Scientists have developed a potentially transformative new technique that could aid in the discovery and development of new therapeutics for a number of globally prevalent autoimmune diseases.

Conditions such as lupus, rheumatoid arthritis and inflammatory bowel disease (IBD) – as well as failures within transplanted cells – are all caused by altered cytokine secretion of immune cells within the human body.

To find treatments for such diseases, experts need to identify the genetic regulators of the secretion so they can explore the most effective ways of inhibiting them.

An international team of researchers has developed a new method, referred to as Secretion-Enabled Cell Ranking and Enrichment (SECRE) and detailed in a study published in Nature Biomedical Engineering.

They have demonstrated the method is accurate in sorting hundreds of millions of CRISPR-edited cells based on their secretion patterns, and identifying the genetic regulators of cytokine secretion in an autoimmune condition.In addition to this, the method takes into account the detailed profiles of approved treatments, and those under development, to establish if therapies already in existence can be reapplied in new ways.

Writing in the study, the researchers detail how they have validated their approach on the cells known to play an essential role in the development and severity of IBD, and proved it has the potential of finding new ways of treating conditions that impact millions of people globally.

The research is the result of a project lasting around four years between scientists in the UK, United States and Canada, world-leading experts in engineering new tools for the diagnosis and treatment of disease, led by Professor Shana Kelley, President of the Chan-Zuckerberg Institute and Professor at Northwestern University.

Dr Mahmoud Labib, Lecturer in the University of Plymouth’s Peninsula Medical School, and the main inventor of the approach said: “This is an incredibly novel approach that can potentially deliver huge benefits for patients, clinicians and the drug companies working to establish new treatments. It gives us the ability to sort large number of cells based on their secretion patterns and identify therapeutic targets that could be applied to help those with conditions for which there are currently few therapeutic options. Through our existing work, we have demonstrated there is the potential for it to help identify ways of treating various autoimmune conditions, but my work is also now extending to types of cancer including some of the most aggressive types of brain tumours.”

A potential treatment for inflammatory bowel disease?

Inflammatory bowel disease (IBD) is a long-term health condition that has been estimated to affect around 7million people worldwide. It is characterised by chronic inflammation of the digestive tract, which can result in severe tummy pain and diarrhoea, and there is presently no known cure.

As part of work to validate their approach, the researchers examined the effect of several kinase inhibitors on CD4+ T cells, which are known to produce interferon gamma, a protein widely implicated in several autoimmune diseases including IBD. The inhibitors looked at included XMU-MP1, a small molecule that has previously been explored as a treatment for heart failure, hair loss and a number of other medical conditions.

In this instance, the researchers used XMU-MP1 to treat mice with a form of colitis that has a similar cell secretion profile to that found in humans with IBD. They found the mice experience significantly less weight loss and reduced colitis symptoms, while their colons remained virtually normal in appearance and did not show any significant loss of intestinal stem cells.

Based on these findings, the researchers say their results suggest that using XMU-MP1 as a means to inhibit interferon gamma production in the gut may represent an ideal means to control IBD. They also say it provides a promising future strategy for the therapeutic molecular targeting of the condition, although extensive clinical trials would be required before it could be considered as a treatment.

How the SECRE technique works

The Secretion-Enabled Cell Ranking and Enrichment (SECRE) technique captures the secreted cytokine on the surface of the cell. These cytokines are then labelled with magnetic nanoparticles and sorted at high resolution within a microfluidic device, fabricated using scaled three-dimensional printing.

The SECRE technique enables rapid and high-throughput sorting of cells based on their secretion patterns, which makes it amenable to large-scale functional genetic screens. This approach also links the functional signature of the cell with its phenotype, allowing for selective sorting of specific subsets of immune cells on the basis of specific cell-surface markers as well as the secretion specific factors. 

New research has revealed a potentially important role ginger supplements can play in controlling inflammation for people living with autoimmune diseases.

The research published today in JCI Insight focused on studying the impact of ginger supplementation on a type of white blood cell called the neutrophil. The study was especially interested in neutrophil extracellular trap (NET) formation, also known as NETosis, and what it may mean for controlling inflammation.

The study found ginger consumption by healthy individuals makes their neutrophils more resistant to NETosis. This is important because NETs are microscopic spider web-like structures that propel inflammation and clotting, which contribute to many autoimmune diseases, including lupus, antiphospholipid syndrome and rheumatoid arthritis.

“There are a lot of diseases where neutrophils are abnormally overactive. We found that ginger can help to restrain NETosis, and this is important because it is a natural supplement that may be helpful to treat inflammation and symptoms for people with several different autoimmune diseases,” said senior co-author Kristen Demoruelle, MD, PhD, associate professor of medicine at the University of Colorado School of Medicine on the University of Colorado Anschutz Medical Campus. 

In a clinical trial, the researchers found that daily intake of a ginger supplement for seven days (20 mg of gingerols/day) by healthy volunteers boosted a chemical inside the neutrophil called cAMP. These high levels of cAMP then inhibited NETosis in response to various disease-relevant stimuli.

“Our research, for the first time, provides evidence for the biological mechanism that underlies ginger’s apparent anti-inflammatory properties in people,” said senior co-author Jason Knight, MD, PhD, associate professor in the Division of Rheumatology at the University of Michigan.

The researchers say that many people with inflammatory conditions are likely to ask their healthcare providers whether natural supplements could be helpful for them or they already take supplements, like ginger, to help manage symptoms. Unfortunately, the precise impact on disease is often unknown. The researchers hope that providing more evidence about ginger’s benefits, including the direct mechanism by which ginger impacts neutrophils, will encourage healthcare providers and patients to more strategically discuss whether taking ginger supplements as part of their treatment plan could be beneficial.

“There are not a lot of natural supplements, or prescription medications for that matter, that are known to fight overactive neutrophils. We, therefore, think ginger may have a real ability to complement treatment programs that are already underway. The goal is to be more strategic and personalized in terms of helping to relieve people’s symptoms,” Knight adds.

As a next step, the researchers hope to use this study to unlock funding for clinical trials of ginger in patients with autoimmune and inflammatory diseases where neutrophils are overactive, such as lupus, rheumatoid arthritis, antiphospholipid syndrome and even COVID-19.

The function of Rin-like in the immune system was clarified in a study

Autoimmune diseases are complex illnesses, the causes of which are diverse and have not yet been fully explained. A research team at MedUni Vienna has now discovered an immunoregulatory protein that could be linked to the development of autoimmune diseases such as rheumatoid arthritis. The identified component of the immune system is called “Rinl”, which could provide a new target for the development of immunomodulatory therapies. The study results were recently published in the Journal of Experimental Medicine.

In the course of their research, the team led by Nicole and Ruth Herbst (Centre for Pathophysiology, Infectiology and Immunology at MedUni Vienna) found particularly high levels of Rinl in special immune cells, the T cells. Rinl, like its siblings Rin 1-3, is a member of the Ras interaction protein (Rin) family and is a comparatively young object of research. While a deficiency or excess of Rin 1-3 proteins has already been linked in recent years in international studies, for example, to cancer, Alzheimer’s disease or the spinal disease scoliosis, Rinl has so far been little researched.

Mechanism in the immune system deciphered
The function of this protein in the immune system has been clarified by the scientific team as part of the current study. “By analysing mouse models and cultures of human T cells, we have discovered that Rinl controls the development of follicular T helper cells, the Tfh,” say study leaders Nicole Boucheron and Ruth Herbst. Tfh are a subset of T cells and support the maturation of other essential components of the immune system, the B cells. Mature B cells, in turn, produce highly effective antibodies and thus play a major role in the body’s immune response: in vaccinations, a large amount of such antibodies is desired, but in autoimmune diseases such as rheumatoid arthritis (RA), they turn against the body’s own body and damage it. “Our study reveals the previously unknown mechanism of how Rinl controls the development of Tfh cells in various immunological reactions, such as during a viral infection or during a vaccination,” explains first author Lisa Sandner.

As the researchers’ investigations of patient data from public databases also showed, there is a low concentration of Rinl proteins in the T cells of rheumatoid arthritis (RA). Based on these results, the protein may represent a new target for the development of immunomodulatory therapies for RA: “Pharmacotherapies that control Rinl and Rinl-dependent signalling pathways could help alleviate the symptoms of RA,” Nicole Boucheron looks to the future. Conversely, interventions that inhibit Rinl could be used in immunodeficiency to help the body fight disease. Further research should confirm the results and show whether the Rinl protein can also open up new therapy options for other diseases that are associated with a disturbed immune response, particularly in the regulation of Tfh cells.