A Surprising Link Between Immune System and Hair Growth

Regulatory T cells interact with skin cells using glucocorticoid hormones to generate new hair follicles and promote hair growth. The could have positive implications for the development of new therapies to treat alopecia and other hair loss disorders findings.

Salk scientists have uncovered an unexpected molyecular target of a common treatment for alopecia, a condition in which a persyon’s immune system attacks their own hair follicles, causing hair loss. The findings, published in Nature Immunology on June 23, 2022, describe how immune cells called regulatory T cells interact with skin cells using a hormone as a messenger to generate new hair follicles and hair growth.

“For the longest time, regulatory T cells have been studied for how they decrease excessive immune reactions in autoimmune diseases,” says corresponding author Ye Zheng, associate professor in Salk’s NOMIS Center for Immunobiology and Microbial Pathogenesis.

“Now we’ve identified the upstream hormonal signal and downstream growth factor that actually promote hair growth and regeneration completely separate from suppressing immune response.”

The scientists didn’t begin by studying hair loss. They were interested in researching the roles of regulatory T cells and glucocorticoid hormones in autoimmune diseases. (Glucocorticoid hormones are cholesterol-derived steroid hormones produced by the adrenal gland and other tissues.) They first investigated how these immune components functioned in multiple sclerosis, Crohn’s disease and asthma.

They found that glucocorticoids and regulatory T cells did not function together to play a significant role in any of these conditions. So, they thought they’d have more luck looking at environments where regulatory T cells expressed particularly high levels of glucocorticoid receptors (which respond to glucocorticoid hormones), such as in skin tissue.

The scientists induced hair loss in normal mice and mice lacking glucocorticoid receptors in their regulatory T cells. “After two weeks, we saw a noticeable difference between the mice—the normal mice grew back their hair, but the mice without glucocorticoid receptors barely could,” says first author Zhi Liu, a postdoctoral fellow in the Zheng lab.

“It was very striking, and it showed us the right direction for moving forward.” The suggested that some sort of communication findings must be occurring between regulatory T cells and hair follicle stem cells to allow for hair regeneration.

Using a variety of techniques for monitoring multicellular communication, the scientists then investigated how the regulatory T cells and glucocorticoid receptors behaved in skin tissue samples.

‘They found that glucocorticoids instruct the regulatory T cells to activate hair follicle stem cells, which leads to hair growth. This crosstalk between the T cells and the stem cells depends on a mechanism whereby glucocorticoid receptors induce production of the protein TGF-beta3, all within the regulatory T cells.

TGF-beta3 then activates the hair follicle stem cells to differentiate into new hair follicles, promoting hair growth. Additional analysis confirmed that this pathway was completely independent of regulatory T cells’ ability to maintain immune balance.

However, regulatory T cells don’t normally produce TGF-beta3, as they did here. When the scientists scanned databases, they found that this phenomenon occurs in injured muscle and heart tissue, similar to how hair removal simulated a skin tissue injury in this study.

“In acute cases of alopecia, immune cells attack the skin tissue, causing hair loss. The usual remedy is to use glucocorticoids to inhibit the immune reaction in the skin, so they don’t keep attacking the hair follicles,” says Zheng. “Applying glucocorticoids has the double benefit of triggering the regulatory T cells in the skin to produce TGF-beta3, stimulating the activation of the hair follicle stem cells.”

This study revealed that regulatory T cells and glucocorticoid hormones are not just immunosuppressants but also have a regenerative function. Next, the scientists will look at other injury models and isolate regulatory T cells from injured tissues to monitor increased levels of TGF-beta3 and other growth factors.

“Glucocorticoid signaling and regulatory T cells collaborate to maintain the hair follicle stem cell niche” by Ye Zheng et al. Maintenance of tissue homeostasis is dependent on the communication between stem cells and supporting cells in the same niche. Regulatory T cells (Treg cells) are emerging as a critical component of the stem-cell niche for supporting their differentiation.

How Treg cells sense dynamic signals in this microenvironment and communicate with stem cells is mostly unknown. In the present study, by using hair follicles (HFs) to study Treg cell–stem cell crosstalk, we show an unrecognized function of the steroid hormone glucocorticoid in instructing skin-resident Treg cells to facilitate HF stem-cell (HFSC) activation and HF regeneration.

Ablation of the glucocorticoid receptor (GR) in Treg cells blocks hair regeneration without affecting immune homeostasis. Mechanistically, GR and Foxp3 cooperate in Treg cells to induce transforming growth factor 3 (TGF-β3), which activates Smad2/3 in HFSCs and facilitates HFSC proliferation.

The present study identifies crosstalk between Treg cells and HFSCs mediated by the GR–TGF-β3 axis, highlighting a possible means of manipulating Treg cells to support tissue regeneration.

Source: A Surprising Link Between Immune System and Hair Growth – bsfqh

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CDC Approves COVID-19 Vaccines For Children Under 5

U.S. health advisers on Saturday recommended COVID-19 vaccines for infants, toddlers and preschoolers — the last group without the shots.The advisers to the Centers for Disease Control and Prevention unanimously decided that coronavirus vaccines should be opened to children as young as 6 months. On Saturday afternoon, CDC Director Rochelle Walensky signed off on the panel’s recommendation.

“Together, with science leading the charge, we have taken another important step forward in our nation’s fight against COVID-19,” Walensky said in a statement. “We know millions of parents and caregivers are eager to get their young children vaccinated, and with today’s decision, they can. I encourage parents and caregivers with questions to talk to their doctor, nurse, or local pharmacist to learn more about the benefits of vaccinations and the importance of protecting their children by getting them vaccinated.”

HHS Secretary Xavier Becerra released a statement calling the CDC’s move a “major milestone.”

“Thanks to the FDA and CDC’s rigorous, comprehensive, and independent review of the data, and their strict commitment to following the science, we are reaching another major milestone in our efforts to protect more children, their families, and our communities as we work to end the pandemic,” Becerra said. “We are following the data and science as we make sure all Americans are eligible and have access to COVID-19 vaccines and boosters to prevent severe disease and save lives. Based on CDC and FDA actions, we now know that vaccination for our children 6 months through 5 years old is safe and effective and we are ready to get millions of children vaccinated.”

The White House also weighed in on the decision in a statement calling the CDC’s decision a “monumental step forward in our nation’s fight against the virus.””For parents all over the country, this is a day of relief and celebration,” President Biden said in the statemente. “As the first country to protect our youngest children with COVID-19 vaccines, my Administration has been planning and preparing for this moment for months, effectively securing doses and offering safe and highly effective mRNA vaccines for all children as young as six months old.

“While the Food and Drug Administration OKs vaccines, it’s the CDC that decides who should get them. The government has been gearing up for the start of the shots early next week, with millions of doses ordered for distribution to doctors, hospitals and community health clinics around the country. Roughly 18 million kids will be eligible, but it remains to be seen how many will ultimately get the vaccines. Less than a third of children ages 5 to 11 have done so since vaccination opened up to them last November.

Two brands — Pfizer and Moderna — got the green light Friday from the FDA. The vaccines use the same technology but are being offered at different dose sizes and number of shots for the youngest kids.

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Pfizer’s vaccine is for 6 months through 4 years. The dose is one-tenth of the adult dose, and three shots are needed. The first two are given three weeks apart, and the last at least two months later. Moderna’s is two shots, each a quarter of its adult dose, given about four weeks apart for kids 6 months through 5. The FDA also approved a third dose, at least a month after the second shot, for kids with immune conditions that make them more vulnerable to serious illness.

Two doses of Moderna appeared to be only about 40% effective at preventing milder infections at a time when the omicron variant was causing most COVID-19 illnesses. Pfizer presented study information suggesting the company saw 80% with its three shots. But the Pfizer data was so limited — and based on such a small number of cases — that experts and federal officials say they don’t feel there is a reliable estimate yet.

Hospitalizations surged during the omicron wave. Since the start of the pandemic, about 480 children under age 5 are counted among the nation’s more than 1 million COVID-19 deaths, federal data show. “It is worth vaccinating, even though the number of deaths are relatively rare, because these deaths are preventable through vaccination,” said Dr. Matthew Daley, a Kaiser Permanente Colorado researcher who sits on the advisory committee.

U.S. officials expect most shots to take place at pediatricians’ offices. Many parents may be more comfortable getting the vaccine for their kids at their regular doctor, White House COVID-19 coordinator Dr. Ashish Jha said. He predicted the pace of vaccination to be far slower than it was for older populations.

Pediatricians, other primary care physicians and children’s hospitals are planning to provide the vaccines. Limited drugstores will offer them for at least some of the under-5 group. U.S. officials expect most shots to take place at pediatricians’ offices. Many parents may be more comfortable getting the vaccine for their kids at their regular doctor, White House COVID-19 coordinator Dr. Ashish Jha said. He predicted the pace of vaccination to be far slower than it was for older populations.

“We’re going see vaccinations ramp up over weeks and even potentially over a couple of months,” Jha said. It’s common for little kids to get more than one vaccine during a doctor’s visit. In studies of the Moderna and Pfizer shots in infants and toddlers, other vaccinations were not given at the same time so there is no data on potential side effects when that happens. But problems have not been identified in older children or adults when COVID-19 shots and other vaccinations were given together, and the CDC is advising that it’s safe for younger children as well.

About three-quarters of children of all ages are estimated to have been infected at some point. For older ages, the CDC has recommended vaccination anyway to lower the chances of reinfection.Experts have noted re-infections among previously infected people and say the highest levels of protection occur in those who were both vaccinated and previously infected. The CDC has said people may consider waiting about three months after an infection to be vaccinated.

Source: CDC approves COVID-19 vaccines for children under 5 | Fox Business

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How a Special Immune System Protects Our Grey Matter

In the past decade, however, scientists have discovered that the job of protecting the brain isn’t as straightforward as they thought. They’ve learnt that its fortifications have gateways and gaps, and that its borders are bustling with active immune cells.

A large body of evidence now shows that the brain and the immune system are tightly intertwined. Scientists already knew that the brain had its own resident immune cells, called microglia; recent discoveries are painting more-detailed pictures of their functions and revealing the characteristics of the other immune warriors housed in the regions around the brain. Some of these cells come from elsewhere in the body; others are produced locally, in the bone marrow of the skull.

By studying these immune cells and mapping out how they interact with the brain, researchers are discovering that they play an important part in both healthy and diseased or damaged brains. Interest in the field has exploded: there were fewer than 2,000 papers per year on the subject in 2010, swelling to more than 10,000 per year in 2021, and researchers have made several major findings in the past few years.

No longer do scientists consider the brain to be a special, sealed-off zone. “This whole idea of immune privilege is quite outdated now,” says Kiavash Movahedi, a neuroimmunologist at the Free University of Brussels (VUB). Although the brain is still seen as immunologically unique — its barriers prevent immune cells from coming and going at will — it’s clear that the brain and immune system constantly interact, he adds (see ‘The brain’s immune defences’).

This shift in attitude is widespread in the community, says Leonardo Tonelli, chief of the neuroendocrinology and neuroimmunology programme at the US National Institute of Mental Health in Bethesda, Maryland. In his experience, almost every neuroscientist who reviews grant proposals for the agency accepts the connection, he says, although many still need to catch up with the latest discoveries in neuroimmunology, which have started to reveal the underlying mechanisms.

The rush to understand how the brain and immune system knit together has prompted a wealth of questions, says Tony Wyss-Coray, a neuroimmunologist at Stanford University in California. “How important is this in normal brain function or disease? That is a very hard question to answer.”

Privileged space

More than two decades ago, when neuroimmunologist Michal Schwartz had just set up her laboratory at the Weizmann Institute of Science in Rehovot,  she couldn’t stop asking herself an unpopular question: could it really be true that the brain is completely cut off from immune protection? “It was completely axiomatic that the brain cannot tolerate any immune activity — everyone thought that if you have any immune activation, this was a sign of pathology,” she says. “But it didn’t make sense that tissue that is so indispensable, like the brain, cannot enjoy the benefit of being assisted by the immune system.”

The idea that the brain was off limits to the immune system took root decades earlier. In the 1920s, the Japanese scientist Y. Shirai reported that when tumour cells were implanted in a rat’s body, the immune response destroyed them, but when placed in the brain, they survived — indicating a feeble or absent immune response. Similar findings followed in the 1940s.

Most scientists also thought that the brain lacked a system for ferrying immune molecules in and out — the lymphatic drainage system that exists elsewhere in the body — even though such a system was first described in the brain more than two centuries ago. The prevailing view, then, was that the brain and the immune system lived largely separate lives. The two were thought to collide only under hostile circumstances: when immune cells went rogue, attacking the body’s own cells in diseases such as multiple sclerosis.

So when, in the late 1990s, Schwartz and her team reported that after an acute injury to the central nervous system, two types of immune cells, macrophages and T cells, protected neurons from damage and supported their recovery, many scientists were sceptical. “Everyone told me, you’re absolutely wrong,” Schwartz recalls.

Since those early experiments, Schwartz’s team and others have amassed a large body of evidence showing that immune cells do, indeed, have a significant role in the brain, even in the absence of autoimmune disease. Researchers have shown, for example, that in mice engineered to lack an immune system, neurodegenerative diseases such as motor neuron disease (amyotrophic lateral sclerosis) and Alzheimer’s disease seemed to progress more rapidly, whereas restoring the immune system slowed their progression. Scientists have also revealed a potential role for microglia in Alzheimer’s disease.

More recently, scientists have shown that immune cells at the brain’s edges are active in neurodegenerative diseases. After examining the cerebrospinal fluid of people with Alzheimer’s, Wyss-Coray and his colleagues found evidence of a rise in numbers of T cells in the brain’s fluid-filled borders5. The expansion of these immune-cell populations suggests that they might have a role in the disease, Wyss-Coray says.

But whether immune cells hurt or help the brain is an open question. In their studies of Alzheimer’s and other neurodegenerative disorders, Wyss-Coray and his colleagues suggest that the immune system could be damaging neurons by releasing molecules that boost inflammation and trigger cell death. Others have suggested that T cells and other immune cells could instead be protective. For example, Schwartz’s group has reported6 that in mouse models of Alzheimer’s, boosting the immune response leads to a clearance of amyloid plaques — a pathological hallmark of the disease — and improves cognitive performance.

Busy borders

It’s now becoming clear that the brain’s margins are immunologically diverse: almost any type of immune cell in the body can also be found in the area surrounding the brain. The meninges — the fluid-filled membranes that wrap the brain — are an “immunological wonderland”, says Movahedi, whose work focuses on macrophages in the brain’s borders. “There’s so much happening out there.”

Some residents are exclusive to the frontiers. In 2021, Jonathan Kipnis, a neuroimmunologist at Washington University in St. Louis, Missouri, and his colleagues reported7 that there is a local source of immune cells: the bone marrow of the skull.

When they explored how the bone marrow mobilizes these cells, Kipnis and his colleagues demonstrated8 that, in response to an injury to the central nervous system or in the presence of a pathogen, signals carried in the cerebrospinal fluid were delivered to the skull bone marrow, prompting it to produce and release these cells (see ‘Private protectors’).

What role these locally produced immune cells have remains to be seen, but Kipnis’s group thinks that they might have a gentler role than immune cells from elsewhere in the body, regulating the immune response rather than being primed to fight. Kipnis says that this distinction, if true, has implications for treatment. In diseases such as multiple sclerosis, he says, symptoms could perhaps be improved by preventing immune cells from other parts of the body from coming in. By contrast, with a brain tumour, he adds, “you want the fighters”.

His team has also detected a network of channels that snake and branch over the surface of the brain, and which swarm with immune cells, forming the brain’s own lymphatic system9. These vessels, which sit in the outermost part of the meninges, give immune cells a vantage point near the brain from where they can monitor any signs of infection or injury.

In sickness and in health

As evidence builds for the involvement of immune cells during brain injury and disease, researchers have been exploring their function in healthy brains. “I think the most exciting part of neuroimmunology is that it’s relevant to so many different disorders and conditions and to normal physiology,” says Beth Stevens, a neuroscientist at Boston Children’s Hospital in Massachusetts.

Many groups, including Stevens’s, have found microglia to be important to the brain’s development. These cells are involved in pruning neuronal connections, and studies suggest that problems in the pruning process might contribute to neurodevelopmental conditions.

Border immune cells, too, have been shown to be essential in healthy brains. Kipnis, Schwartz and their colleagues, for example, have shown that mice that lack some of these cells display problems in learning and social behaviour10. Others reported11 in 2020 that mice that develop without a specific population of T cells in both the brain and the rest of the body have defective microglia. Their microglia struggle to prune neuronal connections during development, leading to excessive numbers of synapses and abnormal behaviour. The authors propose that during this crucial period, T cells migrate into the brain and help microglia to mature.

One big mystery is how exactly immune cells — particularly those around the borders — talk to the brain. Although there is some evidence that they might occasionally cross into the organ, most studies so far suggest that these cells communicate by sending in molecular messengers known as cytokines. These, in turn, influence behaviour.

Researchers have been studying how cytokines affect behaviour for decades, finding, for example, that cytokines sent out by immune cells during infection can initiate ‘sickness behaviours’ such as increased sleep12. They have also shown in animal models that alterations in cytokines — induced by depleting them throughout the body or knocking out specific cytokine receptors on neurons — can lead to alterations in memory, learning and social behaviours13. How cytokines travel into the brain and exert their effects remains an area of active study.

Cytokines might also be a link between the immune system and neurodevelopmental conditions such as autism. When Gloria Choi, a neuroimmunologist at the Massachusetts Institute of Technology in Cambridge, and her colleagues boosted cytokine levels in pregnant mice, they saw brain changes and autism-like behaviours in the offspring14.

Although these insights are tantalizing, much of the work on how immune cells, especially those in the borders, operate in the brain is still in its infancy. “We are very far away from understanding what’s happening in healthy brains,” Kipnis says.

A two-way street

Communication between the immune system and the brain also seems to go in the other direction: the brain can direct the immune system.

Some of these insights are decades old. In the 1970s, scientists conditioned rats to become immunosuppressed when they tasted saccharin, an artificial sweetener, by pairing it with an immunosuppressive drug for several days15.

In more recent work, Asya Rolls, a neuroimmunologist at Technion — Israel Institute of Technology in Haifa, and her team explored the link between emotion, immunity and cancer in mice. They reported16 in 2018 that activating neurons in the ventral tegmental area, a brain region involved in positive emotions and motivation, boosted the immune response and, in turn, slowed tumour growth.

Then, in 2021, her group pinpointed neurons in the insular cortex — a part of the brain involved in processing emotion and bodily sensations, among other things — that were active during inflammation in the colon, a condition also known as colitis.

By activating these neurons artificially, the researchers were able to reawaken the intestinal immune response17. Just as Pavlov’s dogs learnt to associate the sound of a bell with food, causing the animals to salivate any time they heard the noise, these rodents’ neurons had captured a ‘memory’ of the immunological response that could be rebooted. “This showed that there is very intense crosstalk between neurons and immune cells,” says Movahedi, who wasn’t involved with this work.

Rolls suspects that organisms evolved such immunological ‘memories’ because they are advantageous, gearing up the immune system in situations when the body might meet pathogens. She adds that in certain cases, they can instead be maladaptive — when the body anticipates an infection and mounts an unnecessary immune response, causing collateral damage. This pathway might help to explain how psychological states can influence the immune response, providing a potential mechanism for many psychosomatic disorders, according to Rolls.

It could also inspire therapies. Rolls and her team found that blocking the activity of those inflammation-associated neurons lessened inflammation in mice with colitis. Her group hopes to translate these findings to humans, and is examining whether inhibiting activity using non-invasive brain stimulation can help to alleviate symptoms in people with Crohn’s disease and psoriasis — disorders that are mediated by the immune system. This work is in the early phases, Rolls says, “but it’ll be really cool if it works”.

Other groups are exploring how the brain controls the immune system. Choi’s team is tracing out the specific neurons and circuits that modulate the immune response. One day, she hopes to be able to generate a comprehensive map of the interactions between the brain and immune system, outlining the cells, circuits and molecular messengers responsible for the communication in both directions — and connecting those to behavioural or physiological readouts.

One of the biggest challenges now is to tease apart which populations of cells are involved in these myriad functions. To tackle it, some researchers have been probing how these cells differ at the molecular level, by sequencing genes in single cells. This has revealed a subset of microglia associated with neurodegenerative disease, for example. Understanding how these microglia function differently from their healthy counterparts will be useful in developing treatments, Stevens says. They could also be used as markers to track the progression of a disease or the efficacy of therapies, she adds.

Researchers have already begun using these insights into the immune ecosystem in and around the brain. Schwartz’s team, for example, is rejuvenating the immune system in the hope of fighting Alzheimer’s disease. This work has opened up new avenues for therapeutics, particularly for neurodegenerative conditions, Schwartz says. “It’s an exciting time in the history of brain research.”

By: Diana Kwon

Source: Guardians of the brain: how a special immune system protects our grey matter

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Moderna COVID Vaccine May Pose Higher Heart Inflammation Risk

Source: Moderna COVID vaccine may pose higher heart inflammation risk – U.S. CDC

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Psychiatrists Are Uncovering Connections Between Viruses & Mental Health They’re Surprising

Immune responses to viruses like SARS-CoV-2 may affect mental health, and vice versa. Doctors are uncovering exactly how.

When the Covid-19 pandemic hit, one of the biggest questions was: Why do some people get so much sicker than others? It’s a question that has forced researchers to confront some deep mysteries of the human body, and come to conclusions that have startled them.

By the fall of 2020, psychiatrists were reporting that among the many groups who were high risk, people with psychiatric disorders, broadly, seemed to be getting more severe forms of Covid-19 at a higher rate. Katlyn Nemani, an NYU neuropsychiatrist, decided to dig deeper, asking: Just how much more at risk, and which conditions?

In January, she and a group of colleagues published a study of 7,348 Covid-19 patients in New York. One finding was stark: People with a schizophrenia spectrum diagnosis faced more than two and a half times the average person’s risk of dying from Covid-19, even after controlling for the many other factors that affect Covid-19 outcomes, such as cardiovascular disease, diabetes, smoking, obesity, and demographic factors — age, sex, and race.

“That was a pretty shocking finding,” Nemani says. The patients all were hospitalized in the same medical system, in the same region, which implies they weren’t receiving radically different treatments, she says. In sum, it all suggests that the risk was closely linked to the mental illness itself and not to some other variable.

Since then, more studies have come out — as well as metastudies pooling the conclusions of those studies — showing worse Covid-19 outcomes among people with diagnosed mental health disorders including depression, bipolar disorder, and schizophrenia.

Some of this isn’t surprising; a lot of people with mental health issues experience a general increased risk of poor health outcomes. But the pandemic started to shine a brighter light on why, bolstering a hypothesis that’s been accruing evidence in recent years.

It appears that something in the body, something biological associated with these disorders, may be at play. “That suggests there’s a physiologic vulnerability there in these folks,” said Charles Raison, a psychiatrist and researcher at the University of Wisconsin Madison.

A doctor checks on a Covid-19 patient at Providence Cedars-Sinai Tarzana Medical Center in Tarzana, California, on September 2.
Apu Gomes/AFP via Getty Images

It’s not necessarily that people with schizophrenia or mood disorders are more likely to become infected with Covid-19. Rather, once they are infected, “the outcomes are worse,” Nemani says.

Depending on the study and the severity of the mental health diagnosis, people with these conditions are, roughly, between 1.5 and 2 times more likely to die of Covid-19 than average, after adjusting for other risk factors (unadjusted risk is even higher). The level of increased risk, Nemani says, is “on par with what we’re seeing for other well-established risk factors like heart disease and diabetes.”

What’s happening? Why would mental illness make someone more vulnerable to a respiratory disease?

Psychiatrists who study these mental illnesses say the culprit might lie in a connection between mental health and the immune system. They’re finding that mental health stressors could leave people more at risk for infection, and, most provocatively, they suspect that responses in the immune system might even contribute to some mental health issues.

There’s a lot that’s unknown here. But the pandemic is giving researchers a new window into these questions. And the research “might teach us something about how to protect these people from infection going forward,” Nemani says.

How the immune system can impact mental health

In September, the Centers for Disease Control and Prevention updated its list of underlying conditions that put people at higher risk for severe Covid-19, adding mood disorders — like depression and bipolar disorder — and schizophrenia spectrum diagnoses, a group that accounts for around 34 million Americans. It was a recognition of the growing evidence published by Nemani and colleagues across medicine, and prioritizes this group for vaccines and booster shots.

Roger McIntyre, a psychiatrist at the University of Toronto, is one of the co-authors of one of two systematic review studies that the CDC cited in its change. (Nemani is a co-author on the second.) To him, it’s no surprise that mental illness imparts an infection risk. “A thread that has been woven through many of these disorders is immune or inflammatory dysregulation,” McIntyre says.

That is, problems with the immune system tend to coincide with mental health issues. And problems with the immune system can lead people to have worse outcomes when it comes to SARS-CoV 2, the virus that causes Covid-19.

“Most of the time in medicine, it’s hard to have one singular explanation for anything,” he cautions. That’s especially true here in the discussion of why people with certain mental health issues might be more at risk for severe disease. People living with mental illnesses like schizophrenia, bipolar disorder, and major depression tend to have shorter-than-average life spans and worse health overall. They’re more at risk for heart disease and obesity; they smoke at higher rates. All these risk factors put people with these mental health issues — particularly schizophrenia — at higher risk of death from many causes, including severe infections.

The studies that have been conducted to date try to control for these factors, but it’s impossible to control for them all. Other factors like economic insecurity, added isolation brought on by the pandemic, access to diagnostic testing, or behaviors at the individual level that are hard to account for in studies could play a role.

But the scientific literature does find links between mental health and immune system health. The biggest one: Studies have reported that many people with depression, bipolar, and schizophrenia (as well as other mental health issues not highlighted as Covid-19 risk factors by the CDC) have higher levels of inflammation throughout the body.

Inflammation is one of the body’s responses to dealing with dangerous invaders like the SARS-CoV-2 virus. Inflammation is literally a flood of fluids containing immune system cells. They get released from the blood into body tissues to help clear infections. This is why infected areas of the body get swollen.

An engineer shows a model of the coronavirus at the Sinovac Biotech facilities in Beijing in April 2020.
NIcolas Asfouri/AFP via Getty Images

When inflammation is short-lived, it can help clear out an infection. When it is chronic, it can cause problems. It wears on the heart and can contribute to illnesses like diabetes. When it comes to Covid-19, scientists suspect that underlying inflammation — or underlying dysregulation of the immune system — is what causes some patients’ bodies to overreact to the virus, causing the worst symptoms that can land people in hospitals and lead to death.

As Nemani explains, the inflammation tends to increase with the severity of the mental illness. “For people with depression, you see a small increase in systemic inflammation,” Nemani says. It grows higher in people with severe depression, and higher still in people with bipolar and schizophrenia. (All these conditions exist on a continuum, and there are more and less severe versions of each.)

So people with certain mental health issues might have chronic inflammation, and that could lead to poorer outcomes when it comes to Covid-19. The question is, why do they have chronic inflammation in the first place?

Part of the reason may simply be the chronic stress that comes from living with mental health issues, McIntyre and Nemani say. Stress can provoke an inflammatory response, as can a lack of sleep.

But it’s also possible that the immune system has a role to play in generating these diseases. “Beginning in about 2000, we began to show that inflammation can make people depressed,” Raison says. “The best evidence is that there have been a number of studies where inflammatory stimuli [such as drugs known to cause inflammation] of various intensity and durations have been given to people, and they tend to make people feel depressed and exhausted.”

In depression, McIntyre says, scientists often (but not always) find elevated markers of inflammation in the blood. “Now, it may not be the causative role, although it might be,” he says. “It may be the causative role in some people, and it may be playing more of a secondary role in other people.”

This just provokes another question: Why would the immune system change our mood and influence our exhaustion?

McIntyre makes an example of the common cold to explain. “When you have the common cold, I’m not saying you have depression, but what I’m saying is you have a lot of symptoms that look a lot like depression,” he says. “You feel tired, your sleep is disrupted, you lose your appetite. You’re probably not enjoying many things. You’re quite apathetic. Things are bland in your life. That’s the immune system that’s been activated, creating those symptoms. We think that for some people with depression, that can explain your depressive symptoms.”

That is, when your immune system isn’t working properly, it could contribute to, or even possibly generate, depressive symptoms.

A view of Manhattan streets in April 2020, as the coronavirus overwhelmed New York City.
Spencer Platt/Getty Images

Similarly, it’s possible that the immune system plays a role in generating schizophrenia. There’s a theory that viral exposure while in utero is closely tied with developing psychotic illness or schizophrenia later on,” says Ellen Lee, a psychiatrist and researcher with the University of California San Diego. It’s possible that the mother’s immune response during the infection leaves a lasting impact on the child’s brain and immune system. Other studies have suggested that having a prior autoimmune disorder puts a person at risk for schizophrenia. But, Lee stresses, “There’s so much that we don’t fully understand.”

The bigger point, Lee says, is to recognize that schizophrenia is “a whole-body disorder.” “We see inflammation increase in the brain and we see inflammation increase throughout the body.” That leaves people with schizophrenia at risk of a whole host of chronic illnesses. “The inflammation worsens metabolic health, which then in turn usually leads to obesity and worse inflammation,” Lee says. “So it’s all kind of a cycle.”

How infections could precipitate mental health issues

The evidence for this theory — that immune issues can contribute to mental health disorders — is incomplete.

For one, Raison says that while it seems as though inflammation can contribute to depression, “it has not appeared that blocking inflammation is a particularly robust way to either treat or prevent these disorders.” So there’s a big piece of the puzzle missing there. Another missing piece: There are some cases of depression where inflammation does not appear to play a big role, says McIntyre, and there are probably many unrecognized or underrecognized causes or contributors to mental health issues.

Finally, the mental health conditions mentioned in this piece — depression, bipolar, schizophrenia — are not fully understood to begin with. Scientists just generally don’t understand how much biological overlap there is among them. With depression in particular, some scientists suspect it isn’t just one disease, but perhaps many different ones that manifest with similar, overlapping symptoms.

So the big picture is complicated and incomplete.

But if it is true that the immune system can influence the mind and vice versa, it opens up some important, fascinating questions.

For instance: Can getting sick, and the immune system reaction to fighting a virus, provoke changes in mental health? Our bodies get inflamed when we fight off an infection. Could that impact and even possibly cause or contribute to a mood disorder?

Past work suggests it could. An enormous study of the health records of 3.56 million people born between 1945 and 1996 in Denmark showed that a history of infection and autoimmune disorders predicted later diagnosis of mood disorders. More specifically, the study found that the more infections a person had, the more at risk they’d be for mental health issues later on; there could be a causal pathway here. That makes it seem like the infections themselves are a risk factor.

This also might be playing out in the pandemic. “It seems like having Covid puts you at higher risk for psychiatric illness after infection,” Nemani says. A February study of 69 million individual health records, published in The Lancet, found that “the incidence of any psychiatric diagnosis in the 14 to 90 days after Covid-19 diagnosis was 18.1 percent, including 5.8 percent that were a first diagnosis.” (The study made a few comparisons. Covid infections seem to precede more first time mental health diagnoses than breaking a bone, getting a kidney stone or a gallstone, and seem to precede more diagnoses than other infections like the flu.)

Exactly how this unfolds is not fully understood. Some of it might be due to the peculiarities of Covid-19 and how it can infect nervous system tissues, and is possibly a unique symptom of long Covid. (As reported in the Lancet study, Covid-19 patients were around twice as likely to develop a psychiatric illness for the first time compared to a control group of people who were sick with the flu.) But it also could be because many viral infections can nudge people’s mental health in a poor direction.

Consider the common cold example McIntyre laid out above. What if, after getting an infection, the lethargic wasting feeling doesn’t leave? There’s some suspicion that changes to the immune system, wrought by battling the virus, could do that.

Again, this is hardly settled science. But the pandemic presents these psychiatry researchers with an opportunity to ask these questions. When it comes to mental health risk after an infection, “what we’re going to need to do is tease apart what’s due to general stress from the pandemic itself — people losing people that they love, the stress of just getting the diagnosis itself, all of the life changes that came along with it — from the potential immune effects of the virus,” Nemani says.

More questions could be answered, too. “Looking ahead, we might be able to better understand how a viral infection can lead to new onset psychiatric illness,” she says. “If we can better understand that mechanism, we might be able to identify treatment targets that could potentially help treat psychiatric symptoms … and maybe even bolster the immune system of susceptible patients.”

Taking care of mental health can help communities prepare for outbreaks

Despite scientists having an incomplete picture of the science here, they believe it’s still useful to know that mental health issues can be a precursor to infection risk, or vice versa.

Recently, public health researchers at Yale published a study that found a county-level correlation between people’s general mental well-being and confirmed cases of Covid-19. Whereas the meta-reviews mentioned above looked at infection risk for actual diagnoses, this study looked at a more general measure of “poor mental health days.” It’s a self-reported measure that simply has people recall “the number of days that you are kind of feeling down or had some emotional issues,” Yusuf Ransome, the Yale epidemiologist who led the study, says.

In this study, “poor mental health days” is used as a way to take the mean mental health temperature of a region, and it does seem to be correlated to outbreak risk. At this zoomed-out level of analysis, it’s even harder to determine causality. But at least, Ransome says, it suggests that when it comes to the intersection of mental health and infection, we shouldn’t just focus on issues that rise to the level of a diagnosis.

On the left: diagnosed Covid-19 cases between January 22 and October 7, 2020, per 10,000 people. On the right: the average number of days adults had poor mental health.
American Journal of Preventative Medicine

“When we are only focusing on clinical manifestations, we might miss sort of the much more lay version of how people are experiencing mental health,” he says. “We need to look at even the most basic indicators of mental well-being. We don’t necessarily need to have the whole population diagnosed by a clinician for depression to understand the severity of the impact.”

To identify communities where mental health is overall poor, he says, is to potentially target them for interventions and outreach to help deal with future viral outbreaks.

For now, the scientists who research this intersection of mental health and the immune system want the public to know that mental health disorders can be whole-body disorders. They don’t just impact the brain. And for that, they applaud the CDC’s decision to recognize these disorders as being risk factors for severe Covid-19. A lot of people with such disorders are underserved by health care in general.

“People with mental health disorders — especially schizophrenia, severe depression — they don’t receive primary care interventions as often as other people,” Nemani says. “The fact that the CDC updated their high-risk list to include some of these mental health conditions was just, you know, a really great thing that really might help save lives.”

It’s hard to think of any silver linings in the pandemic, but one is the potential to gain knowledge. “We have a single virus at a single point in time, infecting so many people at a scale that we’ve never seen before,” Nemani says.

If scientists can use the pandemic to learn even more about the nature of these mental illnesses and how they interact with the immune system, more future lives could be saved, too.

Source: Can depression worsen Covid-19 and other infections? And can a virus make you depressed? – Vox


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