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A new groundbreaking study by researchers from University of Birmingham, UCL, Great Ormond Street Hospital and Birmingham Children’s Hospital has revealed important clues into what is driving disease in children with arthritis.

Cutting-edge techniques have allowed scientists for the first time to uncover the unique architecture of cells and signals inside the joint as inflammation takes hold.

The new study published in Science Translational Medicine looks at arthritis in children, caused by the immune system mistakenly attacking joints. Juvenile idiopathic arthritis affects more than 10,000 children in the UK. It causes swelling, stiffness and pain in the joints over years or decades, leading to damage of the joints and long-term disability. Whilst treatments are available to manage the condition, and in some cases achieve remission, there is no cure. It can take time to find which treatment works for each person. Treatments don’t work in the same way for every child, suggesting there are hidden differences between individuals that we are only beginning to understand.

Deepening the scientific and clinical community’s understanding of the condition is vital if more effective treatments are to be found, and undertaking biopsies in young children provides a new way forward. Working with families of children with arthritis opened the door to this study, as the families advocated for the potential of the study, agreeing that the procedure would be acceptable to families, especially compared to living with a chronic inflammatory disease.

In a world first, tiny tissue samples were collected from the joint lining when children were having medicine injected into the joint. These samples were then analysed with advanced imaging and gene-profiling technologies. The fine resolution maps of the joints revealed differences between children of different ages and cell changes in those with more severe disease. These unique cellular fingerprints may help researchers understand why some drugs work better for some children, and not others. The joints of children with arthritis looked significantly different to those with adults, demonstrating the need to understand arthritis in children better. 

We know how frustrating it can be for families and young people to find a drug that best works for their arthritis. Finding ways to better predict which medicines will be beneficial for a particular child would mean we were able to treat the disease more rapidly and effectively. To achieve this goal, we first needed to understand what cells make-up the lining of the joint where the inflammation occurs.

Equipped with that knowledge, we can now start to tackle the next challenge, determining how these cellular fingerprints within the joint tissue can help us predict which drug will work best, ensuring we give the right drug, to the right child, at the right stage of their disease.” 

Professor Adam Croft, Versus Arthritis Professor of Rheumatology at the University of Birmingham and chief investigator of the study

One of the children who took part in the study was Aurelia, from London, who was diagnosed with arthritis after injuring her knee while on holiday.

“Aurelia is a sporty child and loves art, drama, music and ballet. We noticed pain and swelling of her knee whilst on holiday. We thought perhaps she had injured it playing, but when this didn’t get better and she was struggling to walk, we realised something else was wrong. She was referred to the Rheumatology team at Great Ormond Street Hospital who diagnosed her with arthritis. This came as a bit of a shock given how active she is!

“They offered her a steroid injection in her knee under general anesthetic to alleviate the symptoms. The team asked if we were happy for her to take part in this research study and collect some tissue samples at the same time.

“We were keen for her to be involved, as there’s still a lot of unknowns with arthritis in children, and not all treatments can work. Given that she was already having an anaesthetic, and it wasn’t an additional operation for her, it was a great opportunity for researchers to take samples and to be better able to study the conditions. We hope the study will help other families with children in similar positions to us,” explained Aurelia’s mum, Emily.

Professor Lucy Wedderburn, University College London Great Ormond Street Institute of Child Health and Consultant of Paediatric Rheumatology at Great Ormond Street Hospital said:

“This study represents a real step change in our work with children and young people who live with arthritis, and has been a huge team effort. Rather than having to rely on blood tests which often do not tell us accurately what is happening in the joint, we can now directly analyse the joint lining, across different types of childhood arthritis and different ages. Our findings show that younger children have different types of immune cells invading their joints compared to older children. Samples from children with arthritis looked different to adult samples, with a different make up of immune cells, blood vessels and distinct connective tissue cells. This suggests that treatments may need to vary depending on age and shows why we can’t just extend studies from adult studies to understand arthritis in children.”

The study was funded by the Medical Research Council, Versus Arthritis, National Institute of Health and Care Research, Great Ormond Street Hospital Charity, amongst others, and delivered through the National Institute for Health and Care Research (NIHR) Birmingham Biomedical Research Centre (BRC).

Lucy Donaldson, Director of Research at Versus Arthritis said:

“People with arthritis should never be reduced to just their condition. Each person deserves to be treated holistically as an individual, including, of course, children and young people with arthritis.

“We are very proud to invest in truly innovative research like the MAPJAG study which is helping us to better understand the individual differences between young people with juvenile arthritis.

“The MAPJAG team’s findings clearly show that children and young people aren’t just small adults, but have a different “cellular fingerprint”. Importantly the team have also shown that this can change with age. The findings can give real hope to all those families that more can be done, sooner, to enable young people with arthritis to live the lives they choose.” 

A wider programme of work, made possible by a Medical Research Council partnership award known as Tissue Research in Childhood Arthritis (TRICIA), supports the infrastructure needed for multi-centre tissue research of the joint. In future, it is hoped that a larger study, involving more centres will allow researchers to dig deeper into the remaining questions about how best to tailor treatments for individual patients.

Instrumental to driving this research forward was Dr Eslam Al-Abadi, a study investigator from the Birmingham Women’s and Children’s Hospital NHS Foundation Trust, who sadly passed away before publication. His incredible efforts in seeking to improve the care of children with this disease are gratefully acknowledged.

Chronic inflammation occurs when the immune system is stuck in attack-mode, sending cell after cell to defend and repair the body for months or even years. Diseases associated with chronic inflammation, like arthritis or cancer or autoimmune disorders, weigh heavily on human health-and experts anticipate their incidence is on the rise. A new study by investigators from Mass General Brigham identified a protein called WSTF that could be targeted to block chronic inflammation. Crucially, this strategy would not interfere with acute inflammation, allowing the immune system to continue responding appropriately to short-term threats, such as viral or bacterial infection. Results are published in Nature.

Chronic inflammatory diseases cause a great deal of suffering and death, but we still have much to learn about what drives chronic inflammation and how to treat it. Our findings help us separate chronic and acute inflammation, as well as identify a new target for stopping chronic inflammation that results from aging and disease.”

Zhixun Dou, PhD, senior author of the Center for Regenerative Medicine and Krantz Family Center for Cancer Research at Massachusetts General Hospital

Using chronically inflamed human cells, the researchers found that WSTF interacts with other proteins inside cell nuclei, which prompts its excretion and degradation. Since WSTF is responsible for concealing pro-inflammatory genes, this nucleus-eviction reveals those genes and, in turn, amplifies inflammation. They confirmed that WSTF loss could promote inflammation in mouse models of aging and cancer. They also found, using human cells, that WSTF loss only occurred in chronic inflammation, not acute. Using these findings, the researchers designed a WSTF-restoring therapeutic to suppress chronic inflammation and observed preliminary success in mouse models of aging, metabolic dysfunction-associated steatohepatitis (MASH), and osteoarthritis.

The researchers went further to examine tissue samples from patients with MASH or osteoarthritis. They found that WSTF is lost in the livers of patients with MASH, but not in the livers of healthy donors. Using cells from the knees of osteoarthritis patients undergoing joint replacement surgery, they showed that WSTF-restoring therapeutic reduces chronic inflammation from the inflamed knee cells. These findings highlight the potential of developing new treatments targeting WSTF to combat chronic inflammatory diseases.

Further research is needed to validate the therapeutic potential of WSTF restoration in broader settings and to develop specific strategies to target WSTF. Additionally, the findings suggest other similar proteins may be involved in chronic inflammation, opening a promising new avenue for studying and treating inflammation in the future.

A study published in Cell Stem Cell reveals that some mutations in blood stem cells might help protect against late-onset Alzheimer’s disease.

A team led by researchers at Baylor College of Medicine discovered that both a mouse model and people carrying blood stem cells with mutations in the gene TET2, but not in the gene DNMT3A, had a lower risk for developing Alzheimer’s disease. Their study proposes a mechanism that can protect against the disease and opens new avenues for potential strategies to control the emergence and progression of this devastating condition.

“Our lab has long been studying blood stem cells, also called hematopoietic stem cells,” said lead author Dr. Katherine King, professor of pediatrics – infectious diseases and a member of the Center for Cell and Gene Therapy and the Dan L Duncan Comprehensive Cancer Center at Baylor. She also is part of Texas Children’s Hospital.

Hematopoietic stem cells live in the bone marrow and generate all the different types of blood cells the body needs to stay alive and healthy – red blood cells, immune cells and platelets. As people get older, blood stem cells can develop mutations, and this occurs in about 20% of 70-year-olds. Most of the time, these mutations don’t cause problems, but sometimes, a mutation drives the cells to divide more than others, forming a clone. This process is called clonal hematopoiesis and it has been linked to a higher risk for conditions such as cardiovascular disease, stroke, blood cancers like leukemia and chronic obstructive pulmonary disease. However, many questions remain regarding the connection between clonal hematopoiesis and Alzheimer’s disease.

“In the current study, we investigated the effect of the two genes most commonly mutated in clonal hematopoiesis, TET2 and DNMT3A, on Alzheimer’s disease,” said first author Dr. Katie A. Matatall, instructor in the King lab. “We also selected these mutations because they are involved in inflammation, which is known to be increased in Alzheimer’s disease.”

The researchers assessed the effect of clonal hematopoiesis on the prevalence of Alzheimer’s disease using human data stored in the UK Biobank. They also evaluated the role of mutations in genes Tet2 and Dnmt3a in a mouse model of Alzheimer’s disease.

The team discovered that the two mutations do not behave the same way. Clonal hematopoiesis with the TET2-mutant was associated with a 47% reduced risk of late-onset Alzheimer’s disease in humans, whereas other mutations of clonal hematopoiesis did not confer protection. In a mouse model, transplantation of Tet2-mutant bone marrow reduced cognitive decline and beta-amyloid plaque formation, effects not observed with Dnmt3a-mutant cells.

“Furthermore, we found that the protective effect seemed to be mediated by TET2-clonal stem cells circulating in the blood,” Matatall said. “Immune cells derived from these clones were able to migrate into the brain where they cleared beta-amyloid deposits, a hallmark of Alzheimer’s disease, more effectively than cells without the TET2 mutation. We think that it’s both the increased migration into the brain and the enhanced ability to clear Alzheimer’s-associated damage that drives the better outcomes.”

Until now clonal hematopoiesis has primarily been associated with promoting the progression of disease. This is the first time that these two mutations in blood stem cells have been shown to influence disease in different ways. The findings show that some clonal hematopoiesis promote disease while others, like TET2, may provide protection. We need to think about clonal hematopoiesis in a mutation-specific way and assess their risks and benefits.”

Dr. Katherine King, professor of pediatrics – infectious diseases, Baylor College of Medicine

The findings establish a novel experimental platform for understanding the role of clonal hematopoiesis in Alzheimer’s disease and may inform future approaches to mitigate the risks of central nervous system degenerative diseases.

Source:

Baylor College of Medicine

Journal reference:

Matatall, K. A., et al. (2025). TET2-mutant myeloid cells mitigate Alzheimer’s disease progression via CNS infiltration and enhanced phagocytosis in mice. Cell Stem Cell. doi.org/10.1016/j.stem.2025.06.006.