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Patients with rheumatoid arthritis have unique autoantibody patterns

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Patients with rheumatoid arthritis have unique autoantibody patterns

Patients with rheumatoid arthritis (RA) all have a unique and diverse set of antibodies that are involved in the development of the disease. Researchers at Utrecht University unveiled the complexity of these antibodies using powerful lab tools capable of analysing our immune system at molecular levels.

Their discovery suggests that current assumptions about the origin of RA are too simple. Still, their findings may point towards improved diagnostics.

Rheumatoid arthritis is a chronic autoimmune disease that primarily affects the joints, causing pain, stiffness, and swelling. It arises when the immune system mistakenly attacks the body’s own tissues, leading to inflammation in the joints and potentially other organs.

The exact cause of RA remains unknown, but a crucial role is played by antibodies, special proteins made by the immune system to help fight off infections. They recognize and attack specific targets, like viruses or bacteria. Some antibodies are wrongly produced, causing them to attack our own body. Normally, our body’s immune system is equipped with a ‘filter’ that cleans up these so-called autoantibodies. Researchers believe that this mechanism is malfunctioning in RA patients.

Extremely broad variety

The extend to which this filter is malfunctioning, now appears to be much greater than expected. Research by Albert Bondt and colleagues from Utrecht University and Leiden University Medical Center (LUMC), published in Nature Communications, reveals that it’s not just a handful of different RA-associated autoantibodies that evade the filter. On the contrary, the researchers found an extremely broad variety of these antibodies.

Unique and diverse

The team used novel mass spectrometry tools that profile specific antibodies typically seen in the blood of RA patients, which are called anti-citrullinated protein antibodies (ACPAs). They discovered that each RA patient possesses a unique and diverse set of ACPAs. Their findings challenge previous assumptions about the backgrounds of RA, that overlooked the antibodies’ diversity and complexity. “This shows that RA is not just a disease occurring due to small errors, but a big structural problem in the immune system”, says Bondt.

More sugar molecules

The study also revealed that these ACPAs are extensively modified with sugar molecules, known as Fab glycans. Intriguingly, some antibodies had multiple sugar molecules attached. This is much more then researchers normally observe in antibody profiles.

Having extra glycans aboard, may help the ACPA antibodies pass the filter of the immune system, says Bondt. The immune system uses several very strict checks during antibody production, to make sure all antibodies are correct. Wrongly produced antibodies are then detected and removed. Bondt suspects that glycans could help ACPAs trick the control system, allowing ACPAs to pass through the filter and form the onset of RA.

Different approaches for treatment

Current efforts to develop treatments for RA are mainly geared towards eliminating autoantibodies directly. This strategy may not be effective, says Bondt. “When you realize that there is such an extreme diversity in RA-related autoantibodies, it seems virtually impossible to eliminate them. A better approach may be to intervene earlier in the disease process, by targeting the malfunctioning filtering mechanism that allows autoantibodies to pass through.”

Understanding these unique proteins is important, as it could ultimately also help doctors diagnose RA better. “When more molecular details about RA-related antibodies are uncovered, the disease may be diagnosed in an earlier stage”, says Bondt.

“Even though RA remains an incurable disease, with an earlier diagnosis you can take better measures to control its progression.”

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New Alzheimer’s treatments could slow memory loss

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Limiting the PTP1B enzyme could slow memory loss in Alzheimer’s, pointing to a potential treatment route, new research suggests.

The enzyme appears to contribute to memory decline in mice by altering how the brain’s immune cells behave, researchers say.

Dialling down PTP1B let microglia clear the protein clumps linked to Alzheimer’s, known as amyloid-beta plaques. Microglia are the brain’s resident immune cells that remove waste.

The study was conducted at Cold Spring Harbor Laboratory, a non-profit in New York, where professor Nicholas Tonks has examined the enzyme since discovering PTP1B in 1988.

Microglia normally sweep up waste in the brain but become less effective as Alzheimer’s, which slowly damages memory and thinking, advances.

The research suggests that PTP1B interacts with spleen tyrosine kinase (SYK), which helps control how microglia respond to damage and remove amyloid-beta.

“Over the course of the disease, these cells become exhausted and less effective,” said Yuxin Cen, the study lead.

“Our results suggest that PTP1B inhibition can improve microglial function, clearing up Aβ plaques,” Cen added.

PTP1B is already known to play a role in metabolic conditions such as obesity and type 2 diabetes, both recognised risk factors for Alzheimer’s disease.

The laboratory is now working to develop PTP1B inhibitors for multiple applications.

For Alzheimer’s disease, Tonks envisages a combination of therapies pairing existing approved drugs with PTP1B inhibitors.

According to the World Health Organisation, cholinesterase inhibitors such as donepezil are currently used to treat Alzheimer’s disease, while NMDA receptor antagonists such as memantine are prescribed for more advanced stages.

“The goal is to slow Alzheimer’s progression and improve the quality of life of the patients,” said Tonks.

More than 55 million people live with dementia globally, with Alzheimer’s disease accounting for up to 70 per cent of cases, according to the WHO.

“It’s a slow bereavement,” said Tonks, whose mother lived with Alzheimer’s.

“You lose the person piece by piece.”

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Technology

Agetech World research and innovation round-up  

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We round up the latest news in agetech research and innovation, from a human trial in ‘reverse ageing’ to the launch of a domestic longevity pod.

Approval has been secured in the United States for the first human trial targeting ‘reverse ageing’.

Boston-based company Life Biosciences will shortly commence trials of its ER-100 treatment which aims to treat eye disease through reprogramming cells.

It will initially treat around a dozen patients with glaucomas – a condition where high pressure inside the eye damages the optic nerve.

Each patient will receive injections of three powerful genes into an eye in an attempt to restore host cells to a healthier state by resetting their epigenetic controls.

It is over 20 years since Dr Shinya Yamanaka’s Nobel Prize work was first able to convert adult cells into pluripotent stem cells.

This reverse cell-editing process allows the regenerated cells – just like those found in an early embryo – to develop into the different, specialised cell types.

This trial has been approved by the Food And Drug Administration (FDA) after initial trials on animals proved a success.

Michael Ringel, chief operating officer at Life Biosciences, said: “It’s an incredibly big deal for us as an industry.

“It’ll be the first time in human history, in the millennia of human history, of looking for something that rejuvenates … So watch this space.”

Inherited longevity

New research claims that longevity-inheritability accounts for around 50 per cent of human lifespan.

For many decades, scientists had rated genetics as being a relatively low factor in human lifespan – compared to other inherited traits – at between 10 per cent and 25 per cent.

However, this new study from the Israeli-based Weizmann Institute of Science, presents an entirely different picture.

Led by Ben Shenhar, a PhD student, from the lab of Prof Uri Alon of Weizmann’s Molecular Cell Biology Department, it analysed three large twin databases from Sweden and Denmark – including a dataset of twins who were raised apart.

The researchers showed that earlier heritability estimates were masked by high levels of extrinsic mortality, such as deaths caused by accidents, infections and environmental hazards.

Their findings are consistent with the heritability of other complex human traits and with findings from animal models.

“For many years, human lifespan was thought to be shaped almost entirely by non-genetic factors, which led to considerable skepticism about the role of genetics in ageing and about the feasibility of identifying genetic determinants of longevity,” said Shenhar.

“By contrast, if heritability is high, as we have shown, this creates an incentive to search for gene variants that extend lifespan, in order to understand the biology of aging and, potentially, to address it therapeutically.”

Longevity blood test

In just a few years a simple blood test should be sufficient to gauge one’s anticipated longevity, claims Dr Tan Min-Han, chief executive and medical director of Singapore and Californian-based firm Lucence.

Dr Tan believes people will be able to go to a clinic near them to take a simple blood test that can detect early signs of ageing.

The results could guide lifestyle changes, such as sleep, diet and exercise, to improve key biomarkers and slow physical decline.

Lucence was founded in 2016 as a spin-off from Singapore’s Agency for Science, Technology and Research. While incorporated and headquartered in Singapore, the company also maintains a co-headquarters in Palo Alto, California.

Since then, it has secured more than US$80m in equity funding, including US$20m in a 2019 funding round led by IHH Healthcare.

He said: “Blood tests are more acceptable and accessible as opposed to uncomfortable procedures like mammograms and colonoscopies. I believe that technology could make a lot of this better.

“Five years ago, being able to detect cancers from blood tests was science fiction. But now, we have made that a reality.”

Longevity pod

A domestic longevity pod known as the E-Salt Cabin has been launched by Eleve Health, a California-based wellness technology company

Roughly the size of a compact car – at just over eight and a half feet long – the pod combines four core therapies: halotherapy, red light therapy, oxygen delivery, and aromatherapy.

Halotherapy disperses a fine, mineral-rich mist designed to support respiratory health. Red light therapy stimulates cellular repair and regeneration. Oxygen delivery aims to improve circulation and energy levels. And custom essential oil blends add a sensory layer

The company says it can be used as a tool to ‘support circulation, clarity, and recovery within a residential setting’.

Eleve said: “The pod reflects a broader shift among ultra-high-net-worth homeowners, with wearable technology, circadian lighting, biophilic interiors, and curated soundscapes becoming standard.”

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Four in ten cancer cases could be prevented globally, report finds

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Up to four in ten cancer cases worldwide could be prevented, a new global analysis has found.

The study examines 30 preventable causes, including tobacco, alcohol, high body mass index, physical inactivity, air pollution, ultraviolet radiation and, for the first time, nine infections that can cause the disease.

Released ahead of World Cancer Day on 4 February, the analysis from the World Health Organization (WHO) and its International Agency for Research on Cancer (IARC) estimates that 37 per cent of all new cancer cases in 2022, around 7.1 million cases, were linked to preventable causes.

Drawing on data from 185 countries and 36 cancer types, the study identifies tobacco as the leading preventable cause of cancer, globally responsible for 15 per cent of all new cancer cases, followed by infections (10 per cent) and alcohol consumption (3 per cent).

Three cancer types, lung, stomach and cervical cancer, accounted for nearly half of all preventable cancer cases in both men and women globally.

Lung cancer was primarily linked to smoking and air pollution, stomach cancer was largely attributable to Helicobacter pylori infection (a bacterial infection of the stomach lining), and cervical cancer was overwhelmingly caused by human papillomavirus (HPV).

Dr André Ilbawi, team lead for cancer control at WHO and author of the study, said: “This is the first global analysis to show how much cancer risk comes from causes we can prevent.

“By examining patterns across countries and population groups, we can provide governments and individuals with more specific information to help prevent many cancer cases before they start.”

The burden of preventable cancer was substantially higher in men than in women, with 45 per cent of new cancer cases in men compared with 30 per cent in women.

In men, smoking accounted for an estimated 23 per cent of all new cancer cases, followed by infections at 9 per cent and alcohol at 4 per cent.

Among women globally, infections accounted for 11 per cent of all new cancer cases, followed by smoking at 6 per cent and high body mass index at 3 per cent.

Dr Isabelle Soerjomataram, deputy head of the IARC Cancer Surveillance Unit and senior author of the study, said: “This landmark study is a comprehensive assessment of preventable cancer worldwide, incorporating for the first time infectious causes of cancer alongside behavioural, environmental and occupational risks.

“Addressing these preventable causes represents one of the most powerful opportunities to reduce the global cancer burden.”

Preventable cancer varied widely between regions.

Among women, preventable cancers ranged from 24 per cent in North Africa and West Asia to 38 per cent in sub-Saharan Africa.

Among men, the highest burden was observed in East Asia at 57 per cent, and the lowest in Latin America and the Caribbean at 28 per cent.

These differences reflect varying exposure to behavioural, environmental, occupational and infectious risk factors, as well as differences in socioeconomic development, national prevention policies and health system capacity.

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