Bowdoin Science Journal

Divya Bhargava

Smoke Signals: The Unexpected Long Term Effects of Smoking on the Immune System

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Image Source: “Smoking has a Lasting Impact on the Immune System, 2024”

When we get sick, our bodies’ immune systems work to fight off infections by invading pathogens, or organisms like bacteria and viruses that cause disease. However, many factors such as lack of sleep and poor nutrition weaken our immune system, meaning that we are less able to stay healthy. It has been known that smoking is another one of these factors that weaken our immune systems, but a recent study from a group at the Institut Pasteur in France looking at the effects of a variety of factors on the immune system showed that the extent to which smoking plays a role is much higher than many would think. But to understand the results of this study, it is important to first understand the mechanisms the immune system uses to fight infection. 

The immune system has many different moving components, including two distinct branches. The first is the faster, more general innate immune system which has a similar response to all infections. The second is the adaptive immune system which is slower, memory-based, and is involved in pathogen specific response. Although the innate immune system involves general molecules that interact with all cells and the adaptive immune system has specialized molecules that interact with pathogens based on memory of past infection, they share one important class of signaling molecules. These molecules are called cytokines and their role is to coordinate both of these types of immune response. Cytokines are small molecules that are released by immune cells to communicate with other parts of the body and each other. This signaling results in deployment of a response by other immune cells against invading pathogens. However, levels of cytokine production exist in a very fine balance. In order to get the desired immune response, you need the exact right level of cytokines present. If levels are too high or too low, they could cause abnormalities including overactive immune response and inflammation or impaired immune responses. 

To investigate the effects of a variety of different factors on the immune system and cytokine responses of healthy individuals, a project called the Milieu Intérieur put together a cohort of 1000 healthy participants and has been studying variability in the immune system between these individuals (“The Milieu Intérieur Project”). In an investigation of this data, the group from Institut Pasteur, Saint André et al, analyzed 136 variables measured in the Milieu Intérieur Project that could be causing differences in cytokine secretion and immune response (Luo and Stent 2024). These variables included everything from demographics, to diet, to health habits like smoking, to social and environmental characteristics (Saint-André et al. 2024).

After they performed their initial statistical analysis, Saint André et al measured production of 13 disease relevant cytokines as a quantitative measure of immune response in populations with different demographics, health habits, and other characteristics. In the lab, they exposed blood samples from their sample population to 12 different molecules meant to serve as stimulants for the immune system (these molecules included things like viral and bacterial proteins). After this exposure, the authors tested cytokine production in both innate and adaptive immune cells, and once they had that data, they took their results one step further. The group also used epigenetics, or the study of changes in gene expression rather than the DNA code that makes up the genome to investigate possible reasons for variability in immune responses associated with factors tested. Their epigenetic evaluation consisted of analyzing the extent to which one epigenetic process, DNA methylation, occurred at specific regulators of signaling and metabolism (Saint-André et al. 2024) to assess changes associated with smoking. 

As previously stated, one of the authors’ main findings from the initial statistical analysis was that smoking had a large effect on cytokine response. In fact it had the same effect as age, sex, and genetics, three things many would consider much more directly impactful to the immune system than smoking. In their in vitro simulations, they found that smoking had a temporary effect on the ability of the innate immune system to function properly. This result is a relatively intuitive one. If you do something that is considered bad for you, it makes sense that you would get sick more easily. 

However, more surprisingly, they also found that smoking leaves a lasting effect on memory based adaptive immune responses even after cessation of smoking, meaning that even after people quit smoking, their immune systems still are impacted. They found that in samples from individuals who smoked there were higher levels of cytokine expression, especially of an inflammatory cytokine called CXCL5 that is secreted in response to bacterial infection. Secretion of this cytokine is associated with the presence of an inflammatory protein called CEACAM6 in the blood. Consistent upregulation of levels of this protein has been found to have links with multiple cancers such as colon cancer (Wu et al. 2024). In Saint André et al’s epigenetic investigation of this association, they found that DNA methylation, which results in a downregulation of gene expression and in this case an increase in cytokine production, is linked to smoking’s lasting effect on the immune system (Greenberg and Bourc’his 2019). DNA methylation was decreased at many of the sites they tested which are involved in regulation of signaling genes and metabolism. Decreased DNA methylation was likely impacting levels of cytokines in response to detection of pathogens. In these populations, smoking caused lasting changes in gene expression which resulted in long term changes in addition to the expected short term effects on the immune system. 

This study demonstrates that smoking can have lasting negative impacts on your health which are not limited to just lung damage. It is also associated with pro-inflammatory cancer pathways and epigenetic markers that cause increased cytokine production. This overproduction of cytokines can confuse cells and also cause increased inflammation. Over time the extra inflammation can damage tissues and lead to developments of other conditions, like the cancers previously mentioned and complications associated with overproduction of cytokines (“What are Cytokines”). These recent findings emphasize that it is important to consider the possible implications of smoking and all things that we expose ourselves to, and to keep in mind that new data is still being discovered.

Works Cited

The Milieu Intérieur Project Institut Pasteur. Luo,Y. and Stent,S. (2024) Smoking’s lasting effect on the immune system. Nature, 626,  724–725.

Saint-André,V., Charbit,B., Biton,A., Rouilly,V., Possémé,C., Bertrand,A., Rotival,M., Bergstedt,J., Patin,E., Albert,M.L., et al. (2024) Smoking changes adaptive immunity with persistent effects. Nature, 626, 827–835.

Wu,G., Wang,D., Xiong,F., Wang,Q., Liu,W., Chen,J. and Chen,Y. (2024) The emerging roles of CEACAM6 in human cancer (Review). International Journal of Oncology, 64, 1–15.

Greenberg,M.V.C. and Bourc’his,D. (2019) The diverse roles of DNA methylation in mammalian development and disease. Nat Rev Mol Cell Biol, 20, 590–607.

What are Cytokines? Types and Function Cleveland Clinic.

Smoking has a lasting impact on the immune system, a new study finds (2024) Euronews.

Inverse Vaccines: A New Way to Treat Autoimmune Disorders

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Williams, 2023

Of the 8.1 billion people in the world, 1 in 10 have an autoimmune disorder. There are 8.1 billion people in the world, and 810 million of these people, or 1 in 10, have an autoimmune disorder (“1 in 10 people”, 2023). Autoimmune disorders are a category of conditions in which the body attacks itself. Although management systems for most of these types of conditions have been developed, autoimmune diseases still cannot be cured (“Autoimmune disorders”). In fact, even with management of their symptoms, up to 50% of patients with autoimmune disorders still experience impairment in their health-related quality of life (Pryce and Fontana, 2017). The development of so-called “inverse vaccines” may provide the much needed mechanism to help find a cure for this class of conditions by teaching the body not to attack itself. 

A traditional vaccine works because it helps the body learn to recognize parts of foreign pathogens and builds up the body’s immune response against these pathogens so that the response is stronger and happens more quickly after recognition. In people with autoimmune diseases, the body also forms an immune response against self molecules because it mistakenly identifies them as foreign antigens, or pathogenic molecules (usually proteins or sugars) that induce an immune response. The idea behind “inverse vaccines” is that instead of building up the immune system’s response to foreign antigens, they could suppress the response to self-antigens by helping to teach the body to recognize these misidentified molecules as self. 

A study led by Andrew Tremain at the University of Chicago’s Pritzker School of Medicine is one of the groups who are involved in this novel inverse vaccine research. The inverse vaccines they developed contain modified copies of the self-antigens that are targeted by the immune system which are attached to long chains of sugars called polysaccharides (Tremain et al., 2023). These polysaccharide chains guide the self-antigens to the liver, which plays an important role in the establishment of tolerance to these molecules. Once these modified self-antigens arrive at the liver, specialized immune cells pick them up and then inhibit the action of T cells against them through T cell uptake (Leslie, 2023). T cells are a type of immune cell that carry out part of the typical response against molecules identified as foreign or invaders through either cytotoxic or signaling based immune responses. The inhibition of the T cell response against misidentified self-antigens reduces or prevents the autoimmune response that causes the body to attack itself, thereby acting as a kind of “inverse vaccine”. 

Once Tremain et al. developed their inverse vaccine, they conducted testing to determine its efficacy and viability as a method for increasing tolerance to self-antigens in those with autoimmune disorders. First, they wanted to ascertain whether inverse vaccines could truly provide inhibition of an immune response. To do this, they injected an egg white protein into mice as an experimental foreign antigen to trigger a strong immune response. Then an inverse vaccine against the egg white protein was injected to suppress the response to the original dose of the protein. In their analysis, they found that the T cells that would’ve responded to the egg white protein were not present. These results suggested that the inverse vaccine blocked the typical immune response, demonstrating viability as a treatment method against stimulated immune responses (Tremain et al. 2023).

However, Tremain and his colleagues still had to demonstrate the efficacy of inverse vaccines in inhibiting an autoimmune response rather than one caused by a foreign antigen. To do this, they induced an autoimmune disease called experimental autoimmune encephalomyelitis (EAE) in mice. In EAE, the immune system attacks myelin, the substance responsible for forming insulation around nerve cell axons. EAE is a particularly informative experimental model in mice because it mimics multiple sclerosis (MS), a human autoimmune disorder. Once they induced EAE, Tremain et al. injected an inverse vaccine made up of a polysaccharide carrying part of a myelin protein. Physiological analysis after injection suggested that this treatment had stopped mice from developing EAE. Furthermore, injection of a different inverse vaccine targeting an alternate form of EAE showed prevention of symptom relapse. This means that Tremain et al. were able to demonstrate inhibition of autoimmune responses against two types of EAE in mice, representing two different types of MS, providing a heartening outlook on this research (Tremain et al., 2023). 

In summary, inverse vaccines had the ability to turn off immune responses to particular antigens in mice. These results are a promising sign for the ability of inverse vaccines to combat autoimmune diseases. Additionally, initial clinical trials testing the safety and efficacy of inverse vaccine strategy to increase tolerance to self-antigens in humans have had positive results so far for immune disorders such as multiple sclerosis and celiac disease where the misidentified self-antigens are known (Leslie, 2023). However research into tolerance-increasing strategies tends to stall both because we do not know which self-antigens are attacked in several autoimmune disorders, and because the mechanisms that produce tolerance after antigens are brought to the liver are not well understood (“Immune Tolerance”). This means that even if autoimmune vaccines prove to be a viable form of treatment for autoimmune disorders, they will only be able to treat diseases with known self-antigens until further research into the antigen and tolerance mechanisms is conducted. Nevertheless, inverse vaccine research is incredibly promising and has the potential to help hundreds of millions of people worldwide.

Works Cited

Pryce, CR., and Fontana, A. (2017). Depression in autoimmune diseases. Current Topics in Behavioral Neurosciences, 31. https://doi.org/10.1007/7854_2016_7 

1 in 10 people suffer from autoimmune diseases. (2023). Neuroscience News.  https://neurosciencenews.com/population-autoimmune-disease-23198/ 

Autoimmune disorders. (n.d.). Retrieved November 5, 2023, from  http://www.betterhealth.vic.gov.au/health/conditionsandtreatments/autoimmune-disorders

Tremain, A.C., Wallace, R.P., Lorentz, K.M. et al. Synthetically glycosylated antigens for the antigen-specific suppression of established immune responses. Nat. Biomed. Eng 7, 1142–1155 (2023). https://doi.org/10.1038/s41551-023-01086-2 

Leslie, M. (2023). ‘Inverse vaccine’ could help tame autoimmune diseases, Science. https://www.science.org/content/article/inverse-vaccine-could-help-tame-autoimmune-diseases 

Immune Tolerance in Autoimmune Disease, Immune Tolerance Network. (n.d). Retrieved November 5, 2023, from https://www.immunetolerance.org/researchers/clinical-trials/autoimmune-disease 

Understanding Multiple Sclerosis, Oregon Health and Science University. Retrieved November 5, 2023, from  https://www.ohsu.edu/brain-institute/understanding-multiple-sclerosis 

Williams, S. (2023). “Inverse vaccine” shows potential to treat multiple sclerosis and other autoimmune diseases. Pritzker School of Molecular Engineering,  The University of Chicago. https://pme.uchicago.edu/news/inverse-vaccine-shows-potential-treat-multiple-sclerosis-and-other-autoimmune-diseases

The Contraceptive Brain Drain: How Birth Control Alters Women’s Brains

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There are millions of women taking steroids every day. But how is this possible? Are they just getting really buff? It feels like we always hear stories about how performance-enhancing drugs, namely steroids, are giving world-class athletes the boost they need to beat out their competition. But women across the globe are taking steroids every day as well, in the form of hormonal birth control. Despite their widespread use, side effects of hormonal contraceptives are largely unstudied, or have been until recently. In the last ten years, several studies have come out about the effect of taking a daily dose of steroids on women’s brains and mental health, which until now has been a severely neglected area where lack of knowledge affects millions of people worldwide. 

People take hormonal birth control, or hormonal contraceptives, for a myriad of reasons, from the obvious (preventing pregnancy) to the not-so-obvious (lessening iron deficiency) and everything in between. This type of medication simply refers to methods of pregnancy prevention that act on the endocrine system. The endocrine system controls growth, development, metabolism, and reproduction via signaling molecules called hormones. Two hormones in particular, estrogen and progesterone, control the menstrual cycle and are therefore the major components of hormonal birth control. Types of hormonal contraceptives come in many forms including the pill, the patch, the implant, injections, and hormonal intrauterine devices or IUDs, but despite the wide variety in the forms this medication takes, all of them contain one or both of these two hormones. As steroids, both estrogen and progesterone affect other body systems besides the reproductive system.

To study the impacts of taking a daily dose of steroids on other areas of the body, specifically the brain, Dr. Belinda Pletzer and her colleagues conducted a study in 2010. The brain is particularly susceptible to change due to an influx of synthetic hormones because it contains a very high quantity of hormone receptors. The brain needs to act as a “sponge” for these molecules since it plays an important role in creating the appropriate responses in the rest of the body. Pletzer’s study investigated how the sponginess of the brain would affect changes in its structure by comparing images of the brains of adult men, adult women during different stages of their menstrual cycle, and adult women taking hormonal contraceptives. To perform this comparison they used a technique called voxel-based morphology on MRIs of study participants (Pletzer et al., 2010). Voxel-based morphology measures differences in the concentration of tissue and the size and shape of different areas of the brain.

Overall, they found that women taking hormonal birth control had smaller areas of gray matter, or areas of the brain that have a high concentration of the cell bodies of nerve cells, when compared to “naturally cycling women” in both their follicular and luteal menstrual phases (Figure 1). Pletzer’s study also found interesting gendered differences in gray matter volume. While men had greater gray matter overall, the volume of gray matter in the prefrontal cortex, the pre-and postcentral gyri, and the supramarginal gyrus of both naturally cycling women and women taking hormonal contraceptives was higher than the volume of gray matter in these areas in men (Figure 2). These areas are involved in decision-making and problem-solving, controlling motor function, and emotional responses. However, the higher amount of gray matter in women in these areas was overshadowed by the larger volume of gray matter in men in the hippocampus, hypothalamus, parahippocampal and fusiform gyri, putamen, pallidum, amygdala, and temporal regions of the brain during the early follicular phase (A), mid-luteal phase (B), and in women taking hormonal birth control (C) (Figure 2). Many of these areas of reduced gray matter are ones of high importance for neurophysical ability and mental health.

Additionally, a study done by Rush University Medical Center showed an association between higher levels of gray matter and better cognitive function (“Everyday Activities Associated with More Gray Matter in Brains of Older Adults”). These findings suggest that taking birth control, and the associated decrease in gray matter, could be directly causing some of the symptoms women on hormonal contraceptives experience, such as brain fog, mood changes, and even anxiety and depression. For example, a smaller hypothalamus, one of the areas of decreased gray matter, is associated with heightened irritability and depression symptoms (“Study Finds Key Brain Region Smaller in Birth Control Pill Users”). Pletzer’s research and the work of others after her on the impact of birth control on structures of the brain represent important first steps in proving a causative relationship between birth control, symptoms associated with it, and structural changes in the brain.

Although this research has made some crucial preliminary steps into researching how taking a daily dose of steroids affects the brains of women taking hormonal contraceptives, the highly complex nature of the brain and its relationship with the regulation of the rest of the body means that further research is necessary. The sheer number of people that this issue affects means that it is essential to continue researching the impacts of this widely used drug. More importantly, knowing the potentially serious negative side effects enables millions of people to make more informed decisions concerning their health and their bodies.

 

Works Cited

Rush University Medical Center. (2018, February 14). Everyday activities associated with more gray matter in brains of older adults: Study measured amount of lifestyle physical activity such as house work, dog walking and gardening. ScienceDaily. Retrieved March 11, 2023 from www.sciencedaily.com/releases/2018/02/180214093828.htm.

Lewis, C. A., Kimmig, A. C. S., Zsido, R. G., Jank, A., Derntl, B., & Sacher, J. (2019). Effects of hormonal contraceptives on mood: a focus on emotion recognition and reactivity, reward processing, and stress response. Current psychiatry reports, vol. 21, no.11, 2019, p 115. PubMed Central, https://doi.org/10.1007/s11920-019-1095-z.

Meyer, Craig H., Kinsley, Elizabeth A. “Women’s Brains on Steroids.” Scientific American, https://www.scientificamerican.com/article/womens-brains-on-steroids/. Accessed 7 Mar. 2023.

Nemoto, Kiyotaka. “[Understanding Voxel-Based Morphometry].” Brain and Nerve = Shinkei Kenkyu No Shinpo, vol. 69, no. 5, May 2017, pp. 505–11. PubMed, https://doi.org/10.11477/mf.1416200776.

Pletzer, Belinda, et al. “Menstrual Cycle and Hormonal Contraceptive Use Modulate Human Brain Structure.” Brain Research, vol. 1348, Aug. 2010, pp. 55–62. ScienceDirect, https://doi.org/10.1016/j.brainres.2010.06.019.

Sharma, Rupali, et al. “Use of the Birth Control Pill Affects Stress Reactivity and Brain Structure and Function.” Hormones and Behavior, vol. 124, Aug. 2020, p. 104783. ScienceDirect, https://doi.org/10.1016/j.yhbeh.2020.104783.

“Study Finds Key Brain Region Smaller in Birth Control Pill Users.” ScienceDaily, https://www.sciencedaily.com/releases/2019/12/191204090819.htm. Accessed 7 Mar. 2023.