Medical Bulletin 29/ February / 2024

A new study from the University of Massachusetts, Amherst focuses on the rare autoimmune disorder, aplastic anemia, to understand how a subset of cells might be trained to correct the aggressive immune response that can lead to fatal autoimmune disorders.

The research, published in Frontiers in Immunology, identifies a specific enzyme, known as PRMT5, as a key regulator of suppressive activity in a specialized population of cells.

The human immune system is remarkable, but in rare cases like aplastic anemia, it can malfunction. In such condition, immune cells, such as theTh1 cells, mistakenly attack healthy stem cells in the bone marrow, disrupting blood cell production essential for fighting infections, carrying oxygen, and preventing bleeding.

“What we want to do is to make a super-suppressive cell,” says Nidhi Jadon, graduate student in the Department of Veterinary and Animal Sciences at UMass Amherst and the paper’s lead author. “If someone is suffering from an autoimmune disorder, we can use these super-suppressive cells to dampen the aberrant immune response instead of drugs.”

Lisa M. Minter, a professor at UMass Amherst, developed an innovative mouse model to simulate human immune responses seen in aplastic anemia. This model featured engineered Th1 cells, inducing the disorder, focusing on training iTregs, cells responsible for suppressing the immune response, within the unique chemical environment Th1 cells create. Th1 cells utilize this environment to summon reinforcements, exacerbating the attack on bone marrow stem cells.

The findings revealed that the iTregs were very effective at reducing the Th1-mediated immune response in the animal model of aplastic anemia. After close observation, it was discovered that iTregs trained in the Th1-like chemical environment increased production of a specific enzyme, called PRMT5, which, in turn blocked the expression of another specific gene—Sirt1—that destabilizes iTregs and makes them less effective.

“No one before us has shown that PRMT5 plays such an important role in mediating the immune suppressive capacity that iTregs display, when they are generated under conditions found in a Th1-mediated immune response,” says Minter. “We’re one step closer to finding that super-suppressive cell that can replace drug therapies.”

Reference: Frontiers in Immunology; DOI:10.3389/fimmu.2023.1292049

Sinusitis may be connected to a 40% elevated risk of rheumatic disease

A study published in the open access journal RMD Open revealed that the common inflammatory condition sinusitis is associated with a 40% increased risk of subsequent diagnosis of rheumatic disease. This risk is particularly notable in the 5 to 10 years leading up to the onset of symptoms.

Sinusitis involves inflammation of the sinuses, the air-filled cavities behind the cheekbones and forehead. Previous research suggests a connection between lung irritants like air pollution and respiratory infections, and conditions like rheumatoid arthritis. However, it remains uncertain whether sinusitis could predispose individuals to other rheumatic diseases.

The scientists conducted a control study using data from the Rochester Epidemiology Project (REP), a medical records-linkage system covering over 500,000 individuals between 1966 and 2014. The study sample comprised 1729 adults newly diagnosed with systemic autoimmune rheumatic diseases or vasculitis, matched with 5187 individuals without rheumatic disease based on age and sex. Patients' history of sinusitis before rheumatic disease diagnosis was analysed in time segments of 1 to 5 years, 5 to 10 years, and over 10 years. Factors such as age, BMI, smoking status, sex, race, and ethnicity were considered in the analysis.

The findings showed that the average time from sinusitis to rheumatic disease diagnosis was around 7.5 years, with rheumatoid arthritis and polymyalgia rheumatica being the most common diagnoses. Sinusitis history was linked to a 40% higher risk of any new rheumatic disease. The association was strongest 5–10 years before symptom onset, with a 70% higher overall risk.

The more frequent the episodes of sinusitis, the greater were the chances of a new rheumatic disease diagnosis. Serial episodes of sinusitis without a previous history also showed a significant dose-response association, rising to a risk for 5 or more episodes.

Reference: RMD Open; DOI: 10.1136/rmdopen-2023-003622

Scientists find leaky gut may be linked to faster biological aging

Recent research published in the journal Microbiome revealed a link between viral damage to the gut and accelerated biological aging. The findings suggest that this association can lead to increased gut permeability and premature aging of systemic and intestinal tissues, particularly in individuals with chronic HIV infection.

Accelerated biological aging, when the body ages faster than its chronological years, increases susceptibility to serious health conditions typically associated with older adults, such as cancer, heart disease, brain disorders, severe infections, and decreased vaccine efficacy. The gut microbiome and its possible leakage into the bloodstream are implicated as key factors in this aging process.

Dr. Abdel-Mohsen, Wistar Institute's associate professor along with his collaborators, investigated how gut leakage can impact the immune system and lead to chronic inflammation, which may accelerate aging by analysing samples from people living with chronic HIV infection, which is known to potentially accelerate biological age. This makes it a suitable model to investigate mechanisms of accelerated biological age in people living with chronic conditions.

The team examined colon, ileum, stool, and blood samples from individuals with chronic HIV infection along with matched controls and discovered a significant correlation between disrupted gut microbiomes, heightened intestinal permeability (leaky gut), and accelerated biological aging. They also found a link between accelerated biological aging and the microbiomes of both the colon and ileum, but not the fecal microbiome.

The findings indicated that the location of the microbiome greatly influences its effects and that the biological age can be assessed through various advanced techniques such as telomere length analysis and epigenetic clocks, which estimate age by examining DNA methylation patterns.

"More investigation is needed to fully understand the underlying causes and potential impacts of our findings," said Dr. Abdel-Mohsen. "Moreover, there's a crucial need to create strategies to prevent intestinal dysbiosis and gut leakiness and to determine how these strategies could affect an individual's biological age. Our work is just the beginning of an exciting journey into enhancing health and longevity."

Reference: Mohamed Abdel-Mohsen. Distinct intestinal microbial signatures linked to accelerated systemic and intestinal biological aging. Microbiome, 2024; 12 (1) DOI: 10.1186/s40168-024-01758-4