The Immune System

The Immune System

Cells • Recall the cells of the immune system: • Granular leukocytes • Neutrophils • Eosinophils • Basophils • Agranular leukocytes • T-cells • B-cells • Monocytes/macrophages

“Lines of defense” • While the book tells you that you have 3 lines of defense: • Chemical & physical barriers • Cellular “innate” • Specific/learned • It’s actually much easier and more common to think of 2 types of immune defenses: • Innate immune system • Adaptive immune system

Innate immunity • Innate immunity refers to: • NON-SPECIFIC immunity • Physical barriers: many layers of skin cells, tight junctions of the gut etc. • Non-specific because these keep EVERYTHING out • Chemical barriers: sweat, oil on your skin, mucus, stomach acid, digestive enzymes • Again, no “individual” target…these chemicals hinder everything • Innate immune cells: • Neutrophils, eosinophils, monocytes/macrophages, “natural killer” cells • Immune proteins • Interferons & complement

Innate immunity • Innate immune cells: • Don’t normally focus on a particular “enemy” • Will destroy/eat anything, as long as: • It is recognized as NOT YOUR OWN, or DOES NOT BELONG HERE • A foreign cell (transplant) • A metaplastic cell (cancer) • These cells destroy ANYTHING • Example: 1 neutrophil from your blood will kill a foreign cell, and can then kill a cancerous cell…it just kills whenever it recognizes something is wrong

Innate immunity • Innate immunity cells: • “professional eaters” = phagocytes (monocytes/macrophages & neutrophils) • Look for a specific “self” marker • If the target does not express that “self” marker (like your own DNA serial number), the phagocyte will “eat” the cell • Usually a complicated process • Monocytes are big enough that they can eat an entire cell • Neutrophils are more common (most common leukocyte…NOT the most common cell in your blood) • Will tell the target cell to commit suicide…then eat the pieces as the cell dies

Phagocytes

Innate immunity • Innate immunity cells: • Natural killer cell (NK cell) • Weird type of cell • Related to T-cells, but not exactly the same • Still a phagocyte (will still eat a target cell) • Uses a 2-signal mechanism • 1 = recognize self (looks for “self” marker just like the monocytes & neutrophils) • 2 = looks for a “don’t kill me” protein as well • Unlike monocyte or neutrophils, who don’t bother looking for this second marker • “natural killer” because the cell WANTS to kill, and WILL kill unless you “beg” it with the “don’t kill” marker as well

Innate immunity • The “self” marker: • Known as the “major histocompatibility complex” (MHC) protein • There are 2 types of this protein (MHC1 & MHC2) • EVERY cell in your body must express MHC1 • If not, it will be targeted and killed by the innate immune system • MHC1 is also the protein that you “type” when looking for a transplant donor/recipient • Looking for a “close match” • Remember that everyone is different, hence your MHC1 is NOT the same as another persons MHC1

Innate immunity • Innate immune proteins: • Interferons: “interfere” with viral invasion • Virus = short piece of RNA…not alive • Why antibiotics are useless against the flu (a virus)…antibiotic = “against life” • Virus invades a target cell, takes over the cellular machinery to “copy” itself • Normally results in destruction of the cell • Cell can let other cells know (as well as the immune system) by releasing “interferons” • Interferon = “interfere with virions” • Act to hinder virus from exiting cell • Also act to draw innate immune cells to the infected cell • Also acts to “train” the neighboring cells in how to protect themselves from this virus

Innate immunity • Innate immune proteins: • Interferons: “interfere” with viral invasion • Why then do we get sick during viral infection? • The interferon system is not perfect • Many virions (virus = the genetic code, virion = particle that holds the virus) can “cheat” this system • The interferon system takes TIME • Remember that this is a protein…coded on your DNA…you have to copy this code onto RNA, export it into the cytoplasm, translate it into protein, and then export the protein out of the cell • During this time, the virus itself is trying to hijack the translation machinery to make copies of itself • Often times, the “sickness” is your innate immune system trying to FIGHT and KILL the cells infected with the virus

Innate immunity • Innate immune proteins: • Complement: group of 20 proteins • Made by liver • Always in the blood • Complement protein #3 (C3) is the key player • Travels through the blood looking for protein/carbohydrate • Once it finds the target, it will cling to it, • Then, it will cut itself in half • Cutting then triggers the “conglomeration” of the rest of the complement proteins • The “target” is a group of proteins that your body DOES NOT make • More common on bacteria

Innate immunity • Innate immune proteins: • Complement: group of 20 proteins • The cells of your body all have the SAME DNA • Hence, the proteins and carbohydrates on their cell membranes are the same • The particular protein/carbohydrate that C-3 (complement #3) looks for is the same in every cell in your body…but different in someone else • Once the 20 complement proteins come together: • Form a pore (a hole) in the plasma membrane • Attacked cell cannot control loss of cytosol, cannot control electro-chemical gradient across plasma membrane, cannot control OSMOLARITY

Innate immunity • Innate immune proteins: • Complement: group of 20 proteins • Remember the short lifespan of C-3? • Only lasts about 2-5 minutes • This is how you can transfuse blood from a donor to a recipient, BUT, you cannot simply transfer it directly • If you hooked a line up from the donor’s arm to the recipients arm, the donor’s complement system would attack the recipient • In your body, the cells of your body produce another group of “complement control” proteins to limit their destructive activity

Innate immunity • Innate immune proteins: • Remember DNA • Everyone is different, hence your DNA is different • This means that your complement is slightly different • Your own complement will see another body as foreign and try to attack it • Complement is a very destructive defense that doesn’t care what it kills • It also works VERY FAST: initial xenotransplants were tested by transplanting pig hearts into baboons • Even though the two animals had been “matched” as donors, the baboon complement system turned the hearts into “jelly” in a few hours

Innate immunity • Innate immune response in action: • Whenever the innate immune system acts, it shows a number of characteristics • Redness (more blood getting to the site of action) • Heat (increased heat = higher metabolic activity…remember what happens when you break ATP?) • FEVER (whole body temperature elevation) • Swelling (because more blood is flowing) • Pain (usually because of the swelling, damage etc.) • All of these actions occur very quickly (pinch yourself hard and watch)

Specific/acquired immunity • In contrast to the non-specific immune system, you also have a specific or “adaptive” immune system • Where the innate immune system just attacks, the adaptive immune system “LEARNS”, then it attacks (hence, this branch of the immune system takes longer to respond) • System requires lymphocytes (agranular leukocytes) • A lot of life forms don’t have an adaptive immune system…they get by with innate immunity

Specific/acquired immunity • Cells of the specific immune system: • T-lymphocytes (T-cells): • T-helper cells = central player…the antigen recognizer • T-effector (cytotoxic T-cell) = the killer • T-memory = long-term “memory” of how to respond to the antigen next time • B-lymphocytes (B-cells): • Secrete antibody after they learn to make it from the antigen-presenting cell, • T-helper cell will tell the B-cell to make more antibody when you are exposed to the antigen again

Specific/acquired immunity • Key term: antigen • Antigen = something that will trigger the specific immune response • Not simply an MHC molecule to tell the immune system if this is “self” or not • Can be a protein, membrane lipid, nucleic acid…almost anything • An antigen will trigger the production of an ANTIBODY • This antibody is another protein, made by the acquired immune system • Antibody specifically recognizes ONLY that antigen

Specific/acquired immunity • Antibody & immunity: • When you say you are immune to something, what you are really saying is: “you have antibodies that recognize that something” • These antibodies are made by the specific/acquired immune system after it learns about the target • In essence, you “acquire” antibodies by “learning” • Much like you “acquire” knowledge by studying

Specific/acquired immunity • Acquired immunity needs the innate immune system • Somehow, you have to “present” antigen to teach the T-cells & B-cells that make up the acquired immune system • Innate immune cells often do this by: • Ingesting the target, • Presenting pieces of that target to the acquired immune cells (immature cells that are learning) • Uses the MHC2 molecule…it acts as a “cup” to hold pieces of the target

Specific/acquired immunity • Innate immune cells therefore act as “antigen presenting cells” • Present antigen that is stuck on MHC2 molecule for the adaptive immune system to “see” • They usually learn from an MHC2 molecule (although MHC1 molecule can do this as well) • Other cells throughout can do the same thing • In lymph nodes, you have special “antigen presenting cells” that take up antigen and present it to immature “learning” cells

Specific/acquired immunity • Antigen-presenting cell presents antigen to the immature (T-helper cell) • This occurs in lymph node & thymus • Where immature lymphocytes go to “mature” / learn • As they learn, they are watched by the antigen presenting cell • If they learn incorrectly, or learn something that is too close to “self”, they are “killed” and not permitted to leave the lymph node/thymus • Why? • If you chop up a foreign cell, there is a chance that a part of it will be very similar to YOURSELF • If this happens, you don’t want to risk your immune system learning to recognize this as an enemy

Specific/acquired immunity • How it works (in short): • Antigen-presenting cell shows its antigens to T-helper cell • T-helper will then recruit immature T-cells to teach them what to look for • T-killer cells • B-cells (to make antibodies) • After this, you have immunity • You’ve acquired immunity against that antigen

Specific/acquired immunity • How long it takes: • This process takes much longer than the innate immune system • First have to recognize and ingest the antigen • Then, have to present antigen • Now, have to present antigen to immature lymphocytes • Have to “train” immature lymphocytes to recognize • Have to “grow” or increase the number of those cells • Whole process usually takes 2-4 weeks • Remember the tetanus example?

Specific/acquired immunity • In the lymph nodes/thymus, lymphocytes learn • They can only recognize 1 target • For every antigen, you have 1 lymphocyte • It will divide when needed (clone itself) • This is why you want to expose yourself to as much as possible when young • When you are young, your adaptive immune system is quickly trying to learn EVERYTHING • Once you stop “learning”, all you can do is “re-arrange” what you know • Hence, as adults, all we can do with our specific immune system is “modify” what it already knows to “adapt” to new enemies

Antibodies • After you have B-cells that produce antibodies, • Antibodies will “clump” around their target • Clumped antibodies are a target for the innate phagocyte cells (monocytes, neutrophils) • Antibodies also can “mask” or “cover” the antigen so that it cannot act/work • If it is a toxin, you can “cover” it so that it can’t interact with its target…again, the innate phagocytes will then eat that “clump”

Adaptive activity & suppression • Since antibodies and learning take a large amount of energy, you don’t want it always active • When you “learn” it, you quickly develop/grow a large number of cells that specifically target that target • AFTER the infection/exposure, the immune system then tries to “limit” those cells • Tells many of them to die • After the infection, you reduce the number of T-killer and B-cells that were grown to specifically deal with that infection • You don’t kill all of them, you keep a small number handy for the next time

Adaptive activity & suppression • The B-cells are reduced in number, but they still make and release antibody (they just release less) • Next time, these antibodies will clump if you are exposed to the antigen again • Starts the process again • T-helper recognizes clumped antibodies • NOW, T-helper does not have to “train” a new group of T-killer cells or B-cells… • T-helper only has to “wake up” those cells from the first time

Adaptive activity & suppression • In subsequent exposures, your adaptive immune system works faster • It already knows how to respond, • All it has to do now is rapidly increase the immune cells that already know how to kill and/or make antibodies against this antigen

Active vs. Passive immunity • You can get antibodies or “train” your adaptive immune system by: • Allowing yourself to be invaded/exposed • Infection • Providing “parts” of a target • Vaccinations = chopped up pieces of the target you need to attack • Body will develop antibodies based on these small pieces • Your mother gave you some of her antibodies and antigens when she breast fed you • You can also “augment” your antibody array by acquiring foreign antibodies • Remember the Tetanus example? The “vaccination” usually has antibodies as well

Active vs. Passive immunity • Whereas your own antibody production will last for life, getting an antibody from another person/animal will not last long • Tetanus antibodies (when they vaccinate you) will only last a few days • Innate immune system will gobble them up and get rid of them

Tolerance & allergies • You don’t want your immune system to attack EVERYTHING • It would take up too much energy • It would pre-occupy your metabolism • You therefore try to “tolerate” many things that are potential antigens • Tolerance = immune system is “suppressed” from developing a response • Allergy = inappropriate immune response to something that should be tolerated

Tolerance & allergies • Seasonal allergies • Hay fever, pollen allergies etc. are all potential antigens • Exposure to these potential allergens should be “tolerated” • However, sometimes adaptive immune system does not tolerate these antigens, and develops a response to them • Runny nose, itchy watery eyes = innate immune system functions (increase blood flow to site of ‘invasion/exposure) triggered by the adaptive immune system • Antibodies will clump, triggering innate phagocyte cells to enter…they are in blood, so you increase blood flow to that region

Tolerance & allergies • Anaphylaxis • Extreme inappropriate immune response • Often dietary antigens • Because your digestive system has over ½ of your total immune system, it is constantly being exposed to antigens • Since there are so many immune cells, the response is magnified in your gut

Tolerance & allergies • Allergy medications: • Anti-histamine = blocks histamine receptor on target cell • Histamine is released by basophils (innate immune system) and mast cells (adaptive immune cell “sentry”) • Allergy = inappropriate immune response • Whenever you trigger an immune response, you need increased blood flow (to deliver the immune cells) • Histamine helps to increase the blood flow because it relaxes blood vessels (makes the bigger = vasodilation) • Anti-histamine = block this increase in blood vessel size, thereby hindering influx of immune cells

Tolerance & allergies • Hindering the effects of histamine = reducing blood flow • There is normal blood flow, just not the INCREASED volume that would be present • Reduces immune cell influx into the tissue • Reduces volume of plasma leaking from capillary bed (tears, runny nose)

Tolerance & allergies • Allergy is a nice example of the ENTIRE immune system working (inappropriately) • Normally “tolerant” of the antigen (dust, pollen etc.) • Adaptive immune system somehow learns to respond to this potential antigen and is permitted to “leave” the “school” and show others • Once you are exposed to the antigen again, the response is much faster • Antibodies clump around the antigen • Redness, heat, swelling, pain = innate immune system attracted by the antibodies to “eat” • Increase blood flow to the region to increase number of innate immune cells to deal with “invader”

Tolerance & allergies • Recall Celiac’s disease: wheat gluten enteropathy • Remember wheat gluten (gliadin) is very resistant to digestion & denaturation • Normally, this intact protein is “tolerated” by the immune system • It knows that this is not a toxin or an invader • Celiac’s disease = intolerance of this protein • Intestinal epithelial cells will endocytose gluten & present it “stuck” onto their MHC1 molecules • Adaptive immune system then learns to mount a response to this protein • Next time patient ingests gluten, it will be presented on the MCH1 molecule again, but immune system will only “see” the antigen, and not the “self”

Tolerance & allergies • Lactose intolerance is not correct: • Lactose = glucose-galactose “dimer” of carbohydrate • Must be digested into glucose AND galactose (separate monomers) by lactase • The lactose intolerance = reduced or no expression of the lactase enzyme • Cannot digest lactose • What kind of diarrhea is this? • Should really be called “lactase deficiency” rather than lactose intolerance

The Immune System