Lupus Innovation Award (LIA)

2021 Funded Grant

Gregory Barton, PhD
University of California, Berkeley

Lupus is caused when a person’s immune system attacks the body’s own genetic material. In healthy people, the molecule Toll-like receptor 7 (TLR7) inside of cells recognizes the ribonucleic acid (RNA) from viruses and other pathogens that have invaded a person’s cells, while leaving a person’s own RNA untouched. In lupus patients, TLR7 mistakenly turns on an immune response against the body’s own RNA, which leads to lupus. In his previous research, Dr. Barton identified 20 genes in mice that, when disrupted, increase TLR7 responses to RNA. In this grant, Dr. Barton proposes to study how the genes he identified influence TLR7 responses and whether such increased responses lead to lupus. First, he will measure how the absence of these genes affects TLR7 in various immune cells. His research team will also generate mice lacking these genes to see if TLR7 responses to their own RNA lead to lupus.

What this study means for people with lupus

By finding new genes that control how the immune system responds to the body’s own genetic material, this work will further our understanding of lupus. This work will also potentially identify new targets for the treatment of lupus.

2021 Funded Grant

Nunzio Bottini, MD, PhD
University of California, San Diego

In lupus, a type of immune cell called plasmacytoid dendritic cells or pDCs produce an excess of a protein called type I interferon that fuels damaging inflammation and lupus. While a therapy like anifrolumab-fnia that blocks type I interferons can help relieve lupus symptoms, it may also lower the immune system’s ability to respond to infections. pDCs have a unique protein called Protein Tyrosine Phosphatase Receptor Type S or PTPRS that can reduce the production of damaging type I interferons. PTPRS can be turned “on” or “off” via a proteoglycan switch. Using this grant, Dr. Bottini aims to reduce lupus symptoms while leaving the important infection-fighting components of the immune system intact. He will repair the broken pDCs in lupus patients by targeting the proteoglycan switch that turns PTPRS “on” or “off.” Dr. Bottini’s research team will also test whether turning PTPRS “on” via the proteoglycan switch enhances the effectiveness of medications such as belimumab that is already approved to treat lupus.

What this study means for people with lupus

This work should pave the way for the development of new anti-lupus medications that inhibit the production of type I interferons with reduced risks of infections.

2021 Funded Grant

Jason Cyster, PhD
University of California, San Francisco

B cells are immune cells that produce antibodies to fight infections. However, in autoimmune conditions such as lupus, some B cells produce autoantibodies which cause the destruction of a person’s own organs. Dr. Cyster and his research team recently found that a small number of lupus patients have a mutated form of the receptor P2RY8, a protein on the surface of B cells that receives signals from the surrounding environment. However, it remains unknown how deficiency in P2RY8 on B cells affects patients with lupus. Dr. Cyster and his team will therefore look at a larger group of lupus patients to see what percentage of patients have the mutated form of P2RY8 or mutations in genes that function in the P2RY8 signaling pathway. They will also look closely at those patients who have the mutated form of P2RY8 to see if that plays a role in B cell autoantibody development and the severity of lupus symptoms.

What this study means for people with lupus

This project will provide novel information to better understand the genetic causes of lupus and potentially identify novel targets for therapeutic purposes in a subset of lupus patients.

2021 Funded Grant

Maria Gutierrez-Arcelus, PhD
Boston Children’s Hospital

Lupus is a complex disease with both genetic and environmental causes. There are over 100 regions in our DNA with potential alternations (genetic variants) that make us susceptible to this disease. However, we do not know how most of the genetic variants cause lupus. B cells are important cells in lupus development since they produce the autoantibodies that cause organ damage. Many of the genetic susceptibility regions contain genetic information that is important for B cell development and function, such as the B cell receptor (BCR) and Toll-like receptor 7 (TLR7). Both BCRs and TLR7 are important in B cell responses and control antibody and autoantibody production. This grant will be used to study how both the BCR and TLR7 affect human B cells and influence the different lupus symptoms that are seen in the clinic. Dr. Gutierrez-Arcelus and her team will use the latest state-of-the-art technology to look at genetic material (RNA) and proteins in B cells from both healthy individuals and lupus patients.

What this study means for people with lupus

To find more effective and personalized treatments for lupus patients, there is a need to understand why the disease is so heterogeneous – differing widely from person to person – and how this disease develops in each patient. This project is expected to add valuable information on how lupus develops and how its causes different symptoms in different people. Findings from this study may also aid in directing lupus patients to the most relevant clinical trials and personalized therapies.

2021 Funded Grant

Bart Lambrecht, MD, PhD
VIB-UGent Center for Inflammation Research

Our microbiome, made up of trillions of micro-organisms, plays a crucial role in maintaining our overall health. Studies have found that there are microbial changes in people with lupus and lupus nephritis, but it is not known whether changes in the microbiome influence or cause lupus. In a mouse model with lupus nephritis, Dr. Lambrecht has seen that lupus disease severity may change based on the animals’ microbiome. Using this grant from LRA, Dr. Lambrecht and his team will study how the microbiome influences B cells, which are immune cells that normally produce antibodies to protect against infection. In lupus patients, B cells produce the autoantibodies that attack the organs and cause complications such as lupus nephritis. Through experiments with individual types of bacteria (monocolonization), the research team will look at how individual bacterial strains may affect lupus. Additionally, Dr. Lambrecht’s team will collect blood and microbiome samples from lupus nephritis patients to study how the microbiome affects B cells, autoantibody production and dysregulated IgA responses in humans.

What this study means for people with lupus

Understanding how changes in the microbiome affect B cells and/or promote autoimmune diseases like lupus will help us develop more effective preventive approaches for individuals at increased risk of developing lupus, as well as better therapies for lupus patients.

2021 Funded Grant

James Oates, MD
Medical University of South Carolina

Inflammation of the kidneys, called nephritis, is one of the most common and dangerous complications of lupus. Current nephritis therapies focus on targeting the immune cells that move into, and cause damage in, the kidneys. However, the cells that line the blood vessels, called endothelial cells, can also influence how tissues respond to inflammation. Endothelial dysfunction is a condition in which the endothelial cells fail to protect tissues. This dysfunction may cause cardiovascular disease and tissue inflammation, including inflammation in the kidneys and other organs. Dr. Oates has demonstrated that endothelial dysfunction worsens kidney disease in a mouse model of lupus and that improving endothelial function decreases inflammation in mice with lupus. Dr. Oates will use this grant to test if the existing medication sepiapterin, which has been shown to improve endothelial dysfunction in diabetes, can restore the protective role of endothelial cells and decrease kidney inflammation in mice with lupus nephritis. The research team will also study the effect of this drug on the cardiovascular system, as this is an important way to determine if the drug improves the function of endothelial cells.

What this study means for people with lupus

Findings from these studies will provide the foundation for future clinical studies with sepiapterin given to lupus patients to repair endothelial function. The sepiapterin therapy could possibly be used as an additional therapy in managing lupus nephritis and as a preventative therapy for lupus-induced cardiovascular diseases.

2021 Funded Grant

Joshua Ooi, PhD
Monash University of South Carolina

With a previous grant from the LRA, Dr. Ooi studied which specific parts of the body were targeted by the misguided immune system in patients with lupus nephritis, a condition causing inflammation in the kidneys. Lupus nephritis affects approximately half of lupus patients and can shorten life expectancy. Dr. Ooi has pioneered the approach of developing specialized regulatory T cells that may be used as a future treatment for lupus nephritis patients. Regulatory T cells are immune cells that in healthy people stop the immune system’s response once an infection has cleared and prevent the immune system from attacking the body’s own tissues and cells. In a mouse model of lupus nephritis, Dr. Ooi found that the specialized regulatory T cells can suppress the misguided immune response that leads to lupus nephritis. With his current LRA grant, Dr. Ooi will produce and test the effectiveness of “clinical-grade” regulatory T cells on lupus nephritis patient samples as well as in mice with lupus nephritis.

What this study means for people with lupus

Findings from this study will provide a foundation for clinical studies testing a potentially first-in-class therapy for lupus nephritis that uses specialized regulatory T cells to treat and even possibly cure this disease.

2021 Funded Grant

Zaida Ramirez-Ortiz, PhD
University of Massachusetts Medical School

In higher organisms, billions of new cells are produced in the body daily and the same number of cells die every day. The effective disposal of dead cells is essential to maintains health. However, if the system that removes dead cells becomes defective, this will lead to an excess of dead cells that are known to cause inflammation and potentially lead to autoimmune diseases, including lupus. Phagocytes, a group of immune cells, are responsible for the removal and disposal of dead cells. Dr. Ramirez-Ortiz previously discovered that phagocytes express a receptor molecule on their cell surface (SCARF1) that detects and removes dead cells. Dr. Ramirez-Ortiz also found that mice without SCARF1 develop lupus-like symptoms similar to what is seen in humans. This latter finding suggests that defective clearance of dead cells may happen when SCARF1 is “broken”. With this grant, Dr. Ramirez-Ortiz will compare SCARF1 on phagocytes from lupus patients and healthy people and look in the blood to see if lupus patients produce autoantibodies against SCARF1. Dr. Ramirez-Ortiz will also develop a mouse model that lacks SCARF1 specifically on phagocytes to test if mice without SCARF1 on these cells develop lupus-like disease.

What this study means for people with lupus

This study will provide new insight on a biological process that may lead to lupus development in humans. Understanding whether SCARF1 is needed to dispose of dead cells in the mouse model and whether this molecule is dysfunctional in lupus patients could lead to the development of new therapeutic approaches that would target defective dead cell removal and/or SCARF1 in patients with lupus.

2021 Funded Grant

Joanne Reed, PhD
Westmead Institute

In healthy people, B cells produce antibodies that protect us from infection by bacteria and viruses. However, some B cells in lupus patients produce autoantibodies, which attack the patient’s cells and organs. Lupus nephritis occurs when autoantibodies attack the kidneys. Unfortunately, the current treatment options are limited to steroids and other drugs that suppress the whole immune system. The grant awarded to Dr. Reed will be used to identify and study the immune cells responsible for making the autoantibodies that attack the kidneys, to determine how they are different from the normal and healthy B cells that produce antibodies to fight infection. This work will be done using state-of-the-art technology that looks at single B cells responsible for producing pathogenic, or disease-causing, autoantibodies. The technology was adapted to identify B cells that produce autoantibodies in lupus nephritis. The collaborative research team will trace the development of the pathogenic B cells over time and compare them to normal and healthy B cells in the same patient.

What this study means for people with lupus

The findings from this study will be a step toward in developing a safe and effective personalized treatment strategy to selectively get rid of the B cells that produce damaging autoantibodies.

2021 Funded Grant

Betty Tsao, PhD
Medical University of South Carolina

Discovering genetic causes of lupus helps researchers identify new therapies. Dr. Tsao and colleagues identified a defect in the SAT1 gene located on the X chromosome that may be associated with lupus in children, especially in boys. While studying mice with the defective SAT1 gene that codes for a factor that helps control amounts of a nutrient called polyamine, which cells need to remain healthy, Dr. Tsao’s research team found that young male mice, like young boys, developed lupus-like autoimmune disease. Furthermore, the research team discovered that mice with the defective SAT1 gene also have abnormal levels of factors controlling polyamine related nutrients, suggesting that difficulties in maintaining polyamine nutrients at healthy levels could cause lupus. Using this grant, Dr. Tsao will investigate how this disruption in healthy polyamine levels caused by the SAT1 gene defect contributes to lupus in children. She will also test if nutritional supplements such as the naturally occurring nutrient spermidine could help restore the healthy polyamine levels and alleviate lupus symptoms in mice with the SAT1 gene defect.

What this study means for people with lupus

This work may reveal new causes of lupus, particularly childhood-onset lupus. Study findings may also suggest new treatment options for people with lupus caused by this genetic variant.

2021 Funded Grant

Lonnie Wollmuth, PhD

Stony Brook University

Lupus patients suffer from many symptoms, including brain disorders ranging from memory loss to more severe problems such as epilepsy and psychosis. These symptoms negatively impact quality of life, and treatments are limited. This grant awarded to Dr. Wollmuth will be used to develop strategies targeting the N-methyl-D-aspartate (NMDA) receptor on nerve cells to prevent or reduce brain disorders in lupus patients. The NMDA receptor is a critical molecule that controls the signals that the brain uses for communication. NMDA receptors are involved in the higher order processes like learning and memory. In some lupus patients, antibodies are produced that attack the NMDA receptor, which damage the receptor and may be linked to brain disorders. Dr. Wollmuth will collaborate with Dr. Betty Diamond to obtain antibodies against the NMDA receptor from lupus patients who have lupus-related brain disorders. The researchers will investigate how these antibodies impair or affect NMDA receptors. Using mouse models, the research team will first look at the damage caused by individual antibodies targeting the NMDA receptor, and then see if the damage can be blocked by various agents.

What this study means for people with lupus

This study will lay the foundation for personalized medicine for lupus patients experiencing brain disorders by showing how the NMDA receptor is affected, and by identifying potential therapeutic agents.

2020 Funded Grant

Simone Caielli, PhD
Weill Cornell Medical College

There is some evidence that defects in mitochondria—the “powerhouse” of every cell—may be involved in the development of lupus. While examining how this happens, Dr. Caielli found a population of red blood cells in some lupus patients that have mitochondria in them—which was very strange, since mature red blood cells don’t usually have anything in them besides hemoglobin! Moreover, he showed that these red blood cells can induce the inflammation that is so problematic in people with lupus and other immune disorders. He was able to generate more of these cells in the lab and hopes to use them to figure out if they correlate with more severe disease activity and progression.

What this study means for people with lupus

With his funding from the Lupus Research Alliance, Dr. Caielli aims to identify the underlying causes of lupus by examining how the defective, mitochondria-containing red blood cells he has found in lupus patients induce inflammation. Only by first understanding the root causes of the rogue inflammation that is so damaging to those with lupus and other immune disorders can we hope to devise effective treatments.

2020 Funded Grant

Joyce Chang, MD, MSCE
The Children’s Hospital of Philadelphia

Pediatric-onset lupus is often more severe than adult-onset lupus. This puts kids with lupus at a higher risk of having heart attacks and strokes when they are young adults. We do not yet know how to monitor this damage as it occurs, much less how to prevent it. With her grant from the Lupus Research Alliance, Dr. Chang will conduct a long-term study of teens with lupus to monitor, over time, their blood pressure patterns along with DNA shed by immune cells in their blood. She hopes to find a marker that will measure early blood vessel injury, so patients with increased risk of cardiovascular trouble later in life can be identified, watched, and appropriately treated.

What this study means for people with lupus

Some children with lupus are at risk of heart disease as they grow up. Dr. Chang aims to devise a non-invasive test using specific markers to help predict their future risk, so they can be monitored and treated before damage occurs.

2020 Funded Grant

Keith B. Elkon, MD
University of Washington

Interferons are immune molecules that cells release when they are infected with viruses to give neighboring cells an alert so they can shore up their own anti-viral defenses. In lupus and other immune disorders, interferons are released even when there is no known infection; in this case, they cause harmful immune activation. There are many different interferon molecules, and most scientists think interferon alpha is the most important one in the development and progression of lupus. But Dr. Elkon has done experiments with mouse models suggesting that interferon beta is the one to watch, especially during lupus flares and when skin is exposed to sun or other ultraviolet light.

What this study means for people with lupus

Dr. Elkon is using his LRA grant support to determine how skin exposure to ultraviolet light initiates an immune response in the blood that leads to lupus flares. Homing in on the specific molecules responsible is essential to targeting them therapeutically.

2020 Funded Grant

Elena Wen-Yuan Hsieh, MD
Children’s Hospital Colorado

Most kids with lupus develop kidney disease, but very few respond to currently available therapies. Grant support from the Lupus Research Alliance will allow Dr. Hsieh to use a new technology to map out individual immune cells in the kidneys of children with lupus—visual and quantitative guides of which immune cells are present and where they are. She plans to compare these two-dimensional maps with those from healthy children and those with other kidney diseases. Her hypothesis is that the kidneys of kids who have lupus and kidney disease have a unique structure. By mapping this structure, she hopes to understand how kidney disease develops in lupus so she can figure out how to treat children who develop kidney trouble. She’ll then correlate these kidney maps with the profiles of immune cells in blood, so that doctors will be able to do a simple blood test instead of invasive kidney biopsy to see how to determine which drugs to use.

What this study means for people with lupus

Dr. Hsieh’s goal of mapping what makes the structure of the lupus kidney unique, and how this uniqueness manifests in blood, should help researchers eventually develop better, more effective treatment options for children whose lupus leads to kidney failure.

2020 Funded Grant

Vipin Kumar, PhD
The Regents of University of California, San Diego

Like any complex system, the human immune system has built-in components to regulate its activity. Among the most key components are T regulatory cells, often called Treg cells, which function to tame overblown inflammation. Dr. Kumar and his lab have discovered a new type of Treg cell; when these cells are injected into or activated in mice, inflammation is reduced. They hypothesize that this type of Treg is deficient or defective in mouse models of lupus, and could be why inflammation can go unchecked in these mice. With support from the Lupus Research Alliance, Dr. Kumar will grow and activate this cell type in hopes of reducing inflammation and kidney disease in lupus.

What this study means for people with lupus

If a subset of T regulatory cells, or Treg cells, can help control kidney disease, activating them might be a promising therapeutic approach.

2020 Funded Grant

Zahi Touma, MD, PhD
University Health Network, Toronto, Canada

At least a third of people with lupus have some sort of cognitive impairment—problems with memory, thinking speed, attention span, and planning abilities—that can negatively impact their quality of life. But there is no organized way to classify them into subtypes in order to identify those most at risk, what puts them at risk, or predict how their cognitive abilities will fare as time passes.

With grant support from the Lupus Research Alliance, Dr. Touma aims to change that using a study of lupus patients linking their demographic data, clinical symptoms, profiles of important cytokines (hormones used by the immune system) and antibodies, with their cognitive abilities over time. He has already collected these data from a few hundred people with lupus at three time points over the course of a year and will use that information to sort the patients into groups. Then he will plug the data into a computer model that he designed to find factors that might put patients at risk so he can try to predict how their cognition will do in the future. After gathering more data from the same patients over the course of the following year, he’ll be able to see how his predictive computer model worked.

What this study means for people with lupus

Dr. Touma is working to divide people with lupus into subtypes based on their cognitive symptoms in order to predict how those symptoms will progress over time.

2020 Funded Grant

Hu Zeng, PhD
Mayo Clinic, Rochester, MN

People with lupus and mouse models of lupus have abnormally high levels of mTORC2  — a signaling molecule that stimulates immune activity by promoting antibody production and destabilizing the regulatory controls that normally keep the immune system in check. Dr, Zeng discovered that when mTORC2 is eliminated from the mouse models, their immune systems calm down and their lupus symptoms improve. The Lupus Innovation Award will allow Dr. Zeng to now figure out how mTORC2 contributes to lupus as well as to search for a molecule that can inhibit its activity in animal models and people to provide a more targeted treatment that might avoid the broad immunosuppressive effects of the current therapies.

What this study means for people with lupus

Dr. Zeng has found a metabolic signaling molecule called mTORC2 that is present at elevated levels in mouse models of lupus; perhaps a molecule that blocks it could point to a promising treatment.

2019 Funded Grant

Carla Cuda, PhD
Northwestern University Feinberg School of Medicine

Lupus can impact the nervous system, but researchers aren’t certain how this disease leads to depression, headaches, memory loss, seizures, and other symptoms. We hypothesize that the culprit is a type of microglia, an immune cell in the brain. While this cell population is believed to reduce neuroinflammation, these cells may not function properly in lupus. To test our hypothesis, we will determine whether this type of microglia is abnormal in mice with neuropsychiatric symptoms. We will also test whether returning normally functioning cells to mice can prevent these animals from developing symptoms. Further, we will determine if a population of microglia-like cells in the fluid surrounding the brain of patients with neuropsychiatric symptoms resembles this type of microglia to potentially translate our findings to human disease.

The study and what it means for patients:

“According to some studies, more than 60% of patients with lupus have neuropsychiatric symptoms that result from the disease’s effects on the nervous system, including the brain, but the cause is still not clear. We will test whether these symptoms result from malfunction of a type of immune cell in the brain that may reduce inflammation. Our findings could lead to development of diagnostic markers and, ultimately, safer, more effective therapies to treat these symptoms.”

2019 Funded Grant

Neelakshi Jog, PhD
Oklahoma Medical Research Foundation

An infection is an emergency for the body, and the immune system can generate more neutrophils to fight invading bacteria. But this emergency response may also occur in lupus, producing large numbers of immature neutrophils that may be harmful. Our research will examine whether the emergency mechanism for making neutrophils is activated in lupus. We will also test whether immature neutrophils promote inflammation and thus could worsen flares. Identifying how the immune system controls production of the immature cells could provide clues about how to reduce their numbers in lupus.

What this study means for people with lupus

“We hypothesize that an immature form of  immune cells known as neutrophils make lupus flares worse. We will investigate how the immune system produces these cells and whether they stimulate inflammation in lupus. The research could uncover new drug targets for blocking these harmful neutrophils.”

2019 Funded Grant

Michelle Kahlenberg, MD, PhD
University of Michigan

Light sensitivity forces many patients with lupus to avoid the sun. Researchers haven’t worked out how ultraviolet light from sunlight or other types of light cause rashes and other problems. Our study will use state-of-the art technology to compare the effects of ultraviolet light on patients with lupus who are sensitive to light, patients with lupus who are not light-sensitive, and people who don’t have the disease. We will measure the changes in skin samples from the three groups to map out differences that are driving skin inflammation. Discovering the changes that occur in skin exposed to ultraviolet light could reveal whether existing drugs will work against the symptoms or provide clues for development of novel therapies.

What this study means to people with lupus

“Many patients with lupus develop skin rashes and other symptoms after exposure to sunlight, but the mechanism for how this happens remains unclear. We plan to analyze skin from patients with lupus to identify the molecular changes that occur after exposure to sunlight. Our findings will identify whether existing drugs might reduce or prevent skin inflammation or help researchers develop new treatments.”

2019 Funded Grant

Benjamin Kile, PhD
Monash University, Clayton, Australia

DNA normally remains locked away within cells, and people who don’t have lupus carry little of it in their blood. However, blood levels of DNA are much higher in patients with lupus. One possible source for this DNA is the billions of cells in the body that kill themselves each day. We will test whether dying cells are an important source of blood DNA in lupus by studying mice that lack key proteins that enable cells to commit suicide. We also recently demonstrated that mitochondria, the structures that function as power plants in cells, also release their DNA, which is another potential source. We will test the importance of DNA from mitochondria in the disease by measuring its levels in patients with lupus. We will then ask if patients with more severe lupus carry more mitochondrial DNA. Our studies could enable researchers to design possible lupus treatments to block cell suicide.

What this study means for people with lupus
“The immune system attacks patients’ own DNA in lupus, but researchers haven’t resolved where the large amount of DNA in their blood comes from. We will identify the sources of this DNA by studying mice and blood samples from patients with lupus. Our research could solve one of the long-standing mysteries about lupus and provide important data for studies to identify new drug targets.”

2019 Funded Grant

Yee Ling Wu, PhD
Loyola University Chicago Health Sciences Division

Patients with lupus may develop atherosclerosis years earlier than people without the disease. They are also more susceptible to blood clots that can lead to strokes and other health problems. We plan to test whether an immune system protein known as C4a, whose levels are often high in patients with lupus, promotes blood clots and atherosclerosis. We will determine whether C4a stimulates the cell fragments in the blood called platelets that spur clots to form. We will also determine whether C4a alters the linings of blood vessels, which could lead to atherosclerosis. The findings could indicate whether C4a is a good target for new lupus treatments and help researchers develop drugs to block it.

What this study means for people with lupus

“Patients with lupus are vulnerable to blood clots and atherosclerosis, the buildup of fatty blockages in arteries. We will test whether an immune system protein stimulates these problems. Our results will indicate whether the protein is a good target for new drugs to treat lupus.”

2018 Funded Grant

Erika Boesen, PhD
University of Nebraska Medical Cente

Lupus nephritis occurs because the kidneys become inflamed. In the process, cells of the kidneys can die and look abnormal to the immune system.  Instead of efficiently clearing these dead cells away, the immune system can then react causing inflammation and potentially making the kidney damage even worse. Cells can die in several ways, and researchers need to pinpoint what triggers their demise to determine if the cause of death impacts the immune system’s reaction. Our project investigates whether a newly recognized type of cell death called ferroptosis contributes to kidney damage in lupus. Ferroptosis differs from other kinds of cell death because it is caused by iron, which is naturally present in small amounts in the body but can cause damage too. To learn if ferroptosis has a role in lupus, Dr. Boesen and colleagues will see if a chemical that blocks it, liproxstatin-1, reduces kidney damage in mice with lupus. Their project will also ask whether ferroptosis causes additional harm to the kidneys by promoting inflammation. This study will improve understanding of how kidney injury occurs in lupus and could provide the impetus for developing new therapies that block ferroptosis.

What this study means for people with lupus

About half of people with lupus suffer from lupus nephritis, or damage caused when the immune system attacks the kidneys. Dr. Boesen’s study investigates a new possible reason why kidney cells die in lupus, which could lead to new drugs that prevent kidney damage in lupus patients.

2018 Funded Grant

Theresa Lu, MD, PhD
The Hospital for Special Surgery

For some patients with lupus, exposure to the sun—or even certain kinds of indoor lighting — can trigger skin inflammation, joint pain, fever, and other symptoms. The lymphatic system, a network of tubes that transports fluid and cells throughout the body, normally limits inflammation and swelling. However, patients with lupus have high levels of type I interferons; we believe this excess of type I interferons reduces lymphatic circulation throughout the body, thereby promoting photosensitivity.

To test this hypothesis, Dr. Lu and her team will measure fluid movement through lymphatic vessels in mice and patients with lupus. They will also test in mice whether stimulating circulation in the lymphatic system can reduce photosensitivity. These studies will show if lymphatic vessels are a good target for future drugs to treat photosensitivity.

What this study means for people with lupus

Many people with lupus are extremely sensitive to light and can develop a rash or other painful symptoms after just minutes in the sun. Dr. Lu’s team aims to discover if this photosensitivity is caused by reduced flow in the lymphatic system, a network of tubes that transports fluid and cells throughout the body.  Their results could open a new avenue for treating lupus photosensitivity, possibly even with certain types of massage that stimulate lymphatic circulation.

2018 Funded Grant

Joshua Ooi, PhD
Monash University

Clinical trials are testing whether increasing the number of regulatory T cells helps people with lupus. One treatment approach being explored involves giving patients large doses of these cells.  But Dr. Ooi and his lab colleagues believe that they can make more effective regulatory T cells that protect specific cells.

In lupus, harmful immune cells hone in on certain molecules and attack cells that carry them. One of the immune cells’ main targets is a portion of the cell nucleus referred to as the Smith antigen. Regulatory T cells that recognize the Smith antigen might be able to shut down these harmful immune cells. Their work will identify which parts of the Smith antigen that immune cells respond to. Once they know that, they will be able to genetically engineer regulatory T cells to protect cells carrying the Smith antigen in mice. If these cells reduce lupus symptoms in the animals, they plan to create regulatory T cells for treating patients with lupus.

What this study means for people with lupus

Researchers are studying regulatory T cells – cells that keep our immune system under control — as a therapy for lupus. Dr. Ooi’s project aims to genetically engineer regulatory T cells that are better at shielding the body’s cells from immune system attack. After evaluating the cells in mice, he and his team hope to test them in people with the disease.

2018 Funded Grant

Jeremy Tilstra, MD, PhD
University of Pittsburgh

In people with lupus, T cells invade the kidneys and other organs and trigger damage. However, Dr. Tilstra’s team has found that some of these T cells have lost the ability to attack—researchers describe them as “exhausted.” In this project they aim to determine whether the cells wear out before or after they enter the kidneys and whether the kidneys cause this change. They will also ask whether the number of exhausted T cells in patients’ kidneys predicts how severe their lupus symptoms will be. Understanding how T cells become exhausted may enable scientists to design treatments that tire out harmful immune cells and reduce the damage to patients’ kidneys and other organs.

What this study means for patients
Immune cells called T cells injure the kidneys and other organs in patients with lupus. But some of the T cells in the organs appear to be worn out and can no longer cause problems. Dr. Tilstra’s work will figure out how these cells become “tired,” so researchers can develop new treatments to exhaust harmful immune cells while sparing the immune cells that protect against infections.

2018 Funded Grant

Michael Waterfield, MD, PhD
University of California, San Francisco

Interleukin-2, which is mostly made by the immune cells called T cells, seems to calm the immune system and has shown promise as a lupus treatment. We have discovered in mice that another protein known as ATF7ip reduces T cells’ production of interleukin-2. Dr. Waterfield’s new study will identify molecules that partner with ATF7ip in T cells, which could lead to drugs that block this protein and spur cells to make more interleukin-2. In the second part of their study, they will genetically modify the T cells of mice with lupus to remove ATF7ip. If symptoms improve, they will know that targeting this protein can offer a new treatment strategy for patients with lupus.

What this study means for people with lupus

Some immune cells in patients with lupus mistakenly attack their own tissues. But other cells release a chemical called interleukin-2 that stops these attacks. Dr. Waterfield and his colleagues are investigating a new way to boost cells’ production of interleukin-2. Their results could help researchers create new drugs to treat lupus by raising interleukin-2 levels.

2017 Funded Grant

Andre Ballesteros-Tato, PhD
University of Alabama at Birmingham

Dr. Ballesteros-Tato is exploring an important interaction between two different cell types of the immune system as a new avenue for targeted drug development in lupus. Specialized immune cells—T follicular helper (Tfh) cells—act as a support system to aid and nurture the B cells, a cell type that produce self-damaging antibodies. It is these antibodies that attack the bodies of people with lupus, damaging their kidneys, brain, skin, and other organs. Dr. Ballesteros-Tato will use his Novel Research Grant to look for ways to selectively eliminate Tfh cells without knocking out other types of T cells that are part of a healthy immune system. He expects that such a treatment would, in turn, power down lupus-related B cells and block disease progression.

What this study means for people with lupus
Currently, no treatments can break the bond between Tfh cells and B cells in people with lupus. Dr. Ballesteros-Tato’s research focuses on this interesting pathway and may lead to innovative directions for the development of new drugs that can add to the therapy arsenal for people with lupus.

2017 Funded Grant

Betsy Jo Barnes, PhD
The Feinstein Institute for Medical Research

Scientists know that for many people some of the risk for lupus is genetic—that is, inherited through their family line. The gene for interferon regulatory factor 5 (IRF5), a key player in the immune system, has been strongly linked to a higher risk for lupus. This means that some versions of the IRF5 gene are more likely to be found in people with lupus, although carrying the high-risk gene does not guarantee that a person will develop lupus. Dr. Barnes wants to understand how these different, high-risk versions of IRF5 help turn a healthy immune system into one that drives an autoimmune attack that leads to lupus. With her Novel Research Grant, she will compare IRF5 in people who carry high-risk versions of the IRF5 gene but do not have lupus with IRF5 in healthy people with low-risk versions of the gene. This study explores a very early stage in lupus development and may reveal why the immune system is triggered to begin an autoimmune attack.

What this study means for people with lupus
Dr. Barnes’ research focuses on people who are at high risk of developing lupus because of their genes, yet who have healthy immune systems and no signs of autoimmunity. If she finds differences in IRF5 that help steer the immune system down a path toward lupus, her study may reveal new targets for the treatment or, even, the prevention of lupus.

2017 Funded Grant

Jason S. Knight, MD, PhD
University of Michigan Medical School

Dr. Knight studies how a type of immune cell called a neutrophil contributes to lupus and its complications. In a model of lupus, he found that turning off elastase, a protein made in neutrophils, reduces autoimmunity, kidney disease, and blood clotting that can lead to strokes. Building on this intriguing discovery, Dr. Knight is now mapping out the molecular pathways that neutrophil elastase uses to damage the kidneys, heart, and blood vessels in lupus. This innovative research project will create a solid foundation for the development of drugs that target elastase as a potential lupus treatment.

What this study means for people with lupus

Dr. Knight has identified a new player in the development of lupus and its complications—neutrophil elastase. His Novel Research Grant will reveal whether elastase is a good target for the development of a new type of treatment for people with lupus.

2017 Funded Grant

Frances E. Lund, PhD
University of Alabama at Birmingham

B cells of the immune system make antibodies that are essential for the body’s defense against infectious diseases; yet, in autoimmune diseases like lupus, some B cells mistakenly go on the offense and attack the body itself instead of focusing on taking out bacteria or viruses. Dr. Lund’s ultimate goal is to improve on existing therapies that remove all B cells from a person’s immune system—such therapies treat autoimmunity but also leave patients vulnerable to new infections. With her Novel Research Grant, Dr. Lund is learning as much as she can about a unique population of B cells found in some people with lupus, but not in people without lupus. These cells (“T-bethi B cells”) have high levels of a gene-controller protein called T-bet. Understanding how these particular B cells are different could reveal new targets for safer drug therapy in lupus.

What this study means for people with lupus

By fully characterizing a specific type of B cell found in some people with lupus, Dr. Lund’s research paves the way for developing better, targeted therapies that specifically block the B cells that make lupus-related antibodies without affecting B cells that produce antibodies to fight infections.

2017 Funded Grant

Keisa Williams Mathis, PhD
University of Texas Health Science Center at Fort Worth

Chronic, long-term inflammation can damage organs throughout the body, including the brain, in people with lupus. Dr. Mathis has discovered that nicotine, a chemical found in tobacco products, can reduce inflammation; however, nicotine is too toxic overall to be used as a treatment in people with lupus. In this exciting translational project, Dr. Mathis is exploring other, nontoxic molecules that might work like nicotine to heal inflammation, but without causing serious side effects. In addition, she will examine whether this type of therapy can reduce inflammation in the brain and, in turn, eliminate negative behavior changes caused by lupus.

What this study means for people with lupus

Dr. Mathis hopes to identify a new treatment for chronic inflammation in lupus that is safe, highly effective, and free of toxic side effects. Importantly, her Novel Research Grant will show whether reducing inflammation in the brain with such treatments can reverse behavioral symptoms of lupus.

2017 Funded Grant

Laurence Morel, PhD
University of Florida College of Medicine

In a previous study, Dr. Lauence Morel showed that drugs that make less sugar available to immune cells could stop the development of lupus in a model of the disease. Sugar is important for many cell processes, so reducing the amount available has a similar effect as when a person eats less food—the cell’s activities slow down and has less energy to fuel an attack. The same treatment also helped immune cells taken from the blood of people with lupus act more like healthy, non-lupus immune cells. Dr. Morel hopes that this treatment might help three existing drugs – belimumab, abatacept, and ruplizumab – that have small effects in people with lupus to work better. With support from her Novel Research Grant, she will test combinations of sugar-reducing drugs like metformin, a drug widely used in diabetes, with the three lupus treatments to see whether she can slow the disease or reverse kidney damage in lupus models.

What this study means for people with lupus

Dr. Morel is pursuing a highly promising translational research project aimed at treating lupus and its complications. Because she is working with drugs like metformin that are already approved for use in people, any positive results could be readily translated into clinical trials to test the efficacy of her drug combinations in people with lupus.

2017 Funded Grant

Alessandra B. Pernis, MD
The Hospital for Special Surgery

Dr. Alessandra Pernis studies a unique type of B cell that has been linked to several autoimmune diseases, including lupus. These “CD11c+Tbet+” B cells have unusually high amounts of two proteins: CD11c, which hangs like a hook on the outer surface of the cell, and T-bet, a protein in the center of the cell that controls the on/off switch for some genes. CD11c+Tbet+ B cells make autoantibodies—or antibodies that mistakenly attack a person’s own tissues and, thus, trigger diseases like lupus. Dr. Pernis will use her Novel Research Grant to learn how CD11c+Tbet+ B cells are made, what molecular pathways help control the function of T-bet in the center, and how and why the cells are triggered to make autoantibodies in lupus.

What this study means for people with lupus 

Dr. Pernis expects her research on CD11c+Tbet+ B cells to fill in vital pieces of the puzzle of how lupus develops. By understanding why these cells develop and how they work, she hopes to find vulnerable points that can be targeted with novel drugs that are specially designed to stop or reverse the disease process in lupus.

2017 Funded Grant

Ziaur Rahman, MD, PhD
Pennsylvania State University College of Medicine

Dr. Rahman will use his Novel Research Grant to map out how the molecular pathways that govern antibody production areas called germinal centers differ in people with lupus from those in healthy individuals. Germinal centers are locations inside a person’s spleen and lymph nodes where immune B cells that make antibodies develop their ability to fight infections or, in the case of lupus, to attack a person’s tissues. Correcting the defects in lupus-related germinal centers could reduce or block the development of disease-causing B cells and the tissue-targeting antibodies they make that cause so much damage in people with lupus.

What this study means for people with lupus

Dr. Rahman’s research on germinal centers represents an novel target for understanding and, ultimately, treating lupus. Understanding the role of germinal centers in lupus should uncover new targets for drug development to complement existing therapies.

2017 Funded Grant

Amr Sawalha, MD
University of Pittsburgh

Dr. Sawalha discovered that the DNA of particular immune cells (CD4+ T cells) changes in people with lupus as the disease progresses. In a process called “methylation,” new molecules are added to the DNA like ornaments hung on a Christmas tree. Methylation of the DNA changes the proteins that are produced and the functions that are turned up or down in the cell. These changes cause the cells to be more active and, so, more able to damage organs. He also found that a protein called EZH2 is a key participant in DNA methylation in CD4+ T cells. With his Novel Research Grant, Dr. Sawalha will delve into the effects of EZH2-led methylation in CD4+ T cells in lupus and look for ways to disrupt the methylation process in CD4+ T cells using new or existing drugs.

What this study means for people with lupus

Dr. Sawalha is studying how the EZH2 protein changes the DNA in immune cells to make them more likely to launch an autoimmune attack on a person’s body. Importantly, several drugs that turn off this protein are already in clinical trials as potential cancer treatments. The results of Dr. Sawalha’s research could provide support for testing these new drugs to treat people with lupus as well.

2016 Funded Grant

Mridu Acharya, PhD
Seattle Research Institute

The B cells of lupus patients are hyperactive, causing inflammation and damage to tissues. By studying mice, she has discovered a new molecular control switch for these cells. In their new study, they want to find out more about how this control switch works in human B cells and why it doesn’t function properly when people develop lupus. Some patients carry varying versions of the switch proteins, and they want to investigate how these differences affect whether someone gets lupus. Better understanding of the control switch will help efforts to develop new treatments that flip it on; in patients with lupus.

What this study means to people with lupus

Dr. Acharya’s group has found a new pathway in lupus, having identified proteins that normally work together to prevent B cells, a type of immune cell that releases disease-fighting molecules, from targeting patients’ cells. Working with human B Cells, she will investigate why these proteins fail to put on the brakes in lupus and potential new treatments to get them working properly again.

2016 Funded Grant

Natalia Giltiay, PhD
University of Washington

Our cells store their DNA by wrapping it around proteins called histones. People with lupus show abnormal immune system responses against their own DNA and against histones. She thinks that histones are a little like the substances that cause allergies — they stimulate the immune system inappropriately, but controlled exposure to them may reduce this reaction. Their strategy to prevent these “allergic” reactions involves delivering small bits of self-proteins to key immune cells known as dendritic cells, which control the responses of other immune cells. They have developed molecules known as antibodies that home in on dendritic cells and bring the histone fragments along with them. They hypothesize that exposing dendritic cells to the fragments will curb the immune system reaction against histones, and the new study will test this approach in mice that are prone to lupus. The goal is to apply their work to the development of a new therapy for lupus patients.

What this study means to people with lupus

Dr. Giltiay’s team plans to teach the immune system to tolerate the body’s own cells in much the same way that allergy shots curb abnormal reactions to allergens. This novel approach to inducing immune system “tolerance” has never been applied to lupus before and may lead to a new effective treatment.

2016 Funded Grant

Shaun Jackson MD, PhD
Seattle Children’s Hospital

B cells usually protect us from bacteria and viruses, but in lupus they release proteins, known as antibodies, that target patients’ own cells. Researchers don’t know which immune system molecules spur B cells to start making these destructive antibodies. In their study, they will use mice to test whether specific immune system molecules, called cytokines, activate B cells to promote production of these antibodies. By identifying the specific signals that trigger B cells to attack patients’ own cells, they hope to provide clues that will allow researchers to develop new, targeted lupus treatments.

What this study means to people with lupus

In lupus, B cells release proteins that damage patients’ own tissues. Dr. Jackson and his colleagues are taking a fresh look at B cells, zeroing in on two recently identified molecules that may act as signals to promote immune attacks. Identifying the specific signals responsible for activating B cells and producing dangerous autoantibodies will inform development of potential targeted lupus treatments.

2016 Funded Grant

Andrea Knight, MD, FRCPC
The Hospital for Sick Children

Up to 50% of young people with lupus have neuropsychiatric disorders, but many of these patients don’t receive the treatment they need. Her study will ask whether a variety of tests, including brain scans with magnetic resonance imaging (MRI) and analysis of proteins in blood samples, can help identify which patients have these disorders due to lupus. They anticipate that the results of the study will lead to early detection and targeted treatment of neuropsychiatric disorders in young people with lupus.

What this study means to people with lupus

Young people with lupus often have neuropsychiatric disorders like depression or anxiety, which may be caused by brain inflammation. Dr. Knight is developing a new biomarker to better detect and diagnose neuropsychiatric disorders like depression and anxiety that are common in pediatric patients so they can receive treatment and get relief sooner.

2016 Funded Grant

Christian Lood, PhD
University of Washington

The energy our cells need comes from structures known as mitochondria that serve as power plants. Dr. Lood recently found that some immune cells throw out their mitochondria, which trigger inflammation and promote development of disease. In the current study he proposes to investigate how the body normally disposes of the released mitochondria so that they don’t cause inflammation and find out if those cleanup mechanisms don’t work well in lupus patients. Those results may provide new opportunities for developing lupus therapies, as well as identify novel biomarkers to monitor, and potentially predict, development of disease.

What this study means to people with lupus

Dr. Lood’s group discovered a new cause for the out-of control inflammation of lupus. Certain immune cells normally eject the mitochondria power plants that provide them with energy. The team is exploring a new treatment approach by examining whether people with lupus do not properly remove mitochondria, thus sparking inflammation. This highly novel project is likely to lead to new targets for therapy and new biomarkers for evaluating disease progression and response to treatment.

2016 Funded Grant

Anthony Rongvaux, PhD
Fred Hutchinson Cancer Research Center

The immune system molecules known as interferons protect us from infections, but they also spur tissue damage in lupus. Dr. Rongvaux has discovered a previously unknown mechanism by which interferons may cause or worsen lupus. Using state-of-the-art technologies, he is investigating how some proteins, known as caspases, block this novel interferon mechanism. He also will test molecules that stimulate caspases, some of which are under development as potential treatments for diseases such as cancer, to determine if they reverse lupus symptoms in mice.

What this study means to people with lupus

Dr. Rongvaux is using state-of-the-art technology to study a newly discovered process that may cause or worsen lupus. His group is trying to find out whether molecules involved in this process are potential targets to validate and advance new treatments, that may reverse symptoms of lupus.

2016 Funded Grant

John Zhang, DVM, PhD
Medical University of South Carolina

Lupus patients with active disease produce higher-than-normal amounts of the protein Fli-1 in their immune cells. The more of the protein they make, the worse their symptoms are. He has found that the drug topotecan, a therapy for ovarian cancer and other types of cancers, curbs production of Fli-1 and reduces the signs of inflammation in cells. He will test whether the drug has beneficial effects in lupus-prone mice. His results will help demonstrate whether the drug has potential as a lupus treatment in patients

What this study means to people with lupus

Dr. Zhang’s team is confirming their initial findings and now testing in human cells whether the chemotherapy topotecan could offer an effective treatment to reduce inflammation in lupus. Topotecan blocks Fli-1, a protein Dr. Zhang and his team have determined worsens lupus symptoms.