lupus and significant organ damage have higher levels of TFH cells in their blood.

The ALR grant will enable the researchers to use unique strains of mice to determine how genetic susceptibility to lupus alters the differentiation and function of TFH cells. They will also investigate options to reverse this differentiation.

What this study means for people with lupus: These experiments hope to directly identify biochemical and cellular pathways that can provide important new targets for drug development to treat and possibly prevent lupus.

Gang Lin, PhD

Joan & Sanford I. Weill Medical College of Cornell University<< view more >>
Immunoproteasome selective inhibitors for lupus treatment

Proteasomes, barrel-shaped protein complexes located within cells, function to break up and clear out proteins that are damaged or no longer useful. Thus, through degradation, the proteasome exerts control over a considerable range of cellular activities.

Inhibiting all activities of the proteasome would be very harmful to a person. A medicine that inhibits the activities of the proteasome is already being used by cancer patients but this medicine has side effects that make it too toxic for long-term use on a regular basis. However, a medicine targeting a subfamily of the proteasome, called immunoproteasome, that are expressed in immune system in a highly specific way and this selective inhibition might be tolerable for long-term use, as is needed for lupus.

Previously Dr. Lin developed inhibitors that affected the proteasomes of bacteria but did not affect the proteasomes of the humans. Recently, he has developed inhibitors that are highly specific for immunoproteasomes whose action can be reversed. All of these inhibitors are within a class of reversible proteasome inhibitors with the tongue-twisting name of N,C-capped dipeptides. At present, his research is seeking to further characterize these inhibitors and to test them in a mouse model of lupus.

What this study means for people with lupus: : We hope this research will develop these inhibitors or other substances related to them into novel lupus therapies.

Tanya Mayadas, PhD

Brigham and Women's Hospital<< view more >>
Analysis And Treatment Of Organ Damage In A Humanized Mouse Model Of Lupus

Systemic lupus erythematosus (SLE) is a chronic, inflammatory autoimmune disorder that affects multiple organs and is associated with abnormalities at all levels of the immune system. Neutrophils, which are white blood cells that are important for defense against infections, can inflict tissue injury in lupus.

Recently, researchers discovered variations of genes important in the activation of white blood cells that may increase susceptibility to developing lupus. Some, including those that code for receptors that bind antibodies, FcãRIIA, FcãRIIIB, and the integrin Mac-1 (ITGAM), are present on neutrophils. The overall objective of this grant is to decipher how these receptors may contribute to organ damage in lupus.

Dr. Mayadas and her team established a model of lupus nephritis (kidney disease) that develops after blood from lupus patients is transferred into genetically engineered mice that express the uniquely human FcãRIIA and FcãRIIIB proteins on neutrophils.

With this grant, they plan to:

  • Determine how neutrophils induce organ damage after antibodies in blood serum from lupus patients are transferred into mice
  • Identify compounds that inhibit FcãRIIA and determine if they can prevent organ damage in the mice that receive lupus blood serum
What this study means for people with lupus: These experiments may lead to a better understanding of the causes of lupus-related organ damage. In the future, this could lead to therapies designed to interrupt the molecular cascade responsible for this damage.
Laurence Morel, PhD

University of Florida, Gainesville << view more >>
CD4 T cell metabolism in lupus: characterization and target identification

Previously Dr. Morel and her team discovered that T cells use of the metabolic substrate (for example, sugars floating in the blood) is impaired in a mouse model of lupus. This impairment accompanies the production of T cells of an inflammatory type that, in turn, drives the disease process. Specifically, the research focuses on the Esrrg gene, which has a role in cellular metabolism. The level of expression of Esrrg in T cells regulates how they use the metabolic substrate as well as their inflammatory potential.

Faulty regulation of T cell metabolism might play an important role in the development of lupus. So, altering T cell metabolism might be an effective lupus therapy. Furthermore, this goal could be achieved by using a set of metabolism inhibitors that have already been shown to be safe for humans.

Dr. Morel's research will, first, use a mouse lupus model to investigate how Esrrg regulates CD4+ T cell metabolism and how this contributes to the development of disease. Second, can inhibition of glucose metabolism using well-known strategies prevent and reverse the illness in mice? Third, how is Esrrg regulation of T cell metabolism different in lupus patients than in healthy people? Strong preliminary results have already been achieved.

What this study means for people with lupus: : In this research, Dr. Morel hopes to discover a previously unknown way to regulate the T cell contribution to the development of lupus, so that medicines and biomarkers can be developed.

Alessandra Pernis, MD

Hospital for Special Surgery<< view more >>
Effector Tregs in Lupus

Defects in the proper regulation of the immune system are fundamental to the development of lupus. Regulatory T cells (Tregs) are a type of T cell that normally prevents the immune system from attacking "self".

Recent studies find that a protein called IRF4 controls Treg function. Dr. Pernis and her group have identified 2 related molecules, Def6 and SWAP-70, that, in turn, regulate IRF4. They found that mice lacking these two molecules (DKO mice) spontaneously develop a lupus-like syndrome that, similar to human lupus, primarily occurs in females. Interestingly, the mice develop a mild form of the disease, which is associated with a marked increase in activated Tregs.

They also found that Tregs express both Def6 and SWAP-70. These findings led the researchers to hypothesize that Def6 and SWAP-70 regulate the function of Tregs via their ability to control IRF4. They also hypothesize that the expansion of these activated Tregs in the DKO mice helps dampen the autoimmune inflammation. The goal of their current proposal is to employ cutting-edge genetic approaches to assess the regulation and role of activated Tregs in lupus.

What this study means for people with lupus: Dr. Pernis and her team hope that a better understanding of the molecular mechanisms that endow Tregs with a potent ability to moderate lupus disease activity will provide crucial insights into the best ways to generate functional Tregs to correct the dysfunctional immune responses that result in lupus.

Fred W. Perrino, PhD

Wake Forest University Health Sciences<< view more >>
Targeting DNA polynucleotides in lupus

In lupus, the antibodies of the human body's immune system fight against that persons own DNA. Some experts think a source of part or all of this DNA lies in the process through which the human body recycles the material in cells. During such recycling, the human body takes the tiny parts of the dying cell being disassembled and uses some of these parts to create new cells.

Previously, research in Dr. Perrino' s laboratory resulted in the discovery of the TREX1 gene, which encodes a powerful DNA disassembly enzyme. What happens when the TREX1 enzyme does not possess its usual and proper structure? In other words, what happens when the TREX1 enzyme is mutated?

In at least some people with lupus, the failure of TREX1 to eliminate DNA from dying cells might be the root cause of the way the human body starts improperly and harmfully to fight against its own DNA. Using a mouse model of lupus involving a mutant form of TREX1, the current research will seek to determine how the TREX1 enzyme dysfunction leads to the development of lupus and related illnesses.

What this study means for people with lupus: : The research may provide new insights into the origins of lupus, which, in turn, might furnish therapeutic targets that in some way involves TREX1.

Shiv Pillai, MBBS, PhD

Massachusetts General Hospital<< view more >>
Targeting the SIAE pathway in lupus

We know that the risk of developing lupus is likely related to several rare genetic variants, or abnormalities. Of particular interest are rare genetic changes that affect the function of the protein the gene encodes for, rather than more "common" variants identified in the large, genome-wide association studies that have already been conducted.

Dr. Pillai and his team are employing a way to identify all such "rare" genetic variants by sequencing the gene's coding segments, or exons. The exons are like letters that form words; while the words together form the story, or, in the case of genetics, the protein the gene is responsible for making. This approach is called "complete exome sequencing," and Dr. Pillai and his team have already used it to sequence genes in people with lupus. In addition, they performed a battery of tests on each participant to examine immune cell function.

Now they will use their ALR grant to put the two together — the clinical features of the disease, including immune function, with the genetic variants. The goal is to obtain a comprehensive understanding of the genetic basis of lupus.

What this study means for people with lupus: Identifying specific defective genetic pathways can help identify new targets for novel therapies.

David Pisetsky, PhD, MD

Duke University Medical Center<< view more >>
Nucleic Acid Binding Polymers in the Treatment for SLE

A key underlying abnormality in the immune system in lupus is the production of antinuclear antibodies (ANA) that bind to the proteins or nucleic acids (DNA and RNA) from the cell nucleus. In fact, high ANA levels are used as a marker for diagnosis and prognosis. In lupus, these autoantibodies can form immune complexes with molecules such as DNA that are released from the cell nucleus, usually as the cell dies. These complexes may then stimulate inflammation as well as deposit in the kidney, causing damage.

The immune complexes that form in lupus have unusual properties since the bound molecules (DNA and RNA) can themselves have immunological activity. When in the form of complexes, these nucleic acids can trigger immune system abnormalities that promote autoimmunity. This activity results from the ability of DNA and RNA to stimulate nucleic acid receptors or sensors that are on the inside of the cell. Normally, DNA and RNA in the blood may not be able to bind to these receptors; but when they are available as immune complexes, DNA and RNA can get into the inside of the cell and access these receptors to promote immune disturbances.

Current therapies for lupus are based on non-specific immunosuppressive agents that, while effective, have limited benefits for many patients and significant side effects. To develop more targeted therapies, researchers are looking at blocking the stimulation of the internal nucleic acid receptors, including toll-like receptors (TLR) and non-TLR systems. Compounds that block TLR 7 and 9, which respond to RNA and DNA respectively, have demonstrated benefits in mice models; since the compounds don’t block non-TLR sensors, however, they may have limited efficacy. Also, compounds that inhibit the TLRs may affect the immune response to viruses and other infections.

Dr. Pisetsky and his team are exploring an alternative strategy to block responses to nucleic acids by investigating the use of nucleic acid binding polymers (NABPs). These polymers can bind tightly to DNA and RNA and prevent the formation of immune complexes and the resulting stimulation of internal receptors, The hope is that the polymers will be able to block the ability of extracellular nucleic acids to stimulate immune system activity that can underlie autoimmunity.

Their plan is to:

  • Define the activity of a series of NABPs, assessing their ability to block stimulation of various immune cells
  • Assess the activity of the NAPBs in mice stimulated with DNA to determine the appropriate dosing for clinical studies
  • Determine the ability of NABPs to block autoimmune disease in mouse models of lupus
What this study means for people with lupus: These experiments provide the first step in moving NABPs into clinical trials in patients to develop a new strategy to treat lupus by blocking immune responses induced by complexes.
Shruti Sharma, PhD

University of Massachusetts Medical School<< view more >>
Innate Sensing of AT-rich DNA During Autoimmunity

Numerous immune system components contribute to disease development and progression in lupus. These include tolllike receptors (TLR), particularly TLR7 and TLR9. These proteins recognize RNA or DNA from dying cells and trigger inflammation in lupus patients by activating immune cells such as dendritic and B cells. Dendritic cells produce inflammatory molecules called type I interferons while B cells generate autoantibodies that eventually cause organ damage in the later stages of the disease.

With their ALR grant, Dr. Sharma and her colleague, Dr. Fitzgerald hope to discover what triggers autoimmune diseases like lupus and rheumatoid arthritis (RA). They suspect that the DNA released from dying cells contains clues to this event. Specifically, it appears that the location of the DNA may affect the disease differently than we initially thought. For instance, in autoimmune diseases like RA, abnormal DNA accumulates within cells and triggers pathways independently of TLR activation. Similarly, in lupus it appears that a different pathway operating separately from TLR9 activation may be responsible for the initial production of interferons, exacerbating subsequent symptoms and organ damage. This pathway may be related to the "nature" of the accumulated DNA. In other words, the location of the DNA within the cell and the enrichment of certain parts of the DNA could provide a clue as to its role in the disease.

The researchers also plan to use complex genetic models to investigate specific proteins involved in detecting this buildup of DNA.

What this study means for people with lupus: This research can help identify important and novel targets and pathways in the development and progression of lupus that could lead to new therapeutic targets.

William Stohl, MD, PhD

University of Southern California<< view more >>
The roles of the individual elements of the BAFF axis in murine lupus

The BAFF (B-cell activating factor) axis plays a central role in B cell survival and development. The BAFF axis is made up of two binders (ligands) called BAFF and APRIL and three receptors, called BCMA, TACI, and BR3. (Note that the term BAFF refers to the entire axis as well as to one of the binders).

Currently some lupus patients use a medicine called belimumab which neutralizes the BAFF binder. This drug helps many people with lupus, but does not help everyone with the disease. Do some interactions with BAFF receptors promote disease while interactions with one of the receptors is protective?

Previously Dr. Stohl and his team have developed a mouse lupus model with mice deficient in the individual components of the BAFF axis. The current research uses this mouse model to look into the possibility that the interaction between the BAFF binder and BCMA and BR3 promotes disease while the interaction between the BAFF binder and TACI may be protective. And what about the presence and absence of APRIL? The research will involve a sort of round-robin tournament with binders and receptors to see how each of these components, and how combinations of them, may affect disease.

What this study means for people with lupus: : By isolating components it may be possible to identify which of the receptors is crucial in promoting lupus. If so, this research will lay the foundation for the development of medicines that interfere with disease-causing interactions within the BAFF axis.

Hideki Ueno, MD, PhD

Baylor Research Institute<< view more >>
Altered T Follicular Helper Cell Subsets In Active Pediatric Lupus

Uncontrolled generation of autoantibodies is a hallmark of lupus. Animal studies show that a type of helper T cells, called T follicular helper (Tfh) cells, contribute to the development of the disease and the dysfunctional autoantibodies. Yet, very little is known about whether Tfh cells play a role in the development of human lupus.

Preliminary data from Dr. Ueno and his team suggest that Tfh cells do play a role in lupus development. With their ALR grant, they plan to determine how these cells differ in quality and quantity in pediatric lupus patients from those in healthy children. They will also investigate whether such alterations correlate with disease severity and/or specific organ damage.

What this study means for people with lupus: This project will establish a cornerstone for the team’s long-term goal, which is to develop novel therapeutic approaches for lupus that reprogram altered Tfh responses.

Paul J. Utz, MD

Stanford University<< view more >>
Target Identification in SLE Using CyTOF and Multiplexed Assays

A hallmark of lupus is the production of autoantibodies that recognize "self" molecules when they should only respond to foreign molecules. Studies by Dr. Utz’ lab and other investigators have identified important roles for 2 classes of molecules in lupus: inflammatory interferons and cytokines, which are proteins that immune cells release to fight off infections and which damage organs like the kidney; and toll-like receptors (TLRs), which appear to control the development and severity of SLE.

With their grant, Dr. Utz and his team will identify ways to tell which autoantibodies are most active in which patients. They will do this thanks to two cutting-edge technology platforms developed in Stanford labs. The first involves printing thousands of biomolecules onto glass slides, which provides a huge amount of data in just a few hours, and then correlating the presence of autoantigen complexes with a "biosignature" related to the individual patient’s disease.

The second technology uses a new methodology called CyTOF, which analyzes patient blood cells to study their defects and responses to potential therapies such as rituximab (Rituxan) and belimumab (Benlysta).

They will also explore whether defects in the way these proteins communicate and interact with each other could also be useful biomarkers and/or novel targets for drugs.

What this study means for people with lupus: Ultimately, these techniques could become the mainstay of all clinical trials in SLE, improving our ability to demonstrate effectiveness and ushering in an entirely new era of patient-specific, customized therapies, or personalized medicine.

Barbara J. Vilen, PhD

The University of North Carolina at Chapel Hill<< view more >>
The role of immune complexes and BAFF in promoting atherosclerosis in lupus

Many people with lupus develop heart disease, diabetes, and become overweight, likely because immune dysregulation affects inflammation. Are regulators of the immune system that contribute to lupus kidney disease linked to problems with regulation of cells processes that lead to atherosclerosis? Earlier studies by Dr. Vilen's laboratory identified one (of several) pathways that leads to increased BAFF (B-cell activating factor) secretion in people with lupus. Now she hopes to identify how that pathway may lead to the development of atherosclerosis.

Lupus is associated with elevated levels of BAFF. Dr. Vilen's laboratory recently found that one of several sources of BAFF is produced when apoptotic debris fails to be degraded and as a consequence is recycled by the cell back to the cell. The recycling in this context is for the un-degraded immune complex to be sent from inside the cell back to the cell surface. This process might lead to chronic activation of the receptors bound by the apoptotic debris, perhaps leading to heightened BAFF production by the cell in the case of FcgRs.

It is possible that over extended periods of time, elevated BAFF activates PI3K/mTOR, which leads to fat cells (adipocytes) being activated and matured, encouraging inflammation. Using mice lacking a part of the immune system, she and her team will seek to determine whether increasing levels of BAFF in the presence of mTOR encourages the production of fatty substances, leading to atherosclerosis. Also, the researchers will use gene neutralization, blocking or deletion to investigate the roles of the BAFF receptor BR3, mTOR, and FcgR1.

What this study means for people with lupus: : This research has the potential to advance researchers' understanding of how and why people with lupus develop heart (cardiovascular) disease. The research has the potential to identify targets for effective therapies.

Joan Wither, MD, PhD

Toronto Western Research Institute, Canada<< view more >>
Identification of Biomarkers for Patient Stratification in Lupus Nephritis

Despite significant improvement in the prognosis of SLE over the past 30 years, people with lupus still tend to have higher mortality rates than those without, often because of kidney disease. Kidney disease, called lupus nephritis, typically develops within the first 5 years of a lupus diagnosis. Yet the condition appears different in every patient. Some suffer more kidney damage earlier in the disease, others very little; some respond well to treatment, others do not.

Unfortunately, there are currently no reliable clinical or laboratory parameters that enable doctors to determine how the disease is progressing or how patients respond to therapy. The only way to tell how much damage has occurred and assess response to treatment is with a kidney biopsy, which is an invasive procedure.

Dr. Wither is part of the LuNNET (Lupus Nephritis New Emerging Team) group, which consists of rheumatologists, nephrologists, pathologists, and biostatisticians. It was formed to develop biomarkers to identify patients who share certain biological characteristics of their nephritis, providing valuable information about the disease progression and response to therapy.

With their ALR grant, the LuNNET group plans to use the large database of renal biopsies, blood, plasma, blood RNA and DNA, and urine it has collected from lupus patients to identify novel biomarkers. They will use technologies that enable them to simultaneously test multiple genes and proteins to identify novel biomarkers. They will also examine gene expression in the kidney biopsies, as well as protein levels in urine samples. They will then correlate these gene/ protein expression patterns with disease-causing and clinical variables to identify potential biomarkers.

During the second phase of the study, Dr. Whither and her group will try to validate these biomarkers with additional kidney biopsies and determine any potential variation over time.

What this study means for people with lupus: The data obtained through this study could help identify biomarkers to improve the diagnosis, monitoring, and treatment of people with lupus-related kidney disease.

Nan Yan, PhD

UT Southwestern Medical Center<< view more >>
Identification of Endogenous Nucleic Acids as Targets in Lupus


Approximately 2 percent of people with lupus have mutations of the TREX1 gene, making it one of the most common causes of single-gene regulated lupus. Such rare but highly frequent causes of lupus are important to study because they provide immediate insight into its underlying causes.

Interestingly, mutations in TREX1, as well as in other genes involved in regulating and metabolizing nucleic acids (the building blocks of genes), are linked to many autoimmune diseases related to inflammatory markers such as elevated type-I interferon expression. One of these is Aicardi-Goutières syndrome (AGS). Most people with AGS have mutations in one of five genes: TREX1, RNASEH2A, 2B, 2C and SAMHD1. These all produce enzymes that regulate or metabolize nucleic acids. People carrying mutations in these genes, or expressing defective enzymes, display lupus or lupus-like phenotypes, making it critical to identity their nucleic acid substrates.

What this study means for people with lupus: With their ALR grant, Dr. Yan and his team plan to identify endogenous nucleic acids in human cells that could be used as biomarkers to track lupus disease progression. Dr. Yan and his team will also evaluate methods for preventing these nucleic acid substances from stimulating unintended immune responses that may lead to lupus, and/or interrupting their activities. This could result in new treatments for the disease.



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