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