New clinician resource available explains biological impact of aging on immunity

The American College of Physicians (ACP), the American Pharmacists Association (APhA), and The Gerontological Society of America (GSA), representing 220,000 clinicians, today released "Aging and Immunity: The Important Role of Vaccines", a new resource highlighting the biological impact of aging on immunity.

08 dec 2017--Developed with support by GSK, the guidebook is designed to help health care professionals understand the biological impact of aging on immunity and reinforce the importance of adult immunization, especially for vaccine-preventable diseases such as shingles, pneumonia, and influenza. The guidebook also offers practical tips and strategies for supporting aging patients' health and overcoming barriers to vaccination.

Age-related decline in immunity

"As we age, our immune system declines, making older adults more susceptible to serious conditions," said Jack Ende, MD, MACP, President, ACP. "Understanding the aging immune system is becoming increasingly important for clinicians because vaccination is an effective solution to overcoming some of this age-related decline in immunity."
Research has shown that one of the most important things health care professionals can do to support aging patients is to provide a strong recommendation for them to be vaccinated.
"At every opportunity, clinicians should recommend vaccination according to the schedule from the Advisory Committee on Immunization Practices, have a program that supports vaccine administration, or refer patients to a health care professional who administers vaccines, and document administration of vaccines," said Kelly Goode, PharmD, BCPS, FAPhA, Board of Trustees Member and Immediate Past President, APhA.

As individuals age, the chances of getting shingles increases

"Aging and Immunity" details how cell-mediated immunity deteriorates as a person ages. For instance, in people who had chickenpox as children, deteriorating cell-mediated immunity is considered a factor for why latent varicella zoster virus commonly becomes reactivated in older adults, causing shingles. About one million cases of shingles are diagnosed in the United States every year. Shingles occurs in one in every three people in the United States, mostly adults over the age of 50. For those who live to age 85, one in every two people will contract shingles. The painful condition occurs in people who are healthy as well as people with chronic diseases or immunosuppression. Vaccination is an important way of reducing risk of getting shingles and its complications, like postherpetic neuralgia (PHN) and necessity of prescribing pain relievers.
"Shingles is an example of a disease that afflicts one million adults every year and costs the economy $1 billion in health care expenses. It especially impacts older adults as a direct result of age-related decline in immunity," said James Appleby, BSPharm, MPH, Executive Director and CEO, GSA. "Shingles can affect anyone who carries the varicella zoster virus, and virtually all adults do, whether they had chickenpox during their childhood or not."

Addressing barriers to vaccination

"Aging and Immunity" explains barriers to vaccination at the patient and practice levels and offers recommendations about how clinicians can overcome them. Strategies to improve vaccination rates include using standing orders, collaborating with other health care team members, identifying a staff vaccine champion in the practice, adding reminders to charts, and counseling patients about recommended vaccines.
"We recognize the critical role health care professionals play in educating patients about vaccine-preventable diseases," said Barbara Howe, M.D., Vice President and Director, North American Vaccine Development, GSK. "Our collaboration with ACP, APhA, and GSA reinforces our commitment to educating health care professionals and patients about the importance of vaccination throughout an individual's life.
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More information: www.acponline.org/system/files … d_immunity_guide.pdf


Provided by American College of Physicians

Host, heal thyself: Immune system self-organizes to minimize biological cost of pathogenic infections

Schematic of a statistical model of antigen recognition by the adaptive immune system. After infection, antigen a encounters immune receptor r at random with a rate λa(t). An encounter leads to a successful recognition with a probability fr,a that reflects the matching between a given antigen–receptor pair. 

15 may 2015—The adaptive immune system – a subsystem of the overall immune system – comprises specialized cells and processes that eliminate or prevent pathogen growth by using the experience of past infections to prepare its limited repertoire of specialized receptors to protect organisms from future threats. Recently, scientists at CNRS and Ecole Normale Superieure, Paris and the University of Pennsylvania developed a general theoretical framework from first principles that allowed them to predict the composition of receptor repertoires optimally adapted to minimize the biological cost of infections from a given pathogenic environment. Their theory predicts that the immune system will have more receptors for rare antigens; individuals exposed to the same infections will have largely different repertoires; and competitive antigen/receptor binding and selective amplification of stimulated receptors are key to creating optimal repertoires. Their findings explain how limited populations of immune receptors can self-organize to provide effective immunity against highly diverse pathogens, and moreover inform the design and interpretation of experiments surveying immune repertoires.

Researchers Thierry Mora and Aleksandra M. Walczak discussed the paper that they and their colleagues published in Proceedings of the National Academy of Sciences. "A great deal of very interesting theoretical work has been done on the problem of avoiding autoimmunity – that is, recognizing self-proteins – essentially viewing the immune system as a device for discrimination," Mora tells Medical Xpress. "We wanted to study the problem from a different perspective: As, in essence, introduced by Sir Frank Macfarlane Burnet's theory of clonal selection1, an adaptive immune system adapts to its pathogenic or antigenic environment. We wanted to see how far we could take the idea that the composition and diversity of the immune repertoire reflects that of the environment – in other words, the repertoire is an internal representation of its environment – aimed at minimizing the cost of infections to the tissues of the organism." In short, Mora says, this is one way to look at the complicated problem of the structure of immune repertoires.

This approach allowed the scientists to create a new framework that makes it unnecessary to explicitly model intracellular communication, cell differentiation, activation of cofactors, coordination of different cell types, the interaction with the innate immune system, and the full complexity of the recognition process. "Our goal was to make concrete predictions about adaptive immune repertoires that are general and not specific to one kind of cell type in specific conditions. While these features all play an important role in the functioning of real immune systems, we wanted to see what the essence was, what an optimal but simplified immune system would look like," Walczak points out. "We didn't want to concentrate on the fine details of repertoires, but rather took a step back and try to see what we could learn from global properties while still being realistic enough to make concrete statements about real immune systems – for example, the fact that two individuals in similar environments can have very different optimal immune repertoires." The scientists discovered that their assumption – that is, the system needs to minimize the cost of infection given a limited number of encounters – actually structures the repertoire.

At a high level, the scientists wanted their model to define an effective cost that could encompass and summarize all the aforementioned factors. They found that the surprisingly simple mathematical equation F_a(m) – a general cost function that measures the harm to an organism caused by non-recognition of a pathogen by the immune receptors associated with antigen a that have had m encounters with any pathogen. "Due to its phenomenological generality," Mora says, "there was no particular challenge in defining it – but we nonetheless considered several possible scenarios because there may be issues in deciding what its exact form and values should be." In short, F_a(m) describes how the harm effectively increases with the number of encounters.

"This is an approach that is common in physics, especially statistical physics," Walczak tells Medical Xpress, "where rather than describing the motion of all the particles that make up a gas, we write an effective equation of the state of the gas, or describe the change in the density distribution of the gas. In this study we do something similar: Since we know that there are many processes contributing to how harm increases with the number of infections, that it's impossible to describe them all, and that their detailed form does not really change the effect, we simply ask how we can describe their effect on the immune system. For example," she illustrates, "if the antigen population increases exponentially in real time – which seems like a sensible assumption seeing that non-inhibited pathogens will proliferate exponentially – and the harm to the organism increases with non-recognition also increases exponentially in real time. A simple calculation shows that this means F_a(m) will be linear in relation to the number of encounters."

At the same time, Walczak illustrates, it is easy to imagine that certain infections do not initially harm the organism, and/or that some do significant harm very quickly and then the harm saturates. In other words, one can imagine different costs – so because one can obtain the same effective cost from different molecular processes due to different instances of the infection, the researchers studied effective cost in different specific forms of this function.

"One of our predictions is that the optimal repertoires of two individuals sensing practically the same environment can be very different" Walczak continues. "The concrete position of the receptors in recognition space does not matter, as long as globally they tile antigenic space and provide good coverage. We showed that the immune system can find many optimal solutions to the same problem, so we should not be surprised if two individuals that live in the same conditions and are genetically close have very different repertoires." While these repertoires are optimal and thereby idealized, she notes, the scientists showed they are reached through traditional dynamics long considered when studying lymphocytes, or white blood cells in vertebrate immune systems.

"We also found that, in many situations, optimal repertoires cover the rare pathogens more thoroughly than we would have expected from just their frequency," Mora notes. "If a pathogen is, for example, 100 times more common than another, an adaptive immune system should probably not devote 100 times, but perhaps only 10 times, more resources."

The immune repertoire can self-organize to a state that minimizes cost and provides protection against infections via competitive evolution of receptor populations stimulated by antigens. 

The study's central finding is that limited populations of immune receptors can self-organize to provide effective immunity against highly diverse pathogens. "It's long been known that receptors and antigens are cross-reactive – that is, one receptor can recognize more than one pathogen and vice versa – which in principle allows the pathogenic space to be covered by a reasonably small number of receptors," Mora explains. "However, this does not have to be the case." Walczak notes that while the optimization problem they solve does not try to minimize the diversity of receptors, the optimal repertoires they found do have this limited diversity. "Cross-reactivity tells us that this is possible, but it being optimal surprised us."

The paper also reports that the fact that cross-reactivity (in which a receptor can bind to a variety of antigens) causes the optimal repertoire to fragment is related to the concept of limiting similarity due to competitive exclusion in ecological settings. "Cross reactivity eliminates the need for a unique receptor specific to each antigen – but only if the receptor can recognize the antigen," Walczak notes. "This means that different regions of the pathogen recognition space can have receptors and no receptors, respectively. In a way, it would be a waste to have receptors in places already covered by the cross-reactivity of other receptors." Their research demonstrates this by showing that tiling patterns emerge in the antigenic space as a result of repertoire dynamics in which receptors compete for antigens if one receptor "wins" another cannot be in the same place, a process similar to that found in ecology when species cannot live in the same niche. The organisms compete and one "wins," the other having to go elsewhere – a salient factor in speciation as the two groups evolutionarily diverge.

"Thanks to cross-reactivity," Mora adds, "it doesn't matter exactly where you put a receptor, as long as the entire antigenic space is covered – an observation related to stochastic hyperuniformity2,3 in disordered systems – that is, local randomness but global order."

The study's results follow from a tension between the statistics of pathogen detection, which favor a broader receptor distribution, and the effects of cross-reactivity, which tend to concentrate the optimal repertoire onto a few highly abundant clones. "There are two features that drive the form of the optimal repertoires," Mora explains. "On the one hand, it's important to protect yourself from the rare pathogens, not just the common ones - so you want to place receptors more or less evenly in recognition space. On the other hand, cross reactivity tells you that you do not have to put a receptor at every point of that space—you just have to space them out so there are no blind spots. It's these two properties that drive the form of the solution.

The paper also details the conceptual connection between the immune repertoire and ecological organization. "Since receptors divide and proliferate upon recognition of the antigens, the latter can be seen as resources on which the receptors thrive. Receptors recognizing the same antigens compete against each other – they belong to the same ecological niche, so to speak." Since each niche has limited capacity, only a few receptors may survive in each of them – a process known as competitive exclusion.

As described above, in order to achieve the tiling patterns of optimal repertoires receptors must compete for antigens. "One of the key results about optimal repertoires is that you want to protect yourself both from the rare antigens and the common ones – so resources must be distributed relatively evenly, depending on the details of how fast the cost grows with the number of unsuccessful encounters between receptors and antigen. Moreover, the system must keep the receptors that are good fits against common antigens from dominating. In terms of dynamics, this is achieved by a limited carrying capacity for each niche." Carrying capacity is the maximum population size of a given species that an environment's resources can sustain indefinitely without significantly depleting or degrading those resources.

Within this ecological context, the paper notes that living systems must often sense, internally represent, and respond to salient aspects of complex exogenous influences – and do so using limited resources, such as cell types or genes. For example, in the retina2 and the mammalian olfactory system3 the limited repertoire of resources constrains information processing, forcing these living systems to judicially parse resources in terms of priorities, costs and limitations in order to adapt to the environment. The scientists comment that they "have shown that these elements also shape the optimal form of the immune repertoire."

The scientists assumed that although the immune system cannot predict precisely which antigens it will encounter and when, it incorporates an estimate of the probabilities of their occurrences. "While the immune system cannot know with certainty when and what it will encounter, its goal is to protect us from the unknown," Walczak points out. "It's also very hard to characterize the set of pathogens because the space is just too big. However, if the set of potential threats was completely random from the point of view of the repertoire, the immune system would not be very efficient." In other words, the fact that the immune system is able to respond efficiently suggests that it has adapted to a specific environment, which in turn translates into it incorporating an estimate of the probabilities of the antigenic environment.

Moving forward, the scientists would like to measure recognition space by testing their predictions in high-throughput surveys of receptor and pathogen diversity. "In order to do this," Walczak comments, "we'd need to figure out how to map the sequence of receptors to recognition or affinity, or measure affinity in a high-throughput way." (Affinity measures the strength of interaction between an epitope – the part of an antigen recognized by the immune system – and an antibody's antigen binding site.)

The researchers expect that the new framework and their results will extend to other distributed protection systems where diverse threats are addressed by an array of specific responses. "Yes," Walczak agrees, "the framework is very general, which is why, as discussed, we see very similar properties in systems as diverse as ecology, neuroscience and the physics of disordered systems." In addition, the immune system of bacteria, or the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) system could be studied within a similar framework to predict the relative abundance of CRISPR spacers and corresponding viruses in a coevolving population of bacteria and viruses. "There's a tradeoff between a large number of threats/impulses and limited resources/processing abilities – and the immune system wants to minimize the chances of missing a threat/signal – and in our paper, she says, we've formalized this idea and made concrete predictions."

In addition to the connections with ecology, neuroscience and the physics of disordered systems discussed above, the study's results also inform the design and interpretation of experiments surveying immune repertoires. "There's a lot of interest in how different individuals – that is, either humans or genetically identical mice – respond to the same antigenic environments, and how different their natural repertoires are," Walczak says. "Our results show that it should not be surprising that the responses can be different, because even if their repertoires were optimal, two individuals would have different repertoires."

"Our predictions are about similarity in an effective recognition space," Mora concludes. "Most large scale probing of immune repertoires is based on sequencing the receptors – so mapping recognition space to receptor sequences is an important challenge for future experiments."

More information: How a well-adapted immune system is organized, Proceedings of the National Academy of Sciences (2015) published online before print, DOI:10.1073/pnas.1421827112

A positive boost to the immune system

A positive attitude can boost your immune system and help you live longer. Credit: iStock

22 sept 2014—A positive attitude can improve your immune system and may help you live longer, according to a University of Queensland study.

The research, published in Psychology and Aging has found that older people who focused on positive information were more likely to have stronger immune systems.

Lead researcher Dr Elise Kalokerinos, from UQ's School of Psychology, said a positive attitude played an important role in healthy ageing.

"Despite the fact that people often think of late life as a period of doom and gloom, older people are often more positive than younger people," Dr Kalokerinos said.

"Our research suggests that this focus on the positive may help older people protect their declining health."

The study involved following 50 adults, aged 65-90 years, across two years.

Participants were shown a series of positive and negative photos, which they were later asked to recall, and their immune function was also measured through a series of blood tests.

Dr Kalokerinos said participants who remembered more positive than negative images also showed better immune functioning up to two years later.

"Participants who recalled more positive than negative images had antibodies in their blood suggesting stronger immune systems than those of their counterparts, who did not show this positivity in memory," she said.

"By selectively remembering the positive, older adults seem to boost their immune functioning just when they need it the most.

"We already know that happiness provides a range of health benefits and this research shows that focusing on positive information may have the same effect for older people.

"A person who focuses on positive information over negative information may be better able to cope with stressful situations, may take a more positive long-term outlook on life, and may maintain positive social interactions, thus reaping the immune benefits.

"These findings raise the possibility that humans have evolved to become more positive late in life in order to enhance their own longevity."

Provided by University of Queensland

Equality of the sexes? Not always when it comes to biology

MUHC researchers demonstrate that estrogen renders the innate immune system of women more powerful than that of men

Montreal, 13 may 2009– When it comes to immunity, men may not have been dealt an equal hand. The latest study by Dr. Maya Saleh, of the Research Institute of the McGill University Health Centre and McGill University, shows that women have a more powerful immune system than men. In fact, the production of estrogen by females could have a beneficial effect on the innate inflammatory response against bacterial pathogens. These surprising results were published today in the Proceedings of the National Academy of Sciences.

More specifically, estrogen naturally produced in women seems to block the production of an enzyme called Caspase-12, which itself blocks the inflammatory process. The presence of estrogen would therefore have a beneficial effect on innate immunity, which represents the body's first line of defence against pathogenic organisms. "These results demonstrate that women have a more powerful inflammatory response than men," said Dr. Saleh.

This study was conducted on mice that lack the Caspase-12 gene, meaning that the mice were extremely resistant to infection. The human Caspase-12 gene was implanted in a group of male and female mice, yet only the males became more prone to infection. "We were very surprised by these results, and we determined that the estrogen produced by the female mice blocked the expression of the human Caspase-12 gene," explained Dr. Saleh. "We were also able to locate where the estrogen receptor binds on the gene in order to block its expression, which indicates that the hormone exerts direct action in this case."

Since these experiments were conducted using a human gene, the researchers consider these results to be applicable to humans. This feature of the female innate immune system might have evolved to better protect women's reproductive role.

The positive effect of natural estrogen on our resistence to infection is also exhibited with synthetic hormones such as 17-beta-estradiol. This finding might therefore open the door to new therapeutic applications that reinforce the immune system, but a question remains: will men be amenable to the idea of being treated with an exclusively female hormone?

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Funding

This study was supported by grants from the Canadian Institutes for Health research and the Canadian Foundation for Innovation.

Dr Maya Saleh

Dr. Maya Saleh is a researcher with the Critical Care Division and the Centre for the Study of Host Resistance at the Research Institute of the McGill University Health Centre (MUHC) as well as an assistant professor with McGill University's Faculty of Medicine.