Tag Archives: immune system

Cytokines in Psychopathology: How the Immune System Can Induce PTSD

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Artistic Rendering of a Cytokine

Artistic Rendering of a Cytokine: 11 April 2018 www.scientificanimations.com

Microscopic proteins, known as cytokines, are the master-coordinators behind a multitude of vital operations in the body. From stitching up a scraped knee, to forging an aching fever, to even activating blood assembly—cytokines are the regulatory bodies behind growth and repair, the immune system and inflammation, as well as cell division. Although these immune communicators are well versed in fighting off infection, mounting evidence has demonstrated their fluency in the nervous system’s language: including the development of mental illnesses. 

However, cytokines function in a highly sensitive regulatory harmony within our bodies. One tiny miscalculation may result in a dysfunction: an overproduction or underproduction of cytokines, particularly those that interact with immune cells, can send the body into disarray. Although cytokines are crucial to the immune response, these miniature communicators transform into harmful vandals when they overwhelm the body. And when they fail to make an appearance, their absence, too, unleashes an assortment of issues.

Pro-inflammatory cytokines, an important component of the immune system, help dispel pathogens during infection—in the short term. But when they linger in the body, smothering it with chronic inflammation, they trigger widespread dysfunction through complex biological pathways. 

Cytokines bridge the gaps in the bigger picture of the body’s functioning: they tell the immune system what substances in the body are foreign, and should be marked for destruction. They signal when cells should divide. However, if these important organizers of the body go haywire, we experience some major misdirection.  

An example of this incompetent signaling, chronic inflammation, can provoke life-threatening complications, including heart disease, diabetes, arthritis, and even cancer. Pro-inflammatory cytokines’ overabundance during chronic inflammation in cancer, for example, can induce cell production and alter cell survival for the worse. By modifying how cells divide, cytokines transform cells in ways that render them cancerous: proliferating out of control. 

Cytokines are impressively effective at altering cell-functioning, such as their potential to mutate healthy cells into ones with cancer. Although the inflammation theory of disease is well-documented and explored for a multitude of disorders, a lesser-known role of cytokines is their influence on the brain: particularly in psychological disorders. Dysfunctional cytokines can manifest in a dysfunctional mind—including disorders such as depression, anxiety, bipolar, and even PTSD. 

Cytokines can induce mental dysfunction by altering neural communication, as well as glial communication, both of which are intrinsic to mental illnesses. Although they command cell-signaling through many pathways, one route by which cytokines veer the brain towards psychopathology (a mental or behavioral disorder) is through changing neurotransmitter functioning. Neurotransmitters are chemical signals that direct neuron firing, and, in excess or deficiency, can lead to mental disorders. 

Once a cytokine’s signal reach the brain, it can influence the synthesis, release, and reuptake of neurotransmitters including serotonin, dopamine, and norepinephrine. These neurotransmitters are especially critical in the development of depression, anxiety disorders, bipolar, and schizophrenia: some of the most common mental illnesses. 

Swiergiel and colleagues have tested these theories about cytokines and psychopathology through experiments assessing cytokines’ effect on mental dysfunction through mice studies, and found that administering IL-1b (an inflammatory cytokine known as interleukin 1 beta) in mice can induce increased anxiety reactions when exploring an open field, or in a maze. 

By inducing an artificial immune dysfunction, we are able to show how real immune dysfunction can alter brain functioning. In this case, these cytokines drastically transformed how the mice responded to their environment: rendering neutral environments threatening, and foreign environments even more daunting. 

Further, in human studies, researchers such as Chang and colleagues have found elevated pro-inflammatory cytokine levels in patients with schizophrenia and those with depression, as well as reduced anti-inflammatory cytokine levels. This finding implies that an imbalance in cytokine concentrations–which can be induced by a variety of factors, including diet, environmental pollutants, obesity, or stress–can play a critical role in the development of anxiety disorders, schizophrenia, and depression.

Additionally, recent research by the Lysle Lab at UNC Chapel Hill has shown that SEFL (stress-enhanced fear learning, a rat model of PTSD) will not develop after a stressful event without the release of IL-1b from the hippocampus, a brain region that stores memories.

This evidence implies that IL-1b, an inflammatory cytokine, is essential to PTSD development.  

When taking a closer look at the role of cytokines in PTSD, we can see that IL-1b increases the hippocampal neurons’ activity—altering how the hippocampus stores memories long term. IL-1b may change memory storage by stripping contextual details from a stressful event: leaving only the event’s fear, and rendering both animals and humans hypersensitive to stress. 

IL-1b’s role in PTSD represents a major breakthrough in neuroimmunology. This evidence holds promising new treatments, focused on cytokine manipulation, to target immunologic dysfunction in psychiatric disorders.

In fact, in rat studies, Jones and colleagues have started to examine these possible treatments for PTSD. For example, these researchers have prevented the development of SEFL, in mice by inhibiting IL-1b expression through morphine injections, and through injections of IL-1ra, which is the antagonist of IL-1b. 

Antagonists bind to IL-1b receptor sites, and prevent IL-1b from acting upon the brain. Evidence that IL-1b inhibition is associated with lower risk of PTSD is also echoed on the battlefield: studies show that soldiers that are administered morphine (which inhibits IL-1b) 48 hours to 72 hours after trauma have lower rates of PTSD.  

These findings demonstrate that IL-1b signaling is crucial to SEFL development, and therefore, should be a target of new PTSD treatments. Additionally, other studies have located brain regions and cell types where these cytokines are produced, finding that astrocytes primarily manufacture the cytokines implicated in SEFL. Not only does this evidence demonstrate one way astrocyte signaling may affect complex behavior, but by specifying astrocytes as IL-1b’s primary source, researchers are able to create astrocyte specific manipulations to inhibit IL-1b.

In fact, researchers can manipulate astrocytes to inhibit IL-1b with chemogenetic technologies. These technologies are valuable tools that can specifically target certain neuronal signaling, such as the way that astrocytes release cytokines, one of them being a technology called DREADD (Designer Receptors Exclusively Activated by Designer Drugs). In the Lysle Lab, researchers engineered DREADDs to specifically activate inhibitory signaling in dorsal hippocampal astrocytes, in turn, suppressing the release of IL-1b. In rats, astrocyte-specific manipulation can inhibit SEFL. 

This research gives us new insight into the complex and daunting inner workings of the human mind, and advances our understanding of psychopathology development. By understanding cytokines in anxiety, depression, and PTSD, we are one step closer to solving an issue that plagues millions of people. 

Further, this research confirms our understanding that the origins of abnormal functioning are chaotically intricate: cytokines do not just have one purpose, just as dysfunction does not have one source. We are constantly untangling the interconnected relationships between our bodily systems, as seen in the intertwinedness of the immune system and the nervous system. 

An adequate level of cytokines will help your body heal from a scrape or cold: while an overabundance may contribute to cancer or depression. Our brain’s functioning, which takes place before our eyes. is truly more unknown and misunderstood than the cosmos.

By: L. Adams

References

Chang, T.-T., & Yen, Y.-C. (2010). Cytokines and Major Psychiatric Disorders. Taiwanese Journal of Psychiatry, 24(4 ), 257–268.

Jones, M. E., Lebonville, C. L., Barrus, D., & Lysle, D. T. (2014). The Role of Brain Interleukin-1 in Stress-Enhanced Fear Learning. Neuropsychopharmacology, 40(5), 1289–1296. doi: 10.1038/npp.2014.317

Jones, M. E., Lebonville, C. L., Paniccia, J. E., Balentine, M. E., Reissner, K. J., & Lysle, D. T. (2018). Hippocampal interleukin-1 mediates stress-enhanced fear learning: A potential role for astrocyte-derived interleukin-1β. Brain, Behavior, and Immunity, 67, 355–363. doi: 10.1016/j.bbi.2017.09.016

Roth, B. L. (2016). DREADDs for Neuroscientists. Neuron, 89(4), 683–694. doi: 10.1016/j.neuron.2016.01.040

Swiergiel, A. H., & Dunn, A. J. (2007). Effects of interleukin-1β and lipopolysaccharide on behavior of mice in the elevated plus-maze and open field tests. Pharmacology Biochemistry and Behavior, 86(4), 651–659. doi: 10.1016/j.pbb.2007.02.010

Image Credit

“3D medical animation still of Cytokines that are important in cell signaling.” Scientific Animations, www.scientificanimations.com,11 April 2018

Women Stronger than Men? – Studies show Women may have better flu defenses than Men

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Elondra Harr

Virtually everyone knows about the influenza (flu) virus. But not many people know, or even think about, which sex it seems to hit the hardest. For quite some time, many people have believed that men were actually “stronger” than women. But recently, studies have shown that women may actually be stronger than men in at least one category: Fighting the flu. International research teams have been studying what exactly might be helping women fight off this virus and what makes men more susceptible to getting the flu virus.

In the U.S, the flu season is usually at its worst during the months of January and February. But, it can actually start as early as October. After the flu virus has already infiltrated the body, the virus reacts the same way in both men and women.

During the first 24 to 48 hours, the flu virus gets into your system through the respiratory tract. That could be from breathing in someone’s cough or sneeze, or touching a surface contaminated with the flu virus and then touching your mouth, nose, or eyes. You typically don’t have any symptoms during this time. After the virus makes its way in, it begins to replicate.

The next five days, your body’s immune cells are sent to the places in your body where the virus is replicating. These cells send out signaling molecules to tell the body to turn on its immune response. This is where women and men’s bodies seem to differ. Your body then rounds up an immune system response to attack the virus so it can’t infect other cells.

Eventually, in the last few days the flu virus begins to leave your system. The inflammation finally decreases.

Estrogen’s Effect on the Flu Virus

Studies are now showing that the female sex hormone, Estrogen, seems to be the reason women are more likely to be able to fight off the flu virus than men. At first, recent studies showed the estrogen hampers the replication of viruses including HIV, Ebola, and hepatitis. The estrogen lessens the infection’s severity and makes the infection less likely to spread to other people. But then, Sabra L. Klein, an associate professor in the Departments of Molecular Microbiology and Immunology, and Biochemistry and Molecular Biology at the John Hopkins Bloomberg School of Public Health, decided to investigate whether or not estrogen might have the same effect on the flu virus.

She and the rest of her research team decided to collect nasal cells. Why nasal cells? Because typically the first cells in the body to get infected with the flu virus are in your nose. She collected nasal cells from both men and women volunteers. The researchers exposed bunches of these nasal cells to different types of estrogens including normal levels of naturally occurring estrogen, different types of selective estrogen receptor parts called SERMs, which are synthetic estrogen-like chemicals used for hormone replacement therapy and infertility treatments, or bisphenol A, an estrogen-like chemical that is found in many plastics. Then, they exposed the nasal cells to the influenza A virus, which is a variant strain of the flu virus.

The tests showed that the female cells the received all three of different types of estrogen, showed sign of a significantly less amount of flu virus replication – Nearly 1,000 times less than other cells that hadn’t been exposed to the estrogens. More research showed that the hormones that caused this effect actually act on the estrogen receptor Beta. With the male nasal cells they tested, it seemed that the nasal cells didn’t have any receptors for the estrogen hormones therefore they didn’t have the same protective effects as the female nasal cells.

When Klein and her research team looked for the reasoning behind estrogen’s protective effect again this virus, they discovered that flu viruses binding to Beta decreases the activity of more than 30 genes used in cell metabolism, slowing the metabolic rate of these cells and preventing them from creating new viral particles.

Men and Testosterone Levels

Well now we talked about the female hormone involved in flu defenses but what about male hormones? Studies are now showing that high levels of the male sex hormone, testosterone, can actually weaken men’s immune systems.

For reasons that have not yet been found out, men are more susceptible to bacterial, viral, fungal, and parasitic infections than women are, and men’s immune systems don’t respond as strongly to vaccinations against the flu and many other diseases. A new study may explain why this seems to be the case.

A multinational team consisting of researchers from Stanford University, France, and the University of North Carolina conducted an experiment taking blood from 54 women and 37 men, all from different age groups and studied a variety of immune system proteins and cells to detect gene expression. They then gave flu vaccinations to all of these volunteers and then checked them for any signs of changes. Men, as a group, responded less to the vaccine.

Thirty-three women and 10 men actually responded to the vaccine out of the 54 women and 37 men. Most of the male non-responders had high levels of testosterone. Men with lower testosterone levels showed to have roughly an equal amount of response to the flu vaccine as the women.

When the team finished the analysis of the genes, they discovered that men with high levels of testosterone had high activation levels of a multi-gene cluster that is involved with immune system regulation called Module 52. This high activation level of Module 52 correlates with reduced antibody levels post-vaccination. But, this only has an effect on men with higher levels of testosterone. Module 52 has no effect on the amount of antibodies produced in men with lower levels and women post-vaccination.

Additional analysis showed that testosterone actually reduces level of certain regulatory proteins that usually prevent Module 52 genes from activating. In other words, higher testosterone levels result in more Module 52 gene expression. Module 52 prevents antibodies from forming in men with high testosterone levels, causing their immune systems to be weak and in turn makes them more susceptible to getting the flu even after they get vaccinated.

So scientifically speaking, women are actually stronger! Their immune systems are stronger due to estrogen and the lack of Module 52 gene expression. Men are more susceptible to getting the flu virus, but especially men with higher levels of testosterone. Even though the odds may be stacked against you, there are some things you can do to help prevent yourself from getting the flu.

Preventing The Flu

The Center for Disease Control and Prevention (CDC) has formulated three steps that they believe will be beneficial to the prevention of the flu.

Step 1: Get the Flu vaccination.

The CDC recommends an annual flu vaccination as the first and most important step in protection again the flu virus. Even for males, some protection is better than no protection!

Step 2: Take everyday preventative actions to stop the spread of germs.

This includes: washing your hands often with soap and water, covering your nose and mouth when you sneeze, keeping your area clean, and while sick, limit contact with others as much as possible to keep from infecting them.

Step 3: Take flu antiviral drugs if your doctor prescribes them.

Even if you believe they won’t work, it’s better to not risk getting worse and possibly spreading it to others by taking the medicine your doctor prescribes for the flu. The world will thank you!