Scientists working in the School of Biochemistry and Immunology in the Trinity Biomedical Sciences Institute at Trinity College Dublin have made an important breakthrough in understanding what goes wrong in our bodies during the progression of inflammatory diseases and – in doing so – unearthed a potential new therapeutic target.

The scientists have found that an enzyme called Fumarate Hydratase is repressed in macrophages, a frontline inflammatory cell type implicated in a range of diseases including Lupus, Arthritis, Sepsis and COVID-19. 

Professor Luke O’Neill, Professor of Biochemistry at Trinity is the lead author of the research article that has just been published in leading international journal, Nature. He said:

“No-one has made a link from Fumarate Hydratase to inflammatory macrophages before and we feel that this process might be targetable to treat debilitating diseases like Lupus, which is a nasty autoimmune disease that damages several parts of the body including the skin, kidneys and joints.” 

Joint first-author Christian Peace added: 

“We have made an important link between Fumarate Hydratase and immune proteins called cytokines that mediate inflammatory diseases. We found that when Fumarate Hydratase is repressed, RNA is released from mitochondria which can bind to key proteins ‘MDA5’ and ‘TLR7’ and trigger the release of cytokines, thereby worsening inflammation. This process could potentially be targeted therapeutically.”

Fumarate Hydratase was shown to be repressed in a model of sepsis, an often-fatal systemic inflammatory condition that can happen during bacterial and viral infections. Similarly, in blood samples from patients with Lupus, Fumarate Hydratase was dramatically decreased. 

“Restoring Fumarate Hydratase in these diseases or targeting MDA5 or TLR7 therefore presents an exciting prospect for badly needed new anti-inflammatory therapies,” said Prof O’Neill.

Excitingly, this newly published work is accompanied by another publication by a group led by Professor Christian Frezza, now at the University of Cologne, and Dr Julien Prudent at the MRC Mitochondrial Biology Unit (MBU), who have made similar findings in the context of kidney cancer. 

“Because the system can go wrong in certain types of cancer, the scope of any potential therapeutic target could be widened beyond inflammation,” added Prof O’Neill. 

The taxonomic profile and the interferon-α-stimulatory capacity of gut virus-like particles in patients with systemic lupus erythematosus CREDIT ©Science China Press

This study is led by Prof. Xuan Zhang (Beijing Hospital) and Prof. Jun Wang (Chinese Academy of Sciences).

Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease that can affect multiple tissues and organs. Common manifestations of SLE include fever, fatigue, malar rash, oral ulcer, alopecia, arthritis, and nephritis. Women of childbearing age are most likely to suffer from SLE. Currently, there is no cure for SLE and lacks an effective and safe treatment regimen because its underlying etiopathogenesis remains elusive.

The gut microbiota refers to the microbial community that distributes along the mucosal surface of gastrointestinal tract. The gut microbes participate in the development and function of host immune system. Disturbed gut microbiota has been associated with the pathogenesis of autoimmune diseases like SLE. However, given the technical limitations, previous studies mostly focused on the abundant gut bacteria, while the gut virome of SLE patients remains under-explored.

In this study, Chen et al. recruited 76 SLE patients and 75 matched healthy participants and collected their feces. The SLE patients are mostly treatment-naive and had not taken any corticosteroids, immunosuppressants, or antimalarials for the last 3 months. Human cells and bacterial cells were removed from the feces and free virus-like particles (VLPs) were enriched by ultracentrifugation. Then, viral nucleic acids were extracted and profiled by shotgun sequencing.

The community richness, evenness, and distribution of gut VLPs were not significantly different between SLE patients and healthy participants. However, the proportion of bacteriophages, the virus that infects bacteria instead of human cells, was significantly higher in SLE patients compared to healthy participants. As regards the differentially abundant viral genera and species, the most discriminating ones in SLE patients were Drulisvirus, Thermoanaerobacterium phage THSA-485A, Caeruleovirus, and Bacillus virus JBP901, whereas the predominant ones for HCs were crAss-like viruses and one of their species Cellulophaga phage phi14:2. Interestingly, the gut abundance of SLE-enriched Staphylococcus phage phiRS7 was positively associated with SLE disease activity index as well as the levels of inflammatory indicators, including C-reactive protein and erythrocyte sedimentation rate.

The intercorrelations between gut virome and bacteriome were also analyzed. Using the Procrustes analysis, a significant transkingdom association between the viral and bacterial community in the gut microbiota was found. In addition, some of the bacteriophages covary with bacterial genera that were not their hosts, suggesting a complicated interplay between the gut virome and bacteriome. Diagnostic models based on differentially abundant viruses and bacteria using a random forest algorithm were constructed. The combination of gut viral and bacterial markers displayed better performance (area under the curve = 0.948) than using data from one kingdom alone in distinguishing SLE patients from healthy participants.

Finally, VLPs were isolated from feces and added to the culture of human cells. VLPs from non-treated SLE patients promoted the transcription and production of interferon-α, a pivotal pathogenic factor in SLE, in both Caco cells (an epithelial cell line) and immune cells separated from human blood compared to VLPs from healthy people. Intriguingly, the interferon-stimulatory capacity diminished in VLPs from post-treated SLE patients.

In summary, this is the first VLPs profiling of the gut virome in SLE patients that revealed the viral signatures in the gut microbiota of SLE patients. They also shed novel insights into SLE pathogenesis by connecting the SLE-related gut virome with the promoted production of interferon-α.

A group of University of Pittsburgh researchers has given new meaning to “knowing your ABCs.” In a new study, published in the Journal of Experimental Medicine, the team showed that a type of immune cell called age-associated B cells, or ABCs, are important drivers of lupus and that targeting these cells in a mouse model reduced disease, pointing the way to new therapies.

The immune system usually does a good job of discriminating between healthy body tissues and potential threats such as bacterial or viral infections. When exposed to a pathogen, B cells make antibodies, which help the body to recognize and eliminate the threat. The immune system then returns to less-active surveillance mode, while retaining a long-lived “memory” of prior infection.

However, in autoimmune disorders such as lupus, B cells become abnormally activated and begin attacking the patient’s organs, including the kidneys, lungs and skin.

“A hallmark of lupus is high levels of autoantibodies that bind to a patient’s own DNA or RNA,” said lead author Dr. Kevin Nickerson, research assistant professor in Pitt’s Department of Immunology.

“Because these genetic materials are never eliminated from the body, the immune system is continually reactivated, leading to inflammation that, over time, causes a great deal of damage to the patient’s body.”

According to Nickerson, existing therapies that broadly target B cells can be effective in some lupus patients, but because they also impair B cells that produce infection-fighting antibodies, these treatments can compromise immunity, suggesting a need for more narrowly focused approaches.

In the new study, Nickerson, senior author Dr. Mark Shlomchik, distinguished professor of immunology at Pitt, and their team set out to better understand the role of ABCs in lupus. Nickerson explains the study’s findings and what they could mean for the future of lupus treatments.

What are age-associated B cells?

KN: Age-associated B cells, or ABCs, are a sub-category of B cell that were first identified as being more frequent in older individuals than younger individuals. It quickly became apparent to researchers that these cells are also found in greater numbers in patients with certain autoimmune diseases, including lupus, and during certain chronic infections such as malaria and HIV. These and other findings led researchers to propose that ABCs are a type of immune memory cell that form during some types of chronic inflammatory immune responses. They might accumulate very slowly over a healthy individual’s entire lifetime, or much more rapidly in a younger patient with lupus.

What motivated this study?

KN: Previous research had shown that higher numbers of ABCs in a lupus patient’s blood often correlated with the severity of their symptoms, particularly lupus nephritis (kidney disease). ABCs were thought to be autoimmune memory B cells that develop into cells that make lupus autoantibodies. In this study, we set out to test whether ABCs were indeed a driver of lupus disease. Using a preclinical mouse model of lupus, we examined ABCs in great detail, studied their relationship to other types of B cells and genetically depleted these cells right after they are formed to see what effect they have on disease.

What were your main findings?

KN: Our most important finding was that reducing the number of ABCs by eliminating them as soon as they form slowed or reduced disease progression in the kidneys in mice, directly demonstrating that ABCs drive disease in this lupus model.  We also found that ABCs are a more diverse subset of B cells than previously known, which could suggest that they have different functions or that multiple pathways are involved in their formation.

We also demonstrated that ABCs are indeed a direct precursor to the cells that make lupus autoantibodies. Although they resemble anti-pathogen memory B cells in some respects, they seem to undergo continual cycles of reactivation, proliferation and differentiation. This makes sense because the DNA and RNA to which they respond are always present, so they can’t fully enter a resting state, unlike the memory response in B cells that recognize pathogens, which are eventually eliminated.

What are the implications of these findings and what do they tell you about potential therapies for lupus?

KN: Several lupus therapeutics in the clinic today aim to reduce B cell numbers by directly killing them or by blocking the factors necessary for their survival. However, these currently available therapies are nonspecific, meaning that they affect all B cells, whether those B cells are autoreactive or directed against pathogens. While depleting all B cells prevents lupus progression and organ damage, it significantly impairs a patient’s ability to respond to infections.

If ABCs are the pathogenic population of B cells in lupus, as our study suggests, then narrowly targeted therapies that focus on eliminating these “bad” cells, while sparing “good” B cells, could be beneficial. To do this, we need a more complete understanding of ABCs and where they come from to help design the best approaches. Our study contributes to this understanding.

What are the next steps for this research?

KN:  An important unresolved question is what makes ABCs so pathogenic? And how are they actually promoting disease? One part of that could be their role in making autoantibodies, but we have reason to believe that ABCs could also activate the T cell arm of the immune system in lupus. Autoreactive T cells, when activated, infiltrate organs and tissues from the bloodstream, causing injury by damaging cells and disrupting normal organ function. We want to know if ABCs are directly promoting this pathogenic process and if they are also found within the inflamed tissues at the sites of damage.  In addition, we want to develop methods to deplete ABCs during ongoing disease in a preclinical model to determine if and how that could slow down or treat disease.

Researchers at Michigan Medicine have uncovered the molecular mechanism that drives the disease-causing effects of the most common genetic risk factor for lupus, a study suggests.

Systemic lupus erythematosus is a common, incurable autoimmune disease that affects millions of individuals worldwide, with a particularly high prevalence among women. A genetic variant, called HLA-DRB1*03:01, is the greatest risk factor for the condition, which involves inflammation in many vital organs, and can lead to severe disability and death.

In a study recently published in Communications biology (a Nature Portfolio journal), investigators found that a protein coded by that HLA variant triggers a cascade of molecular and cellular effects that can cause the inflammatory symptoms seen in lupus patients.

“For the first time, we have found the enigmatic mechanism that genetically predisposes people to the worst effects of the most typical form of lupus,” said Joseph Holoshitz, M.D., senior author of the paper and professor of internal medicine and rheumatology at University of Michigan Medical School. “The findings could potentially facilitate the discovery of safe, simple and effective treatments for SLE by targeting this new pathway.”

The results support a novel theory how genetic variants of the kind of HLA-DRB1*03:01 can lead to autoimmune diseases independent of antigen presentation, the traditionally studied mechanism, which has been long proposed but, so far, not directly proven.

“We have identified a chain of events in cell culture, as well as a mouse model of the disease, that demonstrate how the abnormalities that can cause lupus develop from the first effect of the risk gene, to signaling, all the way to immune abnormalities and clinical manifestations of lupus,” said Bruna Miglioranza Scavuzzi, Ph.D., first author of the paper and a postdoctoral research fellow in the Division of Rheumatology at the University of Michigan Medical School.

The findings of this study are reminiscent of previous findings in rheumatoid arthritis, another HLA-associated disease, that have paved the way for the development of small molecules to effectively treat arthritis in mice, Holoshitz says.

“Human trials in RA with those compounds are being carried out, and I hope that our novel findings will lead to similar efforts to ease the burden of millions of lupus patients as well.” he said.