Sooner or later, disease knocks on all doors. However, it does not always get the same response: some people, for instance, have been through Covid-19 asymptomatically, while others end up in the hospital. Age is usually a risk factor, but not necessarily a decisive one. There were elderly people in nursing homes that overcame the infection without flinching, and young people who ended up in intensive care. There are also substantial differences in susceptibility between women and men. Women live longer, and their immune system tends to be more effective in fighting external enemies; but the other side of the coin, explains infectologist Sunil Ahuja, from the University of Texas Health Science Center at San Antonio, is that they are also “more prone to autoimmune diseases.” Genetic and environmental factors, such as exposure to infections or vaccines, influence this diversity in the response to diseases. Now, Ahuja and his team have put another variable under the spotlight: in a study published in Nature Communications, the researchers suggest that immunologic resilience, which is the body’s ability to restore its immune functions and control inflammation, could have something to do with the response to infections and other ailments.
The Covid-19 crisis was Ahuja’s second pandemic; the first one was HIV, in the 1980s. Despite the distance, highly variable response patterns to infections occurred in both, he explains. “We know that there are people exposed to HIV who do not become infected: before antiretroviral therapy was available, only 10% to 30% of children born to mothers with HIV were infected, and between 70% and 90% of children were resistant to HIV despite documented exposure. There is a variable susceptibility to that infection. The same happens with Covid-19. And with the flu and other viruses. There are also people who live longer lives and others who live shorter lives and have exactly the same environment,” he says.
The specialist admits that genetics can play a role; also that there are other health problems or behaviors that may influence this susceptibility, and that external environmental factors can intervene. But immune resilience could also provide another clue. As he explains in his study, immune resilience is “defined as the capacity to preserve and/or rapidly restore immune functions that promote disease resistance (immunocompetence) and control inflammation.” These are two different things, usually opposed: if a person has high inflammation, immunocompetence is low; if they have controlled inflammation, it will be high.
An optimal immunologic resilience is the one that manages to balance these variables. Ahuja uses a slap to illustrate: “If you slap me right now, I will get inflamed and have a temporary reduction in my immune capacity. When people suffer an attack or an aggression, they have to have inflammation; without inflammation, people die. But you need to have the right amount, in the right place and at the right time. Too much or too little is bad. [The point of immune resilience] is that once you control inflammation, immunocompetence quickly improves.” A person can be slapped many times throughout life, by infections or other ailments that compromise this balance, but there are some whose body “manages to preserve immunocompetence and control inflammation,” he explains.
In the study published in Nature Communications, Ahuja and his team compiled research in humans and animal models of various ailments, such as HIV and Covid-19, and examined the data of nearly 49,000 people to analyze their immune resilience and see how it relates to the response to these attacks on the body. To do this, they measured two variables associated with the strength of the immune system and stratified several degrees of resilience: on one hand, they calculated the count of CD4 and CD8 T-cells, which are immune cells in charge of defending the body, and, on the other hand, they studied gene signatures that are associated with longevity and mortality related to inflammation. “What we found is that [the degrees of immune resilience] are strong predictors of a better or worse health outcome, in terms of mortality and hospitalization, after controlling for age.”
Ahuja admits that immune resilience is an inborn trait, but it can be influenced. He explains: “Our ancestors used to die at the age of 50 due to a high burden of infections, but even then there were people who lived longer. Therefore, an obvious problem for immune resilience is the environmental infectious load: that will decrease your ability to recover. But there may be people who, despite this, have an innate ability to maintain it.”
The authors of the study explain that, as expected, immune resilience declines with age — but not always. “Why do young people die from Covid-19? It is possible that a young person, when exposed to an environmental influence, is more susceptible to having a weakened immune health and immune resilience. And if you’re more susceptible, you could be at higher risk of dying,” Ahuja says.
There are gene signatures that are directly associated with aging, and others that are not. The doctor points out that there is a percentage of very old people with a good level of immunologic resilience and that, in fact, although their risk of hospitalization due to illness is high, it is actually lower than that of a younger person with a much worse level of immunologic resilience. In addition, he continues, in a study on the response to common seasonal viruses such as influenza or rhinovirus, the authors discovered that, after the infectious episode, not all young patients recover the immunologic resilience they had before.
The researchers tested their hypotheses against various ailments. Among the participants in a cohort with early HIV infection, for example, the rate of development of AIDS was fastest for those with the lowest level of immune resilience. In another study with kidney transplant recipients, who are up to 100 times more likely to develop a type of skin cancer, the authors found that the risk of a second tumor of this type was lower in those who had the highest degree of immunologic resilience during the first episode of skin cancer.
Women are more resilient
The researchers noted that more immunologic resilience is observed in women of all ages, young and old, of childbearing age or postmenopausal; they have more immunocompetence, which is the ability to restore immune functions that promote longevity and resistance to disease. “Given the importance of immunocompetence for maternal and fetal health, it is conceivable that the immunologic trait associated with resistance to both infections and premature death may have evolved more prominently in females. This sex bias could provide a basis for the observation that females exhibit advantages for immunocompetence and longevity,” the authors state in the article. Ahuja elaborates: “I suspect that this was an innate, appropriate and evolutionarily conserved trait that was useful for maternity. Otherwise, I think we as a species would have had a problem.”
The researchers argue that this degradation of immune resilience is potentially reversible, especially if people stop exposing themselves to inflammatory stressors. Although this was not analyzed in this research, Ahuja also alludes to other studies in which the role of physical exercise in modulating mortality and longevity markers has been demonstrated. “In other studies we have put middle-aged people on an exercise regimen for 24 weeks, and then stopped for another two weeks, and took blood samples. We examined the data and saw that when people exercise continuously, there is an improvement in the markers associated with mortality and longevity. But as soon as the exercise stops, they go back to the beginning. We suspect that sustained, not temporary, exercise, may play a role.”
Oscar de la Calle, secretary of the Spanish Society of Immunology (who did not participate in the study), considers the research by Ahuja and his team convincing and interesting. “This study will have a great impact and open avenues” of research, says the immunologist. “Two or three years ago, since the arrival of Covid-19, people began to talk more about an interesting concept, which is immune frailty: people whose immune system becomes weaker due to their age or stages of life, such as childhood, pregnancy or some disease. The opposite concept would be immune resilience, and one of the variables used in this study is common and we use it in the laboratory.” He refers to the lymphocyte count. De la Calle opens the door so that, in the future, these indicators can be observed, as in a check-up, to identify “deviations from normality.”
The authors defend the potential of immunologic resilience and the metrics that they designed to monitor the health of patients and the prognosis for certain ailments in the future. “If I want to develop an HIV or Covid-19 vaccine that is universally active, I need to make sure that there is no confounding factor that could play a role, beyond a person’s age. That is the value of this work. The point of this whole idea of immune resilience is not just to describe the characteristics of immune resilience, but also to create markers or metrics or a scoring system so that people can be graded,” Ahuja concludes.
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