A multinational study identifies immune resilience as a factor
that influences life span, HIV/AIDS, flu, sepsis mortality,
recurrent skin cancer and COVID-19 mortality. Researchers from The
University of Texas Health Science
Center at San Antonio and the VA
Center for Personalized Medicine at the South Texas Veterans Health
Care System coordinated the study.
SAN
ANTONIO, June 25, 2023 /PRNewswire-PRWeb/ --
Researchers from The University of
Texas Health Science Center at San
Antonio, working with collaborators in five countries,
revealed that the capacity to resist or recover from infections and
other sources of inflammatory stress — called "immune resilience" —
differs widely among individuals. The researchers developed a
unique set of metrics to quantify the level of immune resilience.
This will aid in decisions for health care and help researchers
understand differences in life span and health outcomes in persons
of similar ages. These findings were published in Nature
Communications.
The study was supported by a MERIT award and other grants from
the National Institute of Allergy and Infectious Diseases (NIAID),
part of the National Institutes of Health; awards from the U.S.
Veterans Health Administration; and a Distinguished Clinical
Scientist Award from the Doris Duke Charitable Foundation.
Not age-dependent
Although age plays an important role in the body's response to
infectious and other inflammatory stressors, some persons preserve
and/or restore optimal immune resilience regardless of age, noted
first and senior author Sunil K.
Ahuja, MD, professor at UT Health Science Center San Antonio
with a specialty in infectious diseases. He is director of the
Veterans Administration (VA) Center for Personalized Medicine, a
national center within the South Texas Veterans Health Care
System.
"Immune resilience is the capacity to maintain good immune
function, called immunocompetence, and minimize inflammation while
experiencing inflammatory stressors," said Weijing He, MD, co-author and senior research
scientist at the VA Center for Personalized Medicine and Foundation
for Advancing Veterans' Health Research. "We found that during
aging and when experiencing inflammatory stress, some persons
resist degradation of immune resilience."
Results
The laboratory tests developed to assess levels of immune
resilience were evaluated in nearly 50,000 persons of differing
ages and types of challenges to their immune systems. This
evaluation demonstrated that individuals with optimal levels of
immune resilience were more likely 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 measured immune resilience in two ways:
- By measuring the balance between CD8+ and CD4+ T-cells, which
are types of white blood cells. T-cells fight infections, but an
imbalance in their levels occurs in many infectious and autoimmune
diseases. The balance between CD8+ and CD4+ T-cells, divided into
four distinct categories called immune health grades, was measured
in varied infection cohorts and across the age spectrum.
- By measuring the expression levels of genes linked with
immunocompetence and a greater chance of survival versus those
linked with inflammation and a higher risk of death. The gene
expression markers signifying high immunocompetence and low
inflammation were identified with the immune health grade tracking
optimal immune resilience.
"Many people think of inflammation alone when considering
disease outcomes," explained co-author Grace C. Lee, PharmD, PhD, research investigator
at the VA Center for Personalized Medicine and assistant professor
at The University of Texas at Austin
College of Pharmacy. "However, the concept of immune resilience
captures levels of immunocompetence and inflammation together."
'A step forward'
The study introduces the novel concept of immune resilience,
which looks at the balance between immunocompetence and
inflammation as a critical contributor to health outcomes,
regardless of age. "This is an advantage and a step forward because
by looking beyond inflammation, we may uncover new prevention and
treatment strategies for chronic diseases such as cardiovascular
disease, COVID-19, HIV/AIDS and cancers," Lee said.
Framingham analysis
Muthu Saravanan Manoharan, MS,
coauthor and senior research scientist at the VA Center for
Personalized Medicine and UT Health Science Center San Antonio,
noted that the study team divided participants from the Framingham
Heart Study into four groups based on the gene expression markers
of immune resilience. "Participants with optimal immune resilience,
defined by gene expression markers signifying high immunocompetence
and low inflammation, lived longer after controlling for the
effects of age and sex," Manoharan said. "Participants with metrics
signifying low immunocompetence-high inflammation died sooner,
whereas those with a combination of high immunocompetence-high
inflammation, or low immunocompetence-low inflammation, had life
spans that fell in between."
Influenza
The study team also examined gene expression markers of immune
resilience in a population of healthy college students and
individuals in the community, all under age 50, who had blood drawn
before the influenza season started. On the day of the first
symptoms, most participants, including those with optimal immune
resilience before the flu-like illness, had gene expression
profiles indicating low immunocompetence and high inflammation,
which is noted in persons with shorter life spans. Many people
restored their initial level of immune resilience during recovery;
however, even some of those who had optimal immune resilience
before influenza infection failed to do so.
"Six months after their flu, some people continued to have gene
expression signatures of poor immune health," noted Nathan Harper, MS, coauthor and senior
biostatistician at the VA Center for Personalized Medicine and
Foundation for Advancing Veterans' Health Research. "This is rather
striking, because it means that inflammatory stressors like
influenza can degrade a vulnerable person's immune health long
term."
Sex workers
The study examined female sex workers from Kenya. During a long-term study, the immune
health grades of those with unprotected sex decreased. "Most of the
HIV acquisition occurred in women who had lower immune health
grades," said Lyle R. McKinnon, PhD,
coauthor and associate professor in the Max Rady College of
Medicine, Department of Medical Microbiology and Infectious
Diseases, at the University of
Manitoba, Canada. "With guidance and tools for safe sex
practices, women with a lower frequency of unprotected sex over a
10-year time frame had restored optimal immune resilience,
suggesting that removal of an immunological stressor could lead to
the restoration of a healthier immune status."
HIV-AIDS
In one of the cohorts, the authors observed a rare ability to
maintain a high level of immunocompetence with a low level of
inflammation despite chronic inflammatory stress, termed elite
immune health status. "Interestingly, we found that some younger
adults preserved optimal immune resilience markers despite HIV
infection," said Jason F. Okulicz,
MD, U.S. Air Force infectious disease physician and senior member
of the study team. "The preservation of these markers associated
with resistance to developing AIDS and a low level of HIV in the
blood. Remarkably, we found that after starting antiviral therapy
early, some HIV-positive persons manifested markers of optimal
immune resilience typically observed in younger adults without HIV
infection."
COVID-19
The association between immune resilience and the response to
infection was noted during other infections. About 80% of
individuals had poor immune health grades at presentation with
acute COVID-19, and their immune grade predicted mortality,
regardless of age. "Even among patients with serious
community-acquired pneumonia and sepsis, those who had higher
levels of gene expression markers of immune resilience at admission
to the intensive care unit were more likely to survive," noted
coauthor Justin Meunier, BS,
research scientist at the VA Center for Personalized Medicine.
Additional reading on this research:
- NIH director's blog
- NIAID blog
- Research team's blog
Kidney transplant recipients
Immune resilience was also measured in kidney transplant
recipients, who have a 100-fold excess risk of developing skin
cancer. Each of the participants had developed this cancer once
after transplant. "We explored the risk of getting a second cancer,
dependent on immune health grades at the time each participant had
the first cancer," said Matthew J.
Bottomley, MD, DPhil, academic clinical lecturer in the
Nuffield Department of Surgical Sciences, University of Oxford. "We found that, if someone
had optimal immune resilience at the time of the first cancer, they
resisted getting their second cancer."
In collaboration with investigators from Sardinia, the authors examined blood immune
cell profiles of nearly 4,000 otherwise healthy individuals. "We
found that irrespective of age, persons with poor immune resilience
had immune cell profiles reflecting increased immune activation,"
noted coauthor Edoardo Fiorillo,
PhD, of the Institute for Genetic and Biomedical Research, National
Council of Research, Lanusei, Italy. "Interestingly, we observed that
nonhuman primates with poor immune resilience also manifested
similar immune cell profiles."
Females show greater immune resilience
One consistent finding throughout the populations studied was
that age was not the single determinant factor in a person's
response to inflammatory stress. Some younger persons with poor
immune resilience had the same signatures and immune health grades
commonly seen in older persons. This finding suggests that the
ability to restore and maintain immunocompetence at younger ages
may be linked to life span. Another factor noted across the
populations and species was that higher levels of optimal immune
resilience were observed more often in females than males. Genetic
studies in humans and evaluation of mice with a genetic basis to
have lower immune resilience suggest that immune resilience may be
calibrated by variations in genes. Notably, mice with lower immune
resilience were most susceptible to severe Ebola infection.
Understanding risks
Public health ramifications of immune checkups could be
significant, Ahuja said. He noted that assessment of immune health
grades estimated by CD8+ and CD4+ counts is a simple way to monitor
immune resilience. These assessments have utility for understanding
who might be at greater risk for developing diseases that affect
the immune system, how individuals are responding to treatment, and
whether, as well as to what extent, they will recover.
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.
Immune resilience despite inflammatory stress promotes longevity
and favorable health outcomes including resistance to infection
Sunil K. Ahuja, MD; Muthu Saravanan Manoharan, MS; Grace C. Lee, PharmD, PhD; Lyle R. McKinnon, PhD; Justin A. Meunier, BS; Maristella Steri, PhD; Nathan Harper, MS; Edoardo Fiorillo, PhD; Alisha M. Smith, PhD; Marcos I. Restrepo, MD, MSc, PhD; Anne P. Branum, BS; Matthew J. Bottomley, MD, DPhil; Valeria Orrù,
PhD; Fabio Jimenez, BS; Andrew Carrillo, BS; Lavanya Pandranki, MS;
Caitlyn A. Winter, MS; Lauryn A. Winter, MS; Alvaro A. Gaitan, MD; Alvaro G. Moreira, MD; Elizabeth A. Walter, MD; Guido Silvestri, MD; Christopher L. King, MD, PhD; Yong-Tang Zheng, PhD; Hong-Yi Zheng, PhD; Joshua Kimani, MD, MPH; T. Blake Ball, PhD; Francis
A. Plummer, MD; Keith R.
Fowke, PhD; Paul N. Harden,
MD; Kathryn J. Wood, PhD;
Martin T. Ferris, PhD; Jennifer M. Lund, PhD; Mark T. Heise, PhD; Nigel Garrett, MBBS, PhD; Kristen R. Canady, MD, PhD; Salim S. Abdool Karim, MD, PhD; Susan J. Little, MD; Sara Gianella, MD; Davey
M. Smith, MD, MAS; Scott
Letendre, MD; Douglas D.
Richman, MD; Francesco Cucca,
MD, PhD; Hanh Trinh, MD;
Sandra Sanchez-Reilly, MD;
Joan M. Hecht, RN; Jose Cadena, MD; Antonio
Anzueto, MD; Jacqueline A.
Pugh, MD; South Texas Veterans Health Care System COVID-19
team; Brian K. Agan, MD;
Robert Root-Bernstein, PhD;
Robert A. Clark, MD; Jason F. Okulicz, MD; Weijing He, MD
First published: Nature Communications, June 13, 2023
https://www.nature.com/articles/s41467-023-38238-6
The University of Texas Health
Science Center at San Antonio (UT
Health San Antonio), is one of the country's leading health science
universities and is designated as a Hispanic-Serving Institution by
the U.S. Department of Education. With missions of teaching,
research, patient care and community engagement, its schools of
medicine, nursing, dentistry, health professions and graduate
biomedical sciences have graduated more than 42,200 alumni who are
leading change, advancing their fields and renewing hope for
patients and their families throughout South Texas and the world. To learn about the
many ways "We make lives better®," visit UTHealthSA.org.
Stay connected with The University of
Texas Health Science Center at San
Antonio on Facebook, Twitter, LinkedIn, Instagram and
YouTube.
Media Contact
Will Sansom, The University of Texas Health Science Center at
San Antonio, 210-567-2579,
sansom@uthscsa.edu
Twitter
SOURCE The University of Texas
Health Science Center at San
Antonio
