News — SAN ANTONIO (June 13, 2023) —A team of scientists from The University of Texas Health Science Center at San Antonio, in collaboration with partners across five nations, unveiled today that the ability to withstand or bounce back from infections and other forms of inflammatory pressure — referred to as "immune resilience" — varies significantly among people. The scientists devised a distinct range of measures to gauge the degree of immune resilience, enabling better healthcare choices and facilitating the comprehension of variations in lifespan and health results among individuals of comparable ages. These discoveries were published in Nature Communications.
The investigation received backing through a MERIT award and additional grants from the National Institute of Allergy and Infectious Diseases (NIAID), which is a division of the National Institutes of Health. Furthermore, it received accolades from the U.S. Veterans Health Administration, as well as a Distinguished Clinical Scientist Award granted by the Doris Duke Charitable Foundation.
Not age-dependent
While age has a significant impact on how the body reacts to infectious and inflammatory stressors, certain individuals manage to maintain or regain optimal immune resilience irrespective of their age, as stated by Sunil K. Ahuja, MD, a professor specializing in infectious diseases at UT Health Science Center San Antonio. Dr. Ahuja, who is both the first and senior author, also serves as the director of the Veterans Administration (VA) Center for Personalized Medicine, a nationwide facility located within the South Texas Veterans Health Care System.
"Weijing He, MD, a senior research scientist at the VA Center for Personalized Medicine and Foundation for Advancing Veterans' Health Research, emphasized that immune resilience refers to the ability to sustain optimal immune function, known as immunocompetence, and reduce inflammation when facing inflammatory stressors. Dr. He, who is a co-author, stated, "Our findings demonstrate that certain individuals are capable of preserving immune resilience even as they age and encounter inflammatory stress, resisting the decline in immune function."
Results
The assessment of immune resilience levels through laboratory tests involved the evaluation of nearly 50,000 individuals across various age groups and with different types of immune system challenges. This comprehensive evaluation revealed that individuals with optimal immune resilience were more inclined to:
- Live longer.
- Resist HIV and influenza infections.
- Resist AIDS.
- Resist recurrence of skin cancer after kidney transplant.
- Survive COVID-19 infection.
- Survive sepsis.
The researchers employed two methods to measure immune resilience:
- They assessed immune resilience by examining the equilibrium between CD8+ and CD4+ T-cells, which are specific types of white blood cells responsible for combating infections. Imbalances in the levels of these T-cells often occur in infectious and autoimmune diseases. The researchers categorized the balance between CD8+ and CD4+ T-cells into four distinct immune health grades. These grades were evaluated across various infection cohorts and across different age groups.
- They measured the expression levels of genes associated with immunocompetence and a higher likelihood of survival, as opposed to genes linked with inflammation and an increased risk of mortality. By identifying gene expression markers indicating high immunocompetence and low inflammation, the researchers were able to track optimal immune resilience using the immune health grade system.
"Commonly, when people contemplate disease outcomes, they tend to focus solely on inflammation," stated Grace C. Lee, PharmD, PhD, a research investigator at the VA Center for Personalized Medicine and an assistant professor at The University of Texas at Austin College of Pharmacy. "Nevertheless, the notion of immune resilience encompasses both levels of immunocompetence and inflammation, providing a more comprehensive understanding."
‘A step forward’
The study introduces the innovative concept of immune resilience, highlighting the significance of maintaining a balance between immunocompetence and inflammation as a crucial determinant of health outcomes, irrespective of age. Grace C. Lee emphasized the importance of this advancement, stating, "This is a notable advantage and a significant step forward because by shifting our focus beyond inflammation, we have the potential to unveil new strategies for the prevention and treatment of chronic diseases, including cardiovascular disease, COVID-19, HIV/AIDS, and various cancers."
Framingham analysis
Muthu Saravanan Manoharan, MS, a senior research scientist at the VA Center for Personalized Medicine and UT Health Science Center San Antonio, pointed out that the study team categorized participants from the Framingham Heart Study into four groups based on the gene expression markers associated with immune resilience. "After accounting for the influence of age and sex, we observed that participants with optimal immune resilience, as indicated by gene expression markers denoting high immunocompetence and low inflammation, lived longer," stated Manoharan. "Participants with metrics indicating low immunocompetence and high inflammation had shorter lifespans, while those with a combination of high immunocompetence and high inflammation or low immunocompetence and low inflammation fell in between in terms of lifespan."
Influenza
The study team also investigated the gene expression markers associated with immune resilience in a population consisting of healthy college students and individuals from the community, all below the age of 50. Blood samples were collected from these participants before the onset of the influenza season. On the day when the participants experienced their initial flu-like symptoms, most individuals, including those who initially exhibited optimal immune resilience, displayed gene expression profiles indicating low immunocompetence and high inflammation, which is typically observed in individuals with shorter lifespans.
During the recovery period, many participants were able to restore their initial level of immune resilience. However, even among those who had optimal immune resilience prior to the influenza infection, some individuals failed to regain their previous level of immune resilience. "Six months after their bout of flu, certain individuals still exhibited gene expression signatures indicative of poor immune health," highlighted Nathan Harper, MS, a senior biostatistician at the VA Center for Personalized Medicine and Foundation for Advancing Veterans' Health Research. "This finding is quite remarkable, as it suggests that inflammatory stressors such as influenza can have long-term detrimental effects on the immune health of vulnerable individuals."
Sex workers
As part of a long-term study, female sex workers from Kenya were examined, and their immune health grades were monitored. The study found that those who engaged in unprotected sex experienced a decline in their immune health grades. Lyle R. McKinnon, PhD, an associate professor in the Max Rady College of Medicine, Department of Medical Microbiology and Infectious Diseases at the University of Manitoba, Canada, explained, "A majority of HIV infections occurred in women who had lower immune health grades."
However, the study also revealed that women who received guidance and tools for safe sex practices and consequently reduced the frequency of unprotected sex over a period of ten years were able to restore optimal immune resilience. This suggests that removing an immunological stressor, such as unprotected sex, can potentially lead to the restoration of a healthier immune status.
HIV-AIDS
In one cohort, the researchers observed a rare ability to maintain high immunocompetence and low inflammation despite chronic inflammation, known as elite immune health. "Interestingly, we noticed that certain young adults maintained optimal immune resilience markers even with HIV infection," stated Jason F. Okulicz, MD, a senior member of the study team and an infectious disease physician in the U.S. Air Force. "Preserving these markers correlated with resistance to AIDS progression and a minimal HIV presence in the bloodstream. Remarkably, early initiation of antiviral therapy resulted in some HIV-positive individuals exhibiting markers of optimal immune resilience typically seen in HIV-negative younger adults."
COVID-19
Similar associations between immune resilience and infection response have been observed in other infectious diseases. Approximately 80% of individuals exhibited low immune health grades upon initial diagnosis of acute COVID-19, and these grades served as a predictor of mortality, irrespective of age. "Even in cases of severe community-acquired pneumonia and sepsis, patients who displayed elevated levels of gene expression markers indicating immune resilience upon admission to the intensive care unit had a higher likelihood of survival," remarked Justin Meunier, BS, a research scientist at the VA Center for Personalized Medicine and coauthor of the study.
Kidney transplant recipients
Immune resilience was also assessed in kidney transplant recipients, a population that faces a significantly higher risk (100-fold excess) of developing skin cancer. All participants had experienced skin cancer once following their transplant. "We examined the likelihood of developing a second cancer based on the immune health grades recorded at the time each participant encountered their initial cancer," explained Matthew J. Bottomley, MD, DPhil, an academic clinical lecturer in the Nuffield Department of Surgical Sciences at the University of Oxford. "We discovered that individuals who exhibited optimal immune resilience during their first cancer episode were resistant to developing subsequent cancers."
In partnership with researchers from Sardinia, the authors conducted a study analyzing the blood immune cell profiles of approximately 4,000 individuals who were otherwise in good health. "We discovered that individuals with low immune resilience displayed immune cell profiles indicative of heightened immune activation, regardless of their age," commented Edoardo Fiorillo, PhD, a coauthor from the Institute for Genetic and Biomedical Research, National Council of Research, Lanusei, Italy. "Interestingly, we also observed similar immune cell profiles in nonhuman primates exhibiting poor immune resilience."
Females show greater immune resilience
An intriguing observation across the studied populations was that age alone did not determine an individual's response to inflammatory stress. Some younger individuals with poor immune resilience displayed similar immune signatures and health grades commonly found in older individuals. This finding implies that the ability to restore and maintain immunocompetence at younger ages might be associated with longevity. Additionally, it was consistently observed across different populations and species that higher levels of optimal immune resilience were more prevalent in females compared to males. Genetic studies conducted in humans and evaluations of mice with genetically determined lower immune resilience suggest that variations in genes may influence immune resilience. Notably, mice with lower immune resilience exhibited the highest susceptibility to severe Ebola infection.
Understanding risks
According to Ahuja, there could be significant public health implications associated with immune checkups. He emphasized that evaluating immune health grades through CD8+ and CD4+ counts provides a straightforward method to monitor immune resilience. Such assessments hold value in identifying individuals who may be more susceptible to immune system-related diseases, assessing treatment responses, and gauging the likelihood and extent of recovery. These checkups can offer valuable insights into the overall status of an individual's immune system.
Funding
This research was supported by the following funders: 1) National Institute of Allergy and Infectious Diseases (NIAID) through grant number R37AI046326 (MERIT award); 2) the U.S. Department of Veterans Affairs (VA) Center for Personalized Medicine through grant number IP1 CX000875-01A1 and a VA MERIT award; and 3) a Distinguished Clinical Scientist Award from the Doris Duke Charitable Foundation. The study with COVID-19 patients was supported by an inter-agency agreement (IAA) from the NIAID Division of Allergy, Immunology and Transplantation (DAIT) to the VA. DAIT manages this IAA; the IAA number is AAI21051-001-00000.
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