Final Exam Notes PDF

lOMoARcPSD|47492800 Eects of Stress on the Immune System Outline  What is the immune system?  Immune response to stress  Stress and eects on the aging immune system  Cancer and stress  Common cold and stress  Wound healing and stress Class question: Is procrastination caused b...

lOMoARcPSD|47492800 Eects of Stress on the Immune System Outline  What is the immune system?  Immune response to stress  Stress and eects on the aging immune system  Cancer and stress  Common cold and stress  Wound healing and stress Class question: Is procrastination caused by stress? Answer: Yes, we usually avoid something because it’s stressful (not because we’re lazy). Putting something o is an emotional response and common coping strategy. Class question: What about learning disabilities? Answer: Not the same at all. Learning disabilities are actually what we would call soft neurological issues, where for whatever reason, the brain has problems processing certain types of materials. By the way, between 10%- 25% of any classroom has something going on (includes attention decit disorder and stu like that). But learning disability is unrelated to intellectual ability or IQ; it’s about neurological processing. VIDEO Specic Immune Response: http://www.youtube.com/watch? v=90hSVkaOG_w&feature=related - The specic immune response involves white blood cells called lymphocytes. The most important are B and T cells. - Each B and T cell is programmed to recognize and respond to one specic protein called an antigen. The antigen is seen by your body as an invader attacking you. - Dierent antigens are present on cell membranes. When lymphocytes encounter their specic antigen, they bind in a lock-and-key manner and destroy the cell. (They don’t destroy everything – they are very specic). - B cells respond by transforming into antibody-secreting cells. Their antibody binds to the antigen causing its destruction. (Note: antibodies ght infection) - Again, they’re specic to the antigen, so the antibody that ghts the coronavirus ONLY works on the coronavirus. (That’s why people get Downloaded by Rebecca Lessard ([email protected])  lOMoARcPSD|47492800 blood tests to see if they have antibodies to ght that virus, for example). That’s also why u shots aren’t useful against every strain of u – the vaccine makes your body build antibodies for that particular strain of u only, nothing else. - Some B cells remain in circulation carrying the memory of that antigen. T cells respond by transforming into helper cytotoxic or memory cells. T-helper cells help B cells change into antibody- secreting cells. Without helper T-cells presenting antigens to a B cell, that B cell does not respond. - Cytotoxic T cells act alone without B cells. The cells destroyed by cytotoxic T cells are those infected by a virus or a cancer cell changed by mutation. T cells can become memory cells and remain in circulation for years, ready to respond again if their antigen should appear. In other words, once you’ve built the antibodies, the memory cells will ght the invader if you’re re-infected. - The rst time B and T cells are exposed to specic antigen, the response takes weeks. (It takes time to build the antibodies to respond to an invader; your body starts building them immediately upon exposure to the antigen, but takes about 2 weeks to get the maximum amount of antibodies you might need to ght something o) - If re-exposure occurs, B and T memory cells respond immediately to destroy the invader. It’s like your body has blueprints of the antibodies stored and can call on the one that’s needed. Normally, the immune response is well controlled. If not, autoimmune disease may occur, and self-antigens may be attacked. Recap: 3 types of T cells: - Helper cells. T-helper cells help B cells build the antibodies to kill antigens. - Memory cells. Just like the B cells, the T cells hold onto a memory of the antigen. - Cytotoxic T cells. These T cells kill on their own. Class Q&A 1. Memory cells do not take the form of the antigen ever. Memory cells are a storage area for the blueprint of the antibody that will be needed to destroy the pathogen. 2. B and T cells have similarities but are also dierent. Downloaded by Rebecca Lessard ([email protected])  lOMoARcPSD|47492800 Same: They're both lymphocytes. They're both white blood cells. They are both part of the specic immune response. Both of them have memories. Dierent: The B-cells are the only cells that produce antibodies. Only Cytotoxic T-cells kill directly on their own; T cells need helper cells to produce the antibodies to kill the foreign invaders. 3. The way vaccines work is by injecting a mutated or dead piece of the virus, whatever it is, so that the body can see it and spend two weeks building up antibodies. Unfortunately, every year, the u strains are dierent. So even though your body retains the memory or blueprint for the antibodies it built from last year’s vaccine, it’s no good against this year’s u, so you have to get a new shot. Remember all this immune system stu is for my body to attack invaders, foreign things. With auto-immune disorders, my body attacks itself. That’s very relevant to stress because stress may be a signicant culprit in that. VIDEO Non-specic Response: http://www.youtube.com/watch? v=HNP1EAYLhOs&feature=fvw - Of all the immune system soldiers, natural killer cells are the most aggressive. They are lymphocytes with no immunological memory and are part of your innate immune system. Natural killer cells make up about 5%-15% of the total circulating lymphocyte population. - Natural killer cells are called natural killers because they do not need to recognize a specic antigen before releasing their toxins and destroying a viral infected cell or cancer cell. They target tumor cells and protect against a wide variety of infectious microbes. - In several immunodeciency diseases including AIDS, natural killer cells function is abnormal, thus allowing the viruses to multiply inside of human cells. Natural killer cells kill on contact: The killer cell binds to its target, aims its weapons, and then delivers a lethal burst of toxins that produces holes in the target cell's membrane and creates events that destroy the cancer cell membrane and cleaves [splits] DNA into many pieces in a programmed cell death. It happens in an apoptosis Downloaded by Rebecca Lessard ([email protected])  lOMoARcPSD|47492800 manner (apoptosis: a programmed cell death that occurs in multicellular organisms) - After releasing its lethal package of chemicals, the natural killer cell can detach from the cancer cell and kill many other circulating abnormal cells. Research has shown that most of the tumor cells that enter the circulation are destroyed during the rst 24 hours, and only a few cells succeed in establishing themselves in distant organs from the primary tumor, which is called metastasis. Natural killer cells may also contribute to immunoregulation by secreting high levels of inuential lymphocytes. - Therefore, research to develop natural products to simulate the natural killer cell activity, especially in immunosuppressed patients undergoing chemotherapy for cancer or in any viral disease such as AIDs or bird u where immune suppression occurs, is very important in the regulation of aspects of the immune system which aects our overall health. - Finally, we come back to the beginning of our knowledge of the natural killer cell. Here lies a natural killer cell amid many sheathed red blood cells, which are perfect targets for the natural killer cell, possessing no MHC1 receptor. - The wrath of the natural killer cell is fully vented on the surrounding sheathed red blood cells. The cytotoxins completely destroy them, leaving clear plaques around the natural killer cell. There is no apoptosis event -- just direct cytotoxicity. The natural killer cell is one of the key soldiers in the ght against viral and cancer growth. Immunity Immunity - the ability of the body to ght infection and/or foreign invaders by producing antibodies or killing infected cells. Immune System - the system in the body responsible for maintaining homeostasis [a balance] by recognizing harmful from non-harmful organisms and produces an appropriate response. Foreign Invaders Pathogens - Viruses, bacteria or other living things that cause disease and/or an immune response. Antigens - Toxins that pathogens produce that cause harm to an organism. Immune System Downloaded by Rebecca Lessard ([email protected])  lOMoARcPSD|47492800  not simply blood cells  it’s a collection of organs (thymus, bone marrow, spleen, lymph nodes)  it’s vital for survival Note: the bone marrow is where B cells are produced. If you’ve ever heard of people who have a bone marrow transplant, that’s because they have a problem with their immune system (in the blood) and the bone marrow is not producing B cells. So a transplant injects new bone marrow that has the ability to create those B cells, which are necessary to make antibodies. Immune System 1. Blood - white blood cells in particular. 2. Lymph nodes. 3. Thymus gland - is where the T-cells are produced (produces T Lymphocytes) 4. Bone marrow - is where the B-cells are produced (produces B Lymphocytes) First Line of Defense The Skin  Provides physical and chemical barriers o Physical - hard to penetrate, made of indigestible keratin o Chemical - tears, sweat My skin will repel a lot of other things that don't get through. And it repels it by being hard to get through it. But also through things like tears in my eyes, and sweat that pushes out things that are sneaking in through my pores. Inammatory response VIDEO: https://www.youtube.com/watch?v=MI-BLaj5nFk - The functioning of the human body is very complex. Our immune system protects the body against intruders such as bacteria and viruses. The skin is an important protection device for the body against intruders. The protection by the skin can be broken, for example, by a splinter. This way, bacteria are able intrude in our body. These bacteria are regarded as non-self substances, and our immune system will try to destroy these non-self cells. We call this an inammatory response. Downloaded by Rebecca Lessard ([email protected])  lOMoARcPSD|47492800 - We will now show you what the process of such an inammatory response is. In our immune system, many cells play a part among which are white blood cells. An important white blood cell is the macrophage. The macrophage recognizes the bacterium is a non-self substance, and engulfs. The bacterium is slowly destroyed in the macrophage until only very small pieces are left. These little pieces of bacterium are made visible on the outside by the macrophage. - This way, the other cells of the immune system are able to notice that a bacterium has entered the body. Apart from that, something else is happening. - Since the macrophage engulfs the bacterium, it creates inammatory substances. These substances are called cytokines. Cytokines bind themselves to receptors on cells. Cytokines exactly t the shape of such a receptor, like a key in a keyhole. In this manner, the cytokine communicates to another cell. - For example, a cytokine is able to warn a macrophage, from the position of another macrophage, that bacteria are near that have to be destroyed. This is an important step in the inammatory response. At the point of the inammation, the amount of macrophages then increases in order to destroy the bacteria. The macrophages are, however, not able to destroy all bacteria. Prof says: So number one, the macrophage identies the foreign cell, it engulfs it, it destroys it, and it puts pieces of it on its surface. It also releases cytokines which are like scouts, which then go to tell other macrophages in the area. “Hey, this macrophage has captured a bacteria and there are more bacteria in the area of the splinter that entered my ngertip.” These cytokines will tell other macrophages in my bloodstream where the bacteria is and that it’s happening in my ngertip, (not my toe). And it will get the macrophages to start moving to that area because it wants to attack the invader. Another example: Think of a wall around me, around my village, around my town. If an enemy breaches the wall on the west side of the town, I want all my weapons and soldiers to head over there because that's where they’re needed. They’ll meet the enemy and ght together. - The macrophages therefore go to the lymph nodes in our body in order to warn other cells of the immune system that an inammatory response is taking place. These lymph nodes are important with regard to the defence of the body. Downloaded by Rebecca Lessard ([email protected])  lOMoARcPSD|47492800 - Lymph nodes are information centers where cells of the immune system meet in order to exchange information. The macrophages that have engulfed bacteria at the point of the inammation come into contact with T-cells in the lymph nodes. B-cells are also present there. Both are white blood cells that play an important part in the inammatory process. T-cells recognize the bacterium pieces on the outside of the macrophage. The T-cells bind themselves to those pieces of bacterium on the macrophage and they become active. The B cells also become active. After this activation, the T-cells and B-cells can divide until a large quantity of these cells has come into being. - The T-cells and B-cells go to the spot of the inammation. At the spot of the inammation, the T-cells help the other inammatory cells to attack the bacteria as eectively as possible. This way they help the macrophages to make more cytokines, which are the inammatory substances, and they attack bacteria in order to destroy them. As soon as all bacteria have been destroyed, the inammatory response ceases. Stopped at 3:42 (where it’s going into autoimmune diseases) Prof says: So this is super cool. The macrophages not only destroy the bacterium, they not only release cytokines to tell other macrophages to come and destroy the bacterium. But they also travel to command central -- the lymph nodes -- the place where the macrophage goes with its captured little piece of bacteria. It has captured a soldier and it brings headquarters where it meets and discusses the situation, examines this soldier with other parts of the army (other parts of the immune system). So at the same time some of the macrophages are trying to kill the bacterium at the point of infection, some of them are traveling to Central Command -- the lymph nodes -- and meet up with B cells and T cells. In other words, the non-specic response of the macrophage communicates at the area of the lymph nodes with this specic response: telling the B cells and T cells that something’s happening. We've been invaded. This is what the invader looks like. Okay, so again, think about what's happening here. - The macrophages - in addition to ghting the antigen itself, the bacteria itself - they travel to the lymph nodes (command central) Downloaded by Rebecca Lessard ([email protected])  lOMoARcPSD|47492800 where they meet with the T-cells and they present this little piece that they've been carrying (the soldier that they've captured). - The T cells identify what it is and they present to the B cells. The B cells start building antibodies. - The T cells and B cells start dividing, taking about two weeks to get the maximum amount of antibodies you’re going to need. - And all of those B cells and T cells, they travel. The macrophage not only shows them what the bacterium looks like - it tells them where it's located. - So, all those B cells and T cells, they start traveling to the infected area where the invasion is. So they have to build the weapons of destruction - the antibodies - but they also have to travel to the right location. - And all of this information happens because the macrophages have told them this is what it looks like and this is where it is. - Plus, the helper T cells not only help the B cells with their antibodies; the helper T cells also help the macrophages kill the bacterium and also release the cytokines to tell other macrophages to kill the bacterium. - Once all the antigens, all the bacteria have been destroyed, you don't need your immune system to be doing anything anymore. You don't need the inammation. You don't need the cytokines. You don't need the B-cells and T-cells to continue multiplying. You don't need more antibodies produced because the invasion has been repelled. You don't need anything else. - You may want to repair your skin (which of course the body does), but there's nothing left to ght. So you don't have to have an immune system response. - We’ll learn later that in autoimmune diseases, the immune response does not cease. The cells your body attacks are your own cells - they’re not a foreign invader. Your body is confusing your own cells as enemy cells and therefore the immune system continues to ght. - Autoimmune diseases are sometimes called inammatory diseases because the inammatory response to ght never ends. Second Line of Defense Downloaded by Rebecca Lessard ([email protected])  lOMoARcPSD|47492800 Nonspecic immune response There are defenses the body uses no matter what the invade may be. These defenses include:  phagocytosis - done by macrophages*  natural killer cells  inammation - the inammatory response is caused by the release of histamine from leukocytes  fever - caused by histamines. The fever (high temperature) kills invaders by denaturing their proteins. *macrophage - a phagocytic cell found in the liver, spleen, brain and lungs. Travels to all areas of the body to nd and eat pathogens. Question: What are the three lines of defense? Answer: 1. The rst line of defence is the skin. 2. The second line of defence is the non-specic immune response that kills anything that comes in that’s foreign, but it can't kill it all. 3. The third line of defense is the specic immune response (the specic B-cells and T-cells designed to kill something specically through the creation of antibodies). Third Line of Defense Specic Immune Response This is a specic response to a specic pathogen/antigen.  the response involves the creation of antibodies Antibodies - Antibodies are produced by the B cells, which are the B- Lymphocytes. And their purpose is to recognize the antigen (remember, each antibody is built for a particular antigen). It binds then and it destroys them. Immune Response Re-Explained 1. The antigen infects the cells. Downloaded by Rebecca Lessard ([email protected])  lOMoARcPSD|47492800 2. The macrophage ingests the antigen and displays portions of it on its surface. 3. It goes to the lymph nodes where it communicates with helper T-cells which become activated when they see the antigen on the surface of the macrophage. 4. The activated helper T-cells activates cytotoxic T-cells and B-cells. 5. Cytotoxic T-cells divide into active cytotoxic T-cells and memory T-cells. 6. Active cytotoxic T-cells kill infected cells. 7. At the same time, B-cells divide into plasma cells and memory B-cells. 8. Plasma cells produce antibodies that deactivate pathogen. 9. Memory T cells and memory B cells remain in the body to speed up the response if the same antigen reappears. 10. Suppressor T-cells stop the immune response when all antigens have been destroyed. Q: How does the immune response stop once it's gotten started? A: There are T cells called suppressor T cells and they stop the immune system response. They stop the inammatory response; they stop the production of more antibodies. Immune Response Summary Here’s another way to see it: The antigen comes into the body. It’s engulfed by the macrophage. The macrophage goes to lymph nodes with pieces of the antigen on its surface. It displays them to the helper T cell. The helper T cell then creates killer T cells and memories of the antigen for the future. It also activates the B cells, which create a memory again for the future (in the sense of a blueprint of the antibodies that need to be created). So, the B cells - the plasma cells - create the antibodies. They are part of the B-cell complex and they also go on to kill or deactivate the antigen. Primary vs Secondary Immune Response When you get infected, the antibodies reach their peak around 14-15 days in the rst exposure. The next time you see that antigen, there's an immediate reaction. You don't have to wait two weeks for your immune system to do this specic response job. It does it right away. Passive vs Active Immunity Downloaded by Rebecca Lessard ([email protected])  lOMoARcPSD|47492800 Active Immunity This is immunity where the body is actively producing antibodies to ght infection. Example: when you have a throat infection, you are actively creating antibodies to ght it. Example: Vaccinations (an injection of a weakened strain of an infection microbe (pathogen) causes the body to undergo active immunity (produces antibodies). Passive Immunity This is immunity where antibodies are given to a person from the blood of another person or animal. This immunity only lasts for a short period of time. Example: Breastfeeding mothers pass antibodies to their children through the milk. Side note: the idea behind herd immunity (COVID-19) is that people who have very mild or asymptomatic cases of it have developed antibodies. So, now they’re immune. They can’t get it and they can’t spread it. Scientists say for every identied case of COVID, there’s probably 60-100 unidentied cases. There's some challenges with that idea, but that's the idea behind that. So active immunity will come by either getting it or by a vaccine. In both cases, the body creates antibodies. Passive immunity is when you get the antibodies from somebody else. While an infant’s immune system is still developing and is developing antibodies, it is protected by the antibodies of the mother, which are passed to the child through breast milk. Formula feeding does not provide antibodies. Autoimmune disease Autoimmune diseases are diseases where the immune system begins to attack itself. Examples:  rheumatoid arthritis - crippling disease of the joints  lupus - disease of blood and organs  multiple sclerosis - disease of the nervous system Allergies Allergy - an exaggerated response by the immune system to an allergen. Allergen - a normally harmless substance that causes an allergic reaction. Examples: dust, pollen, mould, food, insect stings. Downloaded by Rebecca Lessard ([email protected])  lOMoARcPSD|47492800 Types of allergic reactions There are two types of allergic reactions: 1. immediate - occurs within seconds and normally lasts for about 30 minutes. 2. delayed - takes longer to react and can last for a much longer time. What happens during an allergic reaction? During an allergic reaction, antibodies cause histamines to be released from certain cells. Histamines cause:  swelling of tissues  release of uids (runny nose and eyes)  muscle spasms (some cases) Anaphylaxis or anaphylactic shock: This is the sudden and severe allergic reaction to a substance that can cause death. Treatments for allergies:  avoidance of material - especially food  epinephrine - “epi-pen”  antihistamines like Benadryl The Immune System (diagram) What you see here is you see the immune system. On this slide, call the macrophages rst line of defense. We actually learned that the rst line of defense in most people's thinking is the skin itself -- even though the skin is not actually part of the immune system. Downloaded by Rebecca Lessard ([email protected])  lOMoARcPSD|47492800 The macrophages and the natural killer cells, with a non-specic response, go to where the antigens are, where the invasion is happening. They engulf many of these bacterium, and they destroy them. They also signal other macrophages to come to the area. They also go to the lymph nodes and signal the T cells - which then go on to signal the B cells to get busy creating antibodies. So there's the cellular branch: that is the T-cells. There’s the humoral branch: that is the B-cells. He reviewed how the immune system works again, basically repeating this slide: Immune Response Re-Explained 1. The antigen infects the cells. 2. The macrophage ingests the antigen and displays portions of it on its surface. 3. It goes to the lymph nodes where it communicates with helper T- cells which become activated when they see the antigen on the surface of the macrophage. Downloaded by Rebecca Lessard ([email protected])  lOMoARcPSD|47492800 4. The activated helper T-cells activates cytotoxic T-cells and B-cells. 5. Cytotoxic T-cells divide into active cytotoxic T-cells and memory T-cells. 6. Active cytotoxic T-cells kill infected cells. 7. At the same time, B-cells divide into plasma cells and memory B-cells. 8. Plasma cells produce antibodies that deactivate pathogen. 9. Memory T cells and memory B cells remain in the body to speed up the response if the same antigen reappears. 10. Suppressor T-cells stop the immune response when all antigens have been destroyed. Note: all this activity (starting at step 3) is starting in the lymph nodes. Remember, the thymus is where the T cells multiply, and the B cells multiply in the bone marrow. But all the initial communication between the macrophage and the T cells and ultimately the B cells is at the lymph node location. That's like command central. Now how does stress gure into all this? Slide: Interaction of all the systems (diagram) Downloaded by Rebecca Lessard ([email protected])  lOMoARcPSD|47492800 So, this is the way the immune system also is aected by stress. There are two ways, directly and indirectly. We'll talk about the indirectly way rst. 1. you have a stressor 2. it triggers the release of cortisol (through the HPA axis) 3. it can also trigger the release of adrenalin and noradrenalin (through the sympathetic nervous system response) The release of those have an eect on the production of all my lymphocytes (my B cells, my cells, my natural killer cells, all of them). Lymphocytes are white blood cells that are also one of the body's main types of immune cells. They are made in the bone marrow and found in the blood and lymph tissue. The immune system is a complex network of cells known as immune cells that include lymphocytes. So indirectly, when my body gets stressed out and it produces cortisol and adrenaline, that is aecting the production of immune system cells. That's an indirect approach. Another indirect eect: Stress actually increases the growth of two hormones (prolactin and the growth hormone). They also aect the production of the lymphocytes. There's even a direct eect: There's a hard wiring, sympathetic innervation of the lymph nodes. [innervate: to supply (an organ or other body part) with nerves.] That means that when the sympathetic nervous system is activated under stress (which we know it is - that's the ght or ight response), it actually directly aects the lymph nodes. And we know the lymph nodes of course aect the production of the cells, like the T cells and B cells. And so the lymph nodes are critical to the immune system response and they are directly aected by the sympathetic nervous system, therefore, directly aected by stress. The bottom line here is that all of the systems interact: The immune system is directly aected by the hypothalamus and by stress, but it's also indirectly aected by the HPA axis and release of cortisol and the release of adrenaline and noradrenalin. Okay, so when my body's stressed out, everything is now in play. Downloaded by Rebecca Lessard ([email protected])  lOMoARcPSD|47492800 The study of the immune system and stress and psychology is a relatively new phenomenon, probably only the last 40 years or so. And compare it to more than a 100 years of study of the cardiovascular system and the endocrine system. This branch of psychology research is called psychoneuroimmunology, which is the investigation of the bidirectional linkages between the central nervous system, (which is the autonomic nervous system, sympathetic, parasympathetic), the endocrine system, and the immune system, and the clinical implication of these linkages. Flowchart If I have a stressor and I can cope with it well so that I don't nd it stressful, there is no stress and therefore, there is none of this response. But if I do nd it stressful, then the hypothalamus kicks in and triggers the sympathetic nervous system activation, which releases norepinephrine from the cortex, which also releases epinephrine. And all of this aects the immune system. So here you've got one branch. Downloaded by Rebecca Lessard ([email protected])  lOMoARcPSD|47492800 What evidence do we have for this? We know that if norepinephrine is released close to the immune cells, then you have an inuence on T cells, B cells, macrophages, the production of it all. Another way to say that is if you have immediate exposure of norepinephrine and epinephrine as a reaction to stress, they can actually alter how many white blood cells (lymphocytes > natural killer cells) are produced. So when we are in ight or ght mode (you get a splinter, for instance), my body's already producing extra macrophages, extra natural killer cells. It obviously can't produce extra B cells and T cells for a little while. But the whole immune system does kick in during the ght or ight response. However, if the exposure to the stressor is much longer and I end up in a chronic phase of stress, that's when stress actually harms my immune system, and then I have a decrease in natural killer cells. If the stressor is chronic, then eventually the immune system gets compromised. And that would mean a decrease in lymphocytes, and then colds and other things can develop. The short-term response to stress is very adaptive -- in this case, increasing the immune system -- but in the long term, it is maladaptive because it's going to negatively aect the immune system. Norepinephrine can actually ne tune my immune response quickly within minutes. Very quickly, the macrophages and natural killer cells get involved at the site of infection or invasion and then, more slowly, I can begin the production of B cells and T cells. The other branch of this is the pituitary, the HPA axis. Again, if the stressors are deemed to be not stressful, in other words, I can cope well with it, there is no stress. But if I see it as stressful, then I'm going to have an increase in cortisol. Slide: cortisol has some bad eects on the immune system 1. inhibits lymphocyte proliferation (so, you’ll get a cold when under chronic stress) 2. inhibits production of pro-inammatory cytokines (and lymphocytes and macrophages killer cells, B-cells, and T-cells) Downloaded by Rebecca Lessard ([email protected])  lOMoARcPSD|47492800 Slide: Immune system response to acute stressor (minutes to hours after stressor onset) In the minutes to hours post-stress, there's redistribution of immune cells. There's an increase in non-specic immunity, like natural killer cells. There's actually a decrease in specic immunity. In a ght or ight situation, the rst minutes to hours, I'm not going to get a specic immune response. There's no point in my body putting energy to that right now. So those rst couple of hours, it's really putting all its energy into getting the non-specic response, inammatory response, the macrophages and natural killer cells to the site of the infection. Days or weeks post stress, however, we start getting more antibody production. But as we go even further, then both responses are decreased. So, after the nonspecic responses in the rst hours, you still have more antibodies being produced in the following days. But if we go beyond weeks (into months and even years), then you have a decrease in nonspecic and you have a decrease in specic. In other words, you're exposed to a stressor. In the immediate term, your body wants to activate the non-specic response -- because in the rst hours to days you don't really have time for antibodies to be produced. So you really want to focus in on what you can do. And what you can do is the non- specic response. If you move on, a few days to a few weeks, that gives time for the antibodies to be produced. And so they start becoming the predominant way. In the very early stages, our T cells and B cells, are not gonna be ready. So we really have an increase in just the rst line of the immune system defense -- the macrophages. It’s when you go into days, two weeks, that we have a chance for things to be produced. There will be an increase in the antibodies, because we have time to produce them. But if we go really long-term, then both of these are compromised. My immune system starts shutting down or at least functions less eciently. Unfortunately, the inammation keeps on going - and that is why auto- immune disorders where my body attacks itself are also called inammatory disorders. Downloaded by Rebecca Lessard ([email protected])  lOMoARcPSD|47492800 So if you have a very chronic stress situation or very chronic infection, eventually your immune system stops working well, but the inammation continues. In a nutshell, when stress aects the immune system, it has a signicant impact on it by initially making it stronger, but in the longer term - when it comes to chronic stress - it actually compromises the immune system. So what is the eect of stress on the immune system? Ultimately, it makes my immune system weaker. Slide: Individual dierence and the immune system when under stress  age (older people have a weaker response)  disease status  gender  personality  emotions  coping strategies The problem starts even before we're born. Slide: Prenatal exposure to stress and immune function  diminished cytokine response** of leukocytes in rhesus monkeys  altered lymphocyte count in male mice  as compared to females natural killer cell toxicity was lower in male mice  female rates had suppressed proliferation of B-cells whereas the male rates had less natural killer cell strength **cytokines are released by the macrophages to signal the body that there's an infection and where it is. That means a very important part of the immune system is diminished in rhesus monkeys who are born after having been stressed in the womb. So even prenatally, at least in these animal studies, we see the eect of stress on the production of the lymphocytes. Q: denition of Cytotoxicity A: Cytotoxicity means how toxic it is. The cytotoxic T-cell or natural killer cell is how powerful it is, how toxic it is to the antigen, how powerful it is in killing that antigen. That's its cytotoxicity. As we age, our immune system is compromised or more compromised, which is why with COVID, we are particularly concerned with adults over 70 and over 80. Because at that point, their immune system may be more compromised. Downloaded by Rebecca Lessard ([email protected])  lOMoARcPSD|47492800 If a little child gets a cut, it heals very, very quickly. If you're an older adult, it can take days or weeks to heal. That's because wound healing is part of an immune system response. Same reason kids get over colds faster than adults. Slide: Stress and the aging immune system Hawkly and Cacioppo (2003) found that stress:  mimics  intensies  accelerates  changes in functionality of cells  decreases telomere function and length When we stress our immune system, it starts looking like an aging immune system. It actually mimics an aging immune system. Stress actually intensies the eect of aging. It also accelerates the aging of our immune system; it makes us age faster when it comes to our immune system. Because as we age, of course, our immune system gets more compromised. It also intensies the eect of aging. So if I have an older immune system, stress makes that older immune system even older. How? It changes the cells; it decreases telomere length and function as well. Slide: The intensied eects of aging on the immune system (Kiecolt-Glaser & Glaser, 1996) >> he calls it a seminal study Age and chronic stress interacting to predict responses in inuenza vaccine  design: caregivers and well-matched controls  found main eect of stress  heightened decits in older participants What they did is they looked at the eect of age in interaction with chronic stress in predicting how people would respond to the u vaccine. They took caregivers (people who take care of older or special needs people or children) and they compared them to control groups that were matched for age and gender. They gave them the u vaccine (a dead or mutated piece of the u virus that when injected into my body triggers the production of antibodies). Downloaded by Rebecca Lessard ([email protected])  lOMoARcPSD|47492800 We can look at how well the body is responding by looking at how it starts producing antibodies. That gives us a measure of how good my immune system Producing many of them quickly means you’ve got a strong immune system. So they compared the immune system after a vaccination shot of caregivers and controls. Everyone who was chronically stressed had a weaker response to the vaccine. But it was even worse in older adults. So if I am a stressed-out caregiver who is younger than 70, I still see the eect of stress -- it has given me a weaker immune system -- but it's still way stronger than the immune system of someone who is stressed out and older than 70. Being stressed makes a huge dierence. The non-stressed over-70s actually responded a bit better to the vaccine than the stressed-out under 70s. This test shows 2 things: 1. Stay younger longer (stay t, exercise, eat healthy). 2. Live a less-stressed life. Slide: The accelerated eects of aging on the immune system (Kiecolt-Glaser & Glaser) They went on to do more research and found that stress not only accelerates the eect of age as we saw in that last slide, but an average caregiver experiences a four time increase in compromised immunity. In other words, their immune system is four times more compromised. So, the caregiver who was 75, their immune system was similar to that of a non-caregiver who was 90. How do I live longer and healthier? Keep down that stress level. Slide: possible problems related to immune dysfunction  HIV/Aids  cancer  cold/u  herpes  recovery from injury (wound healing)  infection Downloaded by Rebecca Lessard ([email protected])  lOMoARcPSD|47492800 Slide: Stress and Cancer Studies in humans inconsistent:  Cancer is not a homogenous disease (there are lots of dierent types of cancers). Many other risk factors (like family history, aging).  Recent animal models postulate that chronic stress can dysregulate DNA repair and regulation of cell growth, processes that have been shown to be major factors in tumor formation.  Suppression of the immune system may lead to an increase of virus-associated cancers, such as Karposi’s sarcoma. We have a very clear smoking gun relationship between stress and heart disease, stress and stroke, and stress and high blood pressure. We're going to learn about stress and diabetes. But when it comes to stress and cancer, the link is not as direct. We do have some evidence though that there’s a link. Animal models show us that chronic stress can aect DNA repair and cell growth, which can produce tumors. We know that suppression of the immune system may be associated with some particular types of cancers. And there’s some evidence that suggests that stress may be a particular risk factor in breast cancer in women over the age of 40. There's also some evidence that stress plays a role in prostate cancer in men. But what is important to note is that even if stress does not cause all forms of cancer, there is plenty of evidence showing that once you have cancer, stress does aect how it evolves (how it spreads and my response to treatment and recovery). Slide: Stress and Cancer: Growth, Spread and Recovery  Recent animal models have found that chronic stress seems to promote tumor growth and spread.  Suppressing the eect of chronic stress on the immune system also impacts the recovery period after surgery.  More support of strong interaction between chronic stress and cancer growth than between chronic stress and cancer development in humans. Downloaded by Rebecca Lessard ([email protected])  lOMoARcPSD|47492800 The advantage of looking at other things like colds is that they are simpler models. So from a research purpose, they allow us a simpler model of what may be going on with stress and the immune system’s eect on illness. Slide: Re-occurring upper respiratory tract infection (URTI) and stress in children The experimental group were children who get a lot of upper respiratory tract infections (had to have at least ten or more during the past year). The control group had about the same number of boys and girls who had no more than two of these in the past. We can argue that the children who have a lot of these have a less eective immune system because their immune system is not ghting o infections. The control group are kids whose immune system ght it o well, so they don't get the infection. They're exposed to the virus, but they don't get the infection. They gave these kids lots of dierent tests, including:  a major life events scale for children (big things that are happening in your life that are stressful).  a personality questionnaire that measured introversion, extroversion, and neuroticism (which is anxiety or anxiety personality)  depression questionnaire for kids  anxiety questionnaire for kids  a family life satisfaction scale for kids  a peer self-ecacy, which means how well I interact with kids my own age, my peers (peer relationships are one of the major stressors as we become older in childhood). Then they measured the concentration of sIgA, which for our purpose is the permeability of the membranes in the lungs -- it tells us how clear those lungs are or how infected they are. The results slide (salivary immunoglobulin) shows that if you're a healthy child, then you have a higher ratio of SIJ to albumin. For our purposes, we don't even need to know what that means. It just means the higher this ratio, the healthier the child, the lower the ratio, the more ill the child with his upper respiratory tract infection. One thing they found was that children with more of these recurring upper respiratory tract infections had more stressful life events in the past year. In fact, 82% of the ill children had more stressful life events versus 29% of the healthy children. Downloaded by Rebecca Lessard ([email protected])  lOMoARcPSD|47492800 In other words, the upper respiratory tract is caused by the major life events. They also found a lot of psychological factors. Slide: Psychological proles in healthy and ill children Now here you have a bit of a chicken and egg question because maybe if I have a lot of infections, I am more anxious and depressed. We can see that healthy children as compared to ill children, are:  more extroverted (more outgoing)  have less neurotic personality  are less anxious  are less depressed  are more assertive. Children who get more upper respiratory tract infections are:  less outgoing  more neurotic personalities  more anxious  more depressed  less assertive. Now again, you could say that's because they're sick all the time. And it may be, but it may also be that the reason they are sick all the time is because they are less psychologically resilient to manage stress in their lives. And so they are more likely to have an immune system that's compromised by stress. So again, we cannot establish a “direction of association.” Are upper respiratory tract infections causing more emotional problems or are emotional problems (which are a proxy for stress) causing more upper respiratory tract infections? But we do see the greater life event stressors. And that's probably directional. More major life events, more upper respiratory tract infections or more colds. And we do see that relationship with the personality factors as well. Slide: The common cold and stress  This study had 150 women, and 125 men.  40% were exposed to the cold virus  participants who were exposed to chronic stressors had a greater chance of developing a cold  age positive association with incidence of cold Downloaded by Rebecca Lessard ([email protected])  lOMoARcPSD|47492800 They looked at who was gonna get a cold due to strong or weak immune systems. And they found that participants who said they had a lot of chronic stress in their lives had more of a chance of getting a cold. And older people got colds more easily. And if I'm stressed and older, I'm even more likely to get a cold. Slide: Duration of chronic stressors and risk of developing a cold A relative risk of one means no risk. The higher you go, the relative risk is greater. In this chart, it measures the duration of chronic stress.  less than one month of stress  between 1-6 months of stress  between 6-24 months of stress  more than two years of stress. As the duration of stress increases, so does the risk of getting a cold. And this is something we call a dose-response curve. I don't think we've talked about that in this class. Dose-response curves mean that with every dose, I get more of whatever. So it could work that the more doses of medicine, I have a better risk of getting better. Or in this case, the more dose of stress, the greater risk of getting sick. While cause and eect can’t be proven here, it does support cause and eect relationships because it's hard to understand how the relative risk of a cold would make me more likely to have more stress in a chronic manner. So the fact that with every dose (amount of time under stress), I have a higher risk of a cold, these dose-response relationships suggest cause and eect. In other words, this suggests that the longer I'm under stress, the more likely I am to get a cold. In this study, if you've been under chronic stress for more than two years, and have now been exposed to a cold virus, you have a fourfold increase of getting a cold from it. If you've been under stress for anywhere between six months and two years, it's a threefold increase, etc. Downloaded by Rebecca Lessard ([email protected])  lOMoARcPSD|47492800 Slide: Type of chronic stressors and risk of developing a cold  Stressors related to either work or interpersonal problems associated with a greater risk of developing a cold compared to those participants who did not have any chronic stressors.  No statistically signicant correlations between number of chronic stressors and risk of developing a cold. So, it didn’t matter where the stress was from -- it could have been in your workplace, in your relationship, home life. And it didn't matter how many stressors. (One stressor lasting 2 years is worse than 4 stressors lasting a month). It’s not just chronic stress that aects the immune system. There’s also:  smoking  not exercising enough  not getting enough sleep  drinking too much  not getting enough Vitamin C However, they interact with each other. The more stress, the worse smoking is for me, and (in this study), the more likely I’m to get a cold. If I’m a smoker, but I’m under less stress, I’m less likely to get a cold. Same thing with not exercising or sleeping enough -- if you add chronic stress, you’re much more likely to get a cold. Basically chronic stress makes all other risk factors for cold worse. Chronic stress aects my immune system. It doesn't matter how many stressors; it matters how long I've been under it. And it interacts with other factors that aect my immune system like smoking, like exercising, like sleep. They found personality didn't make a dierence. So whether I was an introvert or an extrovert, chronic stress did the same thing. And even social network ties, though it's in the right direction, is what we call a marginally signicant eect. It was only a trend that social ties were a factor in chronic stress and the immune system. If you looked at it in a very strict statistical way, it didn't even matter what your social network was. So in other words, if you are under long-term chronic stress, nothing else seems to matter. Your immune system is compromised. It doesn't matter if you have great friends, no friends; it doesn't matter the type of stressor, or how many stressors. If you're under long-term chronic stress, it is Downloaded by Rebecca Lessard ([email protected])  lOMoARcPSD|47492800 going to make you way more likely to get a cold and overall compromise your immune system in a signicant way. Wound healing is actually accomplished by the immune system. So if I have a powerful immune system, I heal quickly. If I have a weak immune system, I heal slowly. Slide: Pain and wound healing in surgical patients Study:  17 morbidly obese women  ages 21 to 48  gastric bypass surgery (to shrink the size of the stomach) They looked at women  one week before surgery  three hours before surgery  and one to two to three days post surgery  then at weekly intervals after that for a month. They looked at pain and how long it took for their wounds to heal. For our purposes, the pain is a proxy for stress. And what that means is that when they are measuring pain, they are measuring stress. The amount of pain I'm under is always related to the amount of stress. If I'm under a lot of pain, I experience more stress. Less pain = less stress. The study hypothesized: People who had more pain (stress) would heal more slowly. You could argue that maybe they have more pain because the job was less well done. And so they had a poorer recovery because they weren't healing as well. And that was the argument here is that the pain, in other words, the stress is causing the poor healing, but it's also that the poor healing causes more pain as well. So again, oftentimes in these clinical studies we have a chicken and egg issue. Why did they think actually that pain might inuence wound healing? Because: 1. neuroendocrine and the immune system are relevant to wound repair 2. the immune system plays a key role in wound repair. And, in fact, it is what they found: people with more pain (stress) DID heal more slowly. Downloaded by Rebecca Lessard ([email protected])  lOMoARcPSD|47492800 For the rst 10-15 days, both groups (those with less pain and those with more pain) healed at the same rate. So in the rst about 15 days, nobody’s healing. But then as healing begins, the people with less pain healed way faster than the people with more pain. So by the end of the 30-day measurement time, the people who had less pain are completely healed - whereas half the people who had more pain are not healed. Again, you can make the argument that the reason they're not healing is that the pain is a reection of poor healing as opposed to causing the poor healing. But the argument they made is pain - which is stress - triggers an immune system and neuroendocrine response, meaning more cortisol and a less healthy immune system. And all of those are slowing down recovery from wounds. This has been supported by another study. Slide: Enhanced wound healing after emotional disclosure intervention This study looked at people's ability to heal following a psychological intervention. This was 36 men, not women, and it was a biopsy being taken, so a dierent wound. They gave the group a task:  the control group to write about time management (no emotions at all)  the experimental group to write about a traumatic event (express deepest emotions and feelings) All of them also completed questionnaires measuring:  perceived and emotional distress  loneliness  self-esteem  social support  dispositional optimism  health-related behaviors Participants who wrote above traumatic events had signicantly smaller wounds at 14 and 21 days after the biopsy compared to those who wrote about time management. Downloaded by Rebecca Lessard ([email protected])  lOMoARcPSD|47492800 Whereas in the previous study you could argue pain caused the slower healing or slower healing caused pain, here there's really no way to explain this. It's because writing about your trauma is therapeutic. Therapeutic means I manage my stress better. As I manage my stress better, my wounds heal more quickly. In another Glaser study re wound healing, they found high cortisol = less cytokines. We know this because we've learned that higher cortisol due to higher chronic stress = poorer immune system due to lower levels of cytokines. If you've had a procedure done, if you have a wound, it will heal more quickly under less stress. If you are a slow healer, that likely means you are not responding well to stress, it likely means your cortisol levels are higher. You're less optimistic, you have higher overall stress levels. And because of that, you have a poorly functioning immune system. Stress and Autoimmune Disease Autoimmune disease - this is where the body attacks itself. Also often called inammatory diseases, because the inammation that happens with the immune system response in this chronic situation of my body attacking itself (the inammatory response) never goes away. And so my body's in constant inammation. Watch the same video as last time: http://www.youtube.com/watch?v=MI- BLaj5nFk Downloaded by Rebecca Lessard ([email protected])  lOMoARcPSD|47492800 >>the autoimmune stu starts at about 3:50>>video transcript from that point below: - In the case of an autoimmune disease, the self-cells and components are being attacked instead of non-self cells. The exact cause of this is unknown. - In this situation, the macrophages also make cytokines. The inammatory response that accordingly follows against the self-cells is about equal to the response against the non-self cells such as bacteria. - So, in the case of an autoimmune disease, the self-cells are being attacked and damaged. There are many self-cells that are being created over and over again. Because of this, the inammation does not stop - but it continues. - This is what we call a chronic inammatory response. - At the spot of the chronic inammation, many cytokines, macrophages, T-cells, and B-cells are present. The joint activity of these cells and substances causes damage to our body at the location of the inammation. You can see that what happened in autoimmune diseases is that my immune system is in fact attacking itself, and that this inammatory response never stops. Slide: What is inammation? Inammation is the body’s reaction to infection, irritation or other injuries. It’s the rst defense of the immune system itself (our skin is our body’s overall rst defence). (Generally, it is part of the immune response). Inammation allows for dierent components of the immune response to be brought to the compromised site - it allows for macrophages (killer cells) to immediately go to the site of the infection or the invasion. Cytokines are released, histamines are released, whose purpose is to ght o the infection. And if it was a foreign invader responsible for that infection, that's ne - the inammation would stop once it kills the infection. But in autoimmune diseases, my body is attacking itself. Downloaded by Rebecca Lessard ([email protected])  lOMoARcPSD|47492800 Two type of autoimmune disorders:  systemic autoimmune diseases o my body attacks itself o non-organ-specic (damages many organs) o examples: rheumatoid arthritis, lupus  localized autoimmune diseases o it attacks a particular part of the body o organ-specic (only a single organ or tissue is directly damaged by the autoimmune process) o examples: Type 1 Diabetes, celiac disease, Crohn’s disease, Hashimoto's thyroiditis (my immune system attacks my thyroid gland) People can have more than one autoimmune disease. These also run in families. The cause of autoimmune diseases is unknown. One of the likely culprits is stress. In a few types of autoimmune disease (such as rheumatic fever), a bacteria or virus triggers an immune response, and the antibodies or T-cells attack normal cells because they have some part of their structure that resembles a part of the structure of the infecting microorganism. This suggests something's not working right with the immune system for it to make that mistake. And it doesn't normally make that mistake. But one of the theories of how autoimmune diseases happen (at least some of them because they're not all the same) is that a virus turns into an autoimmune disease. Risk factors of autoimmune diseases:  genetics/heredity (autoimmune diseases run in families)  environmental toxins (pollution)  gender (more women than men have autoimmune diseases, except Crohn’s disease is 50/50, and one called “Ankylosing Spondylitis” mostly aects men)  viruses  drugs (prescribed or illegal, in some cases can trigger an autoimmune response)  stress and things related to stress like poor diet, lack of exercise or lack of sleep, abuse of alcohol and tobacco Stress is a signicant risk factor, both in terms of the psychophysiological model and the health behaviors model. Downloaded by Rebecca Lessard ([email protected])  lOMoARcPSD|47492800 With respect to the health behaviors model, that is because we respond to stress with unhealthy behaviors. Under stress, we engage in unhealthy habits as opposed to healthy habits. For example, under stress, we don't eat properly -- we eat the wrong types of foods and we eat a lot of them. When we're stressed, we don't exercise, so when we're stressed we don't sleep as well. And we tend to abuse drugs and alcohol, including cigarettes. Common symptoms of autoimmune diseases  fatigue (makes senses: your body is constantly trying to ght o what it thinks is an infection)  weight loss typically  muscle pain  insomnia  inammation When you look at a specic autoimmune disease, there are very specic things that trigger. Example: Crohn's disease (inammation of the gastrointestinal tract).  strong genetic risk factor (if it’s in your family, it increases your risk of having it)  some environmental risk factors  aects more than half-million people in North America. Not a huge number, but not a tiny number either.  it ares up on a regular basis. Example: Rheumatoid arthritis (inammation of the synovial joints; often leads to destruction of articular cartilage)  more common than Crohn’s disease -- about 1% of the world's population  some genetic risk  more common in women than men (three-to-one) Example: Multiple sclerosis (inammation leading to demyelination of axons in the brain and spinal cord)  probably the worst of the autoimmune diseases  results in physical and cognitive disabilities  genetic variation and environmental risk factors  infections as triggers  aects 2 to 150 per 100,000 in the world Prof googled “myelin sheath” -- pulled up this image from Wikipedia. He explained multiple sclerosis as follows: In multiple sclerosis (MS), your body attacks specically something called the myelin sheath. Downloaded by Rebecca Lessard ([email protected])  lOMoARcPSD|47492800 How do the cells in my body communicate with each other? How do neurons, which have information, pass it on to the next neuron, and the next one and the next one? They do it as follows: There’s the nucleus (that's the center of the cell). That cell body sends a signal along the “axon,” which is almost a kind of wire to the end of it, which is called the “axon terminal.” Here it connects to another neuron (at the dendrites). So the way the body's cells can talk to each other is by sending a signal. It's like an electrical signal, going from one cell to the end of that axon, to the next cell and so on and so on. Now, if you think of this as a wire that's passing an electrical signal, then you can think of the myelin sheath as the rubber or plastic or, whatever it is that typically covers a wire in an electrical power cord, extension cord, or the lamp cord that you plug in to the wall. That rubber covering is non-conductive material. The electrons can't escape it -- they just keep on going down the line to get to where they need to go. If there is a break in that wire covering, the electrons can escape. Your extension cord starts sparking. What does that mean? Why is it sparking? Because electrons are escaping into the air. So the covering of my electrical wire has to be solid to function properly. The myelin sheath is like the covering of that wire. What happens in multiple sclerosis is that the person's body attacks this myelin sheath. It causes it to break apart, to fray. This means that the electrical signal that's sending information from one cell to the next is now getting compromised because it's starting to spark (so to speak), and full signals are not going through. And at some point, when the myelin sheath is destroyed almost completely, there is no signal going through. You see this with MS. For example, some of the rst symptoms are movement issues. The signal from my brain to my leg to move so I can walk is not coming through clearly. It's getting lost along the way. I'm still getting some signals to my leg and all the muscles and nerves in Downloaded by Rebecca Lessard ([email protected])  lOMoARcPSD|47492800 my leg to move. But they can't move in a coordinated fashion because some of the signals are getting lost along the way. The problem is that it doesn't stop with muscle movement. It will eventually destroy all of the myelin in the body, and therefore all the signals in the body, including the signals in my brain. Example: Systemic Lupus Erythematosus (Lupus)  inammation that occurs almost anywhere in the body including the heart, lungs and nervous system  it used to kill people, but we have treatments now  more common in non-European descent  women have a 9X greater chance of getting it than men  genetic and environmental risk factors Slide: Autoimmune Diseases (AD)  heterogeneous group of 70 to 80 inammatory disorders  AD classied according to the organ, tissue, or system target  occurs when the immune response damages tissues in the body  aects 3-8% of the U.S. population (same in Canada) and tends to be chronic  80% women Two ways stress predisposes you to developing autoimmune diseases:  stress alters one or many components of the immune system (especially if stress happens in the womb or early in life) -- this can lead to our immune system being faulty, and incorrectly attacking cells as foreign  stress weakens our immune system, thereby increasing our susceptibility to infectious diseases What evidence do we have that stress predisposes you to developing autoimmune diseases? We know that there's respiratory viral infection that frequently precedes MS exacerbation. This is NOT the cause of MS - but for people who already have it, a respiratory viral infection can make their MS symptoms worse. What's the argument here? The argument here is that stress induces changes in the immune system functioning. The latent (hidden) viral infections that are in my body (which never really go away because I can never ght them o completely, Downloaded by Rebecca Lessard ([email protected])  lOMoARcPSD|47492800 which is why they're called latent viral infections) - are activated because my immune system is suppressed because of stress. Stress suppresses my main function. It makes me more vulnerable to this virus that's been sitting in my body for a very long time. We know this happens in other types of conditions, such as shingles (a very painful skin condition) or Bell's Palsy (where there's a drooping on the side of your face). Both are temporary. And both are thought to be triggered by a latent virus of the same type as chicken pox. This virus could be sitting in your body for years and then stress triggers it - by perhaps suppressing your immune system enough so that the latent virus now becomes clear. Slide: Childhood stress and later autoimmune disease (AD) This is a very interesting study by Dube. All they looked at the number of childhood stressful events and the risk of getting an autoimmune disease later on in life. - See the hazard ratio on the y-axis? This risk ratio? It’s the relative risk - so, if it’s around one, it means there’s no real relationship. - Look at the black squares: If you only have one bad childhood event (like divorce or changing schools or grandparents dying), you don't really have a greater risk of getting an autoimmune disease when you are older, between the ages 19-64. - But if you have two, your risk doubles. And if you have three, your risk is 2.5 times. - Look at the white squares: the older group over 65. It's not as big an eect, but it's still there. The reason it’s not as big an eect is because you've already outlived a lot of things that could potentially kill you or harm you. Plus, you’re moving into a phase of later life where other factors, more environmental factors perhaps than early life events, that can trigger autoimmune diseases. It's a dose-response curve: With more childhood stressors, you’re more likely to get autoimmune diseases as an adult and even in older adulthood. This is strong cause and eect data indicating that the number of childhood events - how much stress I’m under in childhood - predicts whether I'll get any autoimmune disease as an adult. Downloaded by Rebecca Lessard ([email protected])  lOMoARcPSD|47492800 Because getting Crohn's disease at 30 in no way caused my parents to divorce when I was ve. This is very strong support for the role of stress. Note: It doesn't mean that stress is the only factor. There's probably something of a combination. Something called the stress diathesis or vulnerability. So, the stress diathesis model of disease says that I may be born genetically with certain probabilities. I may be more vulnerable to arthritis and maybe more vulnerable to heart disease. I may be more vulnerable to stomach problems, but that genetic vulnerability will not express itself. I will not actually get the disease unless stress comes in and combines with it. So, if my stress is managed well, even if I have a risk, I may never get the disease. And if I don't have the risk - no matter how much stress I'm under - I'm not going to get that disease. So, if I have 0 genetic risk for any autoimmune type disorder, then put me under a lot of stress, I may have a heart attack, but I'm not going to get an autoimmune disease. But if I have a vulnerability, a diathesis towards autoimmune diseases, AND I put myself under stress, I'll get one of those diseases. Dube [researcher] talked about this saying there were long-term changes in the immune response, which is why childhood stress aects us - because there are changes in cortisol levels. The sympathetic nervous and the HPA axis are activated a lot during development because the child is under so much stress and therefore, they indirectly aect the immune system. Some support for this idea comes from a rat experiment Dube did: If you stress out rats and then infect them with a virus, they are more likely to get something called inammatory heart disease (an autoimmune disease). Another autoimmune disease and stress study looked at lupus. (Peralta- Ramirez)  They looked at daily stress, not major life events, with adults.  They found that people with lupus increased in perceived symptoms when they had more daily stress. Downloaded by Rebecca Lessard ([email protected])  lOMoARcPSD|47492800 The researchers argue that when lupus patients have more stress, it triggers more symptoms. They point to the increased prolactin, which is part of the stress response. Increased prolactin suppresses the immune system, which can in turn cause more symptoms. Slide: Stress-vulnerability rheumatoid arthritis (Sue Evers) She looked at the eect of stress aecting the course of disease. We can’t say there’s a smoking gun that stress causes cancer, for example. In some cases, yes, maybe more so breast cancer and prostate cancer, but it's harder to nd that direct link. However, stress DOES exacerbate the progression of cancer and aects the treatment of cancer. That for sure we have strong data for. Her study found:  that “coping with stress” and “social support” are two factors that are strongly related  that the presence of the lack of a social support can cause stress to the person with the disease Related slide (graphs): Stress-vulnerability and rheumatoid arthritis: If you cope well with stress, you have less symptoms. If you have more social support, you have less symptoms.  Remember, avoidance coping is bad (means you’re not dealing with the problem).  Low avoidance coping is good (means you’re guring out some way to cope).  Problem-solving coping is good.  Emotion-focused coping is good. The graph looks at 5 years since diagnosis. Initially in the rst month everybody isn’t coping perfectly with the stress of the disease. Over time, after they learn how to cope, they have less symptoms in the rst year. After that initial drop in the rst year, the symptoms for people who don’t cope well (or are avoiding dealing with it) stay about the same. Same thing with social support. So, if I have any of the autoimmune diseases but I cope well and have good social support, I'm going to have much less problems with it. Downloaded by Rebecca Lessard ([email protected])  lOMoARcPSD|47492800 Slide: Stress and personal master in relation to arthritis (Younger) Does the level of personal mastery one has predict stress reactivity?  It is already established that stress-associated are-ups in arthritis are a real phenomenon and that it does in fact aect one’s well-being.  Personal mastery is dened as “one psychological factor that may buer an individual from the negative eects of chronic pain.”  Higher personal mastery should then reduce the levels of stress and would reduce the occurrence of ares as a result. This is this idea of internal locus of control (like I have control over my job). In other words, how much do I feel I have control over my stress? Remember personal mastery (or internal locus of control) makes me appraise my stress as less stressful. So, the more control I feel I have, the less stressful the event is. Slide - Table III: Stress and personal mastery in relation to arthritis The primary results here suggest that the more control I have, the less symptomatology I have. With pain, it's a very powerful response. A low control (high fatalism) person exposed to stress has a baseline pain factor of 28. A high control (low fatalism) person exposed to stress has a baseline pain factor of 10. Doesn't do much on blood pressure, but it does improve fatigue a lot. And it does aect my overall stress levels a lot. Slide: Stress and Crohn’s Disease (Vallis & Leddin)  People with the disease are more stressed than healthy controls.  Of the people with the disease, those who are labeled as poorly functioning are even more stressed than their average functioning counterparts.  Is the fact that they are poorly functioning what makes them stressed? The poorly functioning group has signicantly more stress overall. They have not just health stress, but also signicantly more nancial stress and a lot of stressors in other areas of their lives. This suggests that it's the stress that causes the Crohn's than the Crohn's that causes the stress. Because a lot of these stresses are unrelated to the disease itself. Why would nancial stress be dierent between people with Crohn's? Financial stress doesn't aect my stomach. What they're nding though is that all types of stress create poor Crohn’s functioning. Downloaded by Rebecca Lessard ([email protected])  lOMoARcPSD|47492800 Again, it's not direct cause and eect, but it's more likely that the stressors are causing Crohn's symptoms because there's no reason why Crohn’s symptoms should cause, for example, more friendship stress or more nancial stress. So, to summarize, autoimmune diseases are those diseases where my immune system attacks itself. There are many of them. Some aect my life less, some very, very seriously. So they all do have an impact. We don't know why autoimmune diseases develop. Some may be triggered by a virus, but even then not everybody who gets the virus gets the auto- immune disease. We think that stress plays a role because number one, people stressed from an early age seems to predict autoimmune diseases later on. Stress seems to predict the exacerbation of many autoimmune disease symptoms. How does stress make autoimmune disease worse? In two ways (and it could be both): 1. Stress may mutate my immune system so that even though it shouldn't see my own cells as foreign, it does. So, there's something malfunctioning in the machine or identifying the wrong objects. Or, and it could be both. 2. The immune system is also weaker. So, when the viruses do come in, they are not destroyed by the body. They sit in the body for a longer time and therefore can trigger some confusion in this already malfunctioning immune system with my own body. And then what happens is that inammatory response, which is part of my immune system response under healthy circumstances, ends when the foreign bodies are destroyed. But because it's not a foreign body, cells on my own body, it never is destroyed, it never ends. And so I am forever in inammation which creates a serious problem. Stress and Diabetes Lecture outline  Diabetes Type I and II  Biological factors in stress and diabetes  Environmental factors in stress and diabetes Downloaded by Rebecca Lessard ([email protected])  lOMoARcPSD|47492800  Psychological factors in stress and diabetes There are two kinds of diabetes. One of them is Type 1 or Juvenile Diabetes and it is an autoimmune disorder. The other is Type 2 (sometimes called Adult Diabetes), which is caused by lifestyle and is not an autoimmune disorder, even though it’s more prominent than Type One. There's a very strong link between stress and diabetes. Video (9 min): http://www.youtube.com/watch? v=X9ivR4y03DE&feature=iv&src_vid=jHRfDTqPzj4&annotaiton_id=annotatio n_3720898155 Video transcript: - When you eat food that contains carbohydrates, it's broken down in the stomach and digestive system into glucose, which is a type of sugar. We need glucose because that's what gives us energy. - Carbohydrate-containing foods are things like starchy foods, sugary foods, milk and some dairy products, and fruit. - This glucose moves into the bloodstream and the body detects that the blood glucose level is rising. In response to that, the pancreas (which is a little gland that sits just underneath the stomach) starts to release a hormone called insulin. - Its insulin that helps our body get the energy from the food we eat. - The bloodstream then takes the glucose and the insulin to every cell in our body that needs it. - To make this easier to understand, let's look at muscle cells. - At the muscle cells, it’s insulin that allows the glucose to get into the cells where it can be used for energy. It's a bit like insulin is a key unlocking the door to the cells so the glucose can get in. - That way, the blood glucose level starts to drop. The blood glucose level can be topped up at any point by the liver releasing extra glucose that it has stored. The blood glucose rises again, and again the pancreas produces more insulin to move with that glucose through the bloodstream to the muscle cells, open the doors and let the glucose in. Downloaded by Rebecca Lessard ([email protected])  lOMoARcPSD|47492800 - The body functions best with the blood glucose at an optimum level. It doesn't like it if the blood glucose rises too high. Normally, there’s a cycle within the body which balances out the glucose and the insulin level. - This is achieved by the food you eat, by the pancreas and by the liver. - However, in some people, the system doesn't work properly and they will develop diabetes. There are two main types of diabetes, Type 1 and Type 2. In Type 1 Diabetes, the body isn't making any insulin at all. This is because of an autoimmune response whereby the body has destroyed the insulin producing cells in the pancreas. We don't entirely know why that happens in some people and not others. Type 1 diabetes  accounts for about 10% of all cases.  most often found in people under 40  most common type of diabetes in childhood In Type 1 diabetes, the carbohydrate containing food is broken down into glucose, as normal. That glucose then moves into the bloodstream. Normally the body would produce insulin to let that glucose into the cells. But in Type 1 diabetes, there is no insulin being produced. So, the glucose can’t get into the body cells at all. So, the level of glucose in the blood rises and rises. The body tries to lower the level of glucose by getting rid of it through the kidneys. That's why people who have undiagnosed Type 1 diabetes tend to go to the toilet a lot to pass urine. As the kidneys lter the glucose out of the blood, they also take a lot of water with it, so the person with diabetes will get very thirsty. Urine contains a loss of glucose and that creates an environment where it's quite easy for bacteria to thrive. That means it’s also quite common for diabetics to get thrush (yeast infection) or genital itching. In the same way, the blood contains a high level of glucose as well. So more bacteria than usual will tend to breed and esh wounds and they might be slow to heal. Glucose can also build up in the lens at the front of the eye, causing the liquid in the lens to become cloudy. That can mean that some Downloaded by Rebecca Lessard ([email protected])  lOMoARcPSD|47492800 people with undiagnosed Type 1 diabetes can have blurred vision. Because the glucose can’t get into the cells to be used for energy, someone with undiagnosed Type 1 diabetes is going to start feeling very tired, lethargic and unable to go about their normal daily routine. But the body still needs an energy source in order to work properly. So it starts to break down its fat stores and that can lead to weight loss. The main symptoms of Type 1 diabetes:  urinating a lot  thirst  thrush or genital itching  slow healing of wounds  blurred vision  tiredness  weight loss These symptoms generally happen quite quickly, often over a few weeks, and can be reversed once the diabetes is treated with insulin. Type 2 diabetes  accounts for about 90% of all cases  most common in the 40+ age group in the white population and in the 25+ age group in the South Asian population. Type 2 diabetes is a little more complex because there are a few more processes at work. Either (1) the body isn't producing enough insulin; or (2) the insulin is being produced, but isn’t working properly. #2 can be due to being overweight because a buildup of fats can stop insulin from doing its job properly. But it can also happen in people of healthy weight. So, in Type 2 diabetes, the carbohydrate-containing food is broken down into glucose in the stomach and digestive system as normal. That glucose then moves into the bloodstream. The pancreas starts to produce insulin, which moves with the glucose through the bloodstream to all the body cells which need glucose for energy. However, the glucose can’t always get into the cells, because the locks to the cell doors have become “furred up” with fat deposits. That means that the insulin can’t open the cell doors properly. So, the level of glucose in the blood continues to rise. Downloaded by Rebecca Lessard ([email protected])  lOMoARcPSD|47492800 In response to this, the pancreas produces even more insulin, so the blood glucose levels continue to rise, and the insulin levels continue to rise. The situation is further complicated by the cells which are desperate for energy, sending out emergency signals to the liver to release stored glucose. The blood glucose level goes up and up, and the pancreas produces more and more insulin until it can't cope anymore, and eventually it can wear out. As with Type 1 diabetes, the symptoms of Type 2 diabetes are  excessive urination  thirst  thrush or genital itching  slow healing of wounds  blurred vision  tiredness  weight loss in some people Symptoms of Type 2 diabetes come along very slowly, and some people don't have any symptoms at all. For that reason, people can live with Type 2 diabetes for up to 10 years before they realize they have it. Type 2 diabetes can be treated in a number of dierent ways. Initially, it may be sucient to make changes to the food you’re eating, lose weight and get exercise. But it is a progressive condition, and most people will need some form of medication to treat it. Q: What is diabetes? A: Diabetes is its metabolic disorder caused by a decit in insulin secretion. So, in other words, my pancreas is not producing enough insulin, or there is some reason that the insulin is not being used. I end up having hyperglycemia, which means too much blood glucose in my bloodstream that is not being absorbed by the cell. It has to do with function of the pancreas. The pancreas produces insulin (which is a hormone). Insulin is the key that unlocks the door to the cell so glucose can go in. Long-term complications from untreated diabetes include:  nervous system disorders  blindness  kidney disease  sexual malfunction Downloaded by Rebecca Lessard ([email protected])  lOMoARcPSD|47492800  amputation Slide: Classication of diabetes Type 1 (sometimes called juvenile diabetes because it's most commonly found in children) It is an autoimmune disease, where for some reason my immune system destroys the pancreas and so cannot produce insulin. That means there is no way for the glucose to get into the cells. Therefore, my body is starved of that energy. With no glucose going in, the cells are crying out for glucose, so the liver produces even more glucose. We have this whole hyperglycemic event of very high blood sugar levels. And the only way to treat this is through insulin injections. People who have juvenile diabetes have to inject insulin into their body every day. This is a rapidly developing disorder. Type 2 is NOT an autoimmune disorder and it's not necessarily an insulin only issue. It’s an adult disorder, and in large part is caused by environmental/lifestyle What's happening is either the pancreas is not producing insulin or it's producing insulin but in insucient amounts. Or even that you're producing sucient amounts of insulin, but for some reason, the insulin is not unlocking the cell doors. With both types, you end up with the same problem -- you have all this glucose circulating through your blood that the cells need that they're not getting because insulin is not opening up those locks. You can learn to manage Type 2 (adult) diabetes through lifestyle changes though eventually you may need insulin as well. A keto diet, for example, has been shown to be eective for diabetics (due lower carbohydrate consumption; the body uses its own fat instead of carbs for energy; when fat breaks down it releases ketones). It would have NO impact on Type 1 diabetes. What are some of the biological factors by which stress might aect diabetes? Slide: Sympathetic nervous system (SNS) response and diabetes We know when the sympathetic nervous system kicks in, we have epinephrine and norepinephrine released from the adrenal medulla. This is our ght or ight response. And it turns out that during the ght or ight response, the liver is releasing extra glucose into the bloodstream. Downloaded by Rebecca Lessard ([email protected])  lOMoARcPSD|47492800 That’s because my body's going: I need more energy! Insulin is NOT produced in the pancreas at this time; there’s already insulin circulating in the body as it naturally would be. So the pancreas is not busy producing more insulin -- but the insulin there is unlocking the doors so all that glucose is going in. So again, in our ght or ight response, which is our typical stress response to an immediate stressor, there really is no issue in terms of a danger for the ght or ight response to treatments of diabetes. In the ght or ight response, again, assuming you have a healthy system, extra glucose is released, circulating insulin unlocks the key to the door and all that glucose goes in. It's a very simple, elegant system, all designed to make me ready to ght or ee. The problem comes in when we look at the more chronic stress response. Slide: HPA and diabetes We know the chronic response: it’s the HPA axis response which releases cortisol. Cortisol is a big problem for diabetes. It’s NOT a problem in the short-term cortisol response because that's adaptive. But when you have extended cortisol, it’s a big problem. Slide: Cortisol and diabetes  Increase blood glucose levels causing hyperglycemia (high blood sugar)  Despite normal or even elevated insulin levels, blood glucose cannot be taken up by the cells due to the blocking eect of cortisol increase  Higher HPA axis activation is signicantly associated with chronic diabetes complications such as neuropathy, retinopathy and macroangiopathy  Depressed immune system = autoimmune diseases Remember in the video they show how if you have obesity (which is why obesity and diabetes are called the twin epidemics) your fatty deposits in your body can block the lock in the cell door that needs to be opened by insulin for the glucose to get in. Downloaded by Rebecca Lessard ([email protected])  lOMoARcPSD|47492800 So the insulin, even though circulating, cannot open those doors. Another thing that blocks that lock, however, is cortisol. So despite normal or even elevated insulin levels, the blood glucose cannot enter into the cells because the cortisol blocks it. Cortisol binds to the same area that insulin binds and blocks the insulin from opening the door. People who are managing their diabetes measure their blood glucose, keeping it from going too high or low. When a person is under stress, it is much more dicult to adjust your sugar levels. One of the main reasons for this (from a biological perspective) is the release of cortisol. You end up with blood sugar levels that are way too high. Also, extended cortisol depresses the immune system (and may in fact may be one mode by which Type 1 diabetes develops). Slide: stress eect on diabetes (shows same info in diagram format) Slide: Family history and diabetes  If one identical twin has Type 1 diabetes, the other twin only has a 50% of also having it. So, it’s not entirely genetic; there’s something environmental going on that causes their autoimmune system to attack the pancreas (maybe something in the womb?)  If one identical twin has Type 2 diabetes (the “lifestyle disease”), the other twin is almost 100% likely to have it too. Slide (graph): Stress eects on rats with Type 2 diabetes (Niklasson) In this study, both rat groups have Type 2 diabetes. Their blood glucose levels are measured over time after they are exposed to stress. So we see that their starting blood glucose levels are high (because they’re diabetics), but they’re all the same. Look how the glucose levels of the rats exposed to stress take o. They are signicantly higher than the rats who are not under stress. The eect of stress on blood glucose levels is clear. Class question: Is this considered prolonged stress or acute stress? Answer: Well, since it's rats, and the event is two hours long, it would be considered prolonged stress. (Acute stress would be much shorter). The main Downloaded by Rebecca Lessard ([email protected])  lOMoARcPSD|47492800 point is that if you stress out some diabetic rats, their blood glucose level goes way up. Slide: Environmental stressors and Type 2 diabetes If I want to control my glucose levels, I cannot do it well if I'm under stress, because stress is bumping them up because of cortisol. In other words, stress impairs control. Stress aects my ability to control my blood sugar levels as a diabetic because it's pumping up cortisol and therefore blocking any insulin that I have circulating in my system already. But there's another way in which stress eects Remember, in order to manage my blood glucose levels as a diabetic, I have to be monitoring my glucose levels, my food intake, etc., to keep my blood sugar levels at the right level. When kids are diagnosed with diabetes, they spend a lot of time in a clinic that helps them (and their parents) to learn how to control it. So when they grow up, they control it. If I'm an adult with Type 2 diabetes, I need to learn how to monitor my blood glucose level so I can control my diabetes. That requires really careful monitoring of what I eat, what I drink, how much, what time of day, and what my blood sugar levels are. It's denitely doable and people do it all the time. But it does require a commitment and that is an eort. We already know that when we're under stress, we do a much poorer job with all types of health behaviors -- and that includes managing my diabetes. So if I have diabetes and I am under stress, I'm going to do a poorer job of managing my diabetes than if I'm not under stress. He has a 40-year old patient who is not controlling her diabetes. She is developing some quite serious diabetes-related symptoms. The reason she’s not controlling her diabetes is that she has high levels of stress as well as anxiety and depression and other factors. Her emotional eating is making her obesity worse. So her stressors are denitely making her noncompliant. Answer to class question: Blood pressure and diabetes are related. Diabetics develop high blood pressure because of all the vascular changes they co- occur quite a lot. You can have high blood pressure due to your diabetes. Downloaded by Rebecca Lessard ([email protected])  lOMoARcPSD|47492800 Interesting note: If you have sugar cravings and you're on a normal carb diet, you probably have way more glucose in your system than you need. In other words, sugar cravings are typically not because you have low blood sugar.  34% of adults in America have Type 2 diabetes (same in Canada)  another 57 million US individuals are at risk for diabetes  you don't have to be morbidly obese to be obese Slide: Dietary factors and Type 2 diabetes (Stoeckli & Keller)  Type 2 diabetes and obesity are twin epidemics  Linear correlation between eating patterns and the development of Type 2 diabetes.  Western-diet:  red meat  rened carbohydrates  sweets  full-fat dairy products Type 2 diabetes is a lifestyle disorder because my lack of exercise and my obesity are contributing to fat, which causes Type 2 diabetes. My higher stress levels are contributing to Type 2 diabetes as well. So we want to modify our diet and at least to lose weight to deal with the obesity -- when you lose the obesity, you lose the diabetes in many cases. It's not easy to change your lifestyle without a