Immune System Function: Adaptive Immune Response

1. Immune System Function: Adaptive Immune Response

2. Review Concept: Purpose of the Immune system is to protect from damage caused by pathogenic microorganisms such as: - Bacteria - Viruses - Fungi - Parasites

3. Review Concept: Innate Inflammatory Response is the first line of defense: Recruitment and activation of inflammatory cells which then kill whatever doesn’t belong...

4. Adaptive Immune Response can be initiated by the non-specific innate inflammatory response Adaptive response is highly specific to antigens Greatly enhances neutrophil/macrophage/NK-cell activation “Remembers” antigens

5. When macrophages recognize pathogens as foreign entities they are stimulated to engulf the pathogen and then digest them, in effect, destroying them. In this way invading pathogenic organisms are prevented from causing us harm. (At least we hope they are all killed before we are harmed.) With really virulent pathogens (such as the ebola virus) the “killing the pathogen” process doesn’t happen fast enough; the pathogen multiplies very fast and damages our cells far faster than we can repair them so the cells end up dying in large numbers (and we die along with them due to multiple organ failure) before we can kill all of the pathogens. With pathogens that are not too virulent, our adaptive immune response has time to respond, and produce lots of antibody-producing B-lymphocytes. The antibodies bind to the specific pathogens and then trigger a very aggressive activation of neutrophils and macrophages and NK cells and compliment and CTL’s to effectively kill off the invading pathogen (ie. kill it faster than it reproduces and kills our cells).

6. Adaptive Immune Response Major Functional Cells Include: Lymphocytes - T-Lymphocytes - B-Lymphocytes - Natural Killer Cells - Macrophages All lymphocytes originate from precursor cells in the bone marrow - B LYMPHOCYTES: mature in marrow then circulate in blood/spleen/lymph those with “antigen receptors” which recognize “self antigens” are destroyed before they reach maturity - T LYMPHOCYTES: mature in the thymus then circulate in blood/spleen/lymph only MHC-recognizing Tcells are allowed to mature and of these, only those which do not recognize both MHC and self-antigens are allowed to fully mature White Blood Cells - Neutrophils - Monocytes - Mast Cells - Eosinophils - Basophils - Platelets

7. Major Functional Tissues Include: - Bone Marrow - Lymph Nodes - Spleen - Thymus Thymus Spleen

8. T-cells are “born” in the bone marrow by the hundreds of millions every day. They migrate to the thymus where they mature into antigen-responsive (but still naïve) T-cells and then circulate throughout the lymph, spleen, and blood. The process of maturing in the thymus is actually a two-step selection process. First, only those T-cells that recognize MHC protein complexes are allowed to mature. Then, of these maturing cells, those that do not react strongly with both MHC and self-antigens are allowed to complete the maturation process. This produces a population of naïve T-cells that do not react with “self” antigens but are still able to interact with the antigen-presenting cells that express both MHC and antigens. Approximately 2% of the original T Lymphocytes that are “born” in the marrow survive this process. Each individual naïve T-cell has a T-cell receptor on its surface that is capable of binding to a specific antigen (an antigen that could have come from a digested bacterium that was then bound to the surface of an antigen-presenting cell) and each T-cell receptor on different T-cells will recognize different antigens. Thus, in total, our T-cells are born with the ability to recognize millions and millions of different antigens before we are actually exposed to the pathogens that they are derived from. An interesting concept is that if we do not have the appropriate array of genes to produce the specific T-cell (and B-cell) receptors that recognize antigens, from a particular strain of virus for example, we will not be able to develop an immune response to that particular virus and we may die from the resulting viral infection. From a historical perspective, Europeans who could not make antibodies against influenza and measles (and a pile of other diseases) had long-since died of these diseases so that by the time they “invaded” N. America in the late 1400’s, the Europeans simply got sick for a week or so if they were exposed to the pathogens that caused the flu or measles. The N. American natives were not so lucky. They had never been exposed to such diseases and there had been no “selection” for those who had the genetic ability to develop immunity against these “European” diseases. Within a decade, almost 90% or more of the native population had been wiped out by the common diseases. Only those who already had naïve T-cells with T-cell receptors that recognized antigens from the new pathogens could survive. In a very short time the unbelievable power of viruses to almost completely wipe out humans was demonstrated very clearly. Of course “hind-sight is 20:20”, viruses were unknown then and no one could have recognized this at the time.

9. Bone Marrow Lymph Nodes The other lymphocytes directly involved in the adaptive response are the B-lymphocytes. B-lymphocytes also are “born” in the bone marrow but unlike the T-cells the B-cells mature in the marrow before circulating throughout the lymph, spleen, and blood. The maturation process weeds out those B-cells that have antigen receptors that recognize self-antigens so that only about 10% of the new T-cells actually survive the maturation process. B-cells also express antigen receptors on their cell-surface which interact with the antigen-presenting cells

10. Antigens Molecular shapes made from just about any biological components that can be recognized by “immune cells” as “not self”. Soluble and Cell Surface Antigens can include the following: Antigen Recognized by Proteins (native) B Lymphocytes Peptides (digested proteins) B & T Lymphocytes Nucleic Acids B Lymphocytes Polysaccharides B Lymphocytes Lipids B Lymphocytes Small Chemicals B Lymphocytes

11. T Lymphocytes • Antigen presenting cells (macrophages, dendritic cells, B lymphocytes) process original antigen and express it on their cell surface in conjunction with MHC. • T lymphocytes with receptors for the displayed peptide interact with APC and are stimulated to proliferate and differentiate into helper T lymphocytes, cytolytic T lymphocytes, and memory T lymphocytes. • Helper T lymphocytes secrete cytokines to stimulate other cells, especially the B Lymphocytes • Cytolytic T lymphocytes lyse antigen-bearing target cells • Memory T lymphocytes remain in circulation for many years to stimulate a swift response to a subsequent infection

12. Macrophages which engulf invading pathogens, bacteria for example, will digest them and small pieces of proteins (peptides - short amino acid chains of 5 to 12 amino acids long) or lipids from the bacteria’s cell membranes, or lipopolysaccharides from the bacteria’s cell membrane are displayed on the macrophage’s cell surface in conjunction with the MHC (major histocompatability complex). These small pieces of the bacteria (or some other pathogen) proteins are called antigens and other antigen-presenting cells (dendritic cells, B-lymphocytes) also can stimulate T-cells as described next. The dendritic cells happen to be the major antigen-presenting cell but because we started with macrophages in the inflammatory section, we will continue with that concept. After digesting the foreign pathogen and building the antigen-MHC complexes on the cell membrane, the macrophage (actually, a whole whack of them) migrates into the lymph and then moves through the lymph to (hopefully) come in contact with a T-lymphocyte (T-cell) which has a cell surface receptor capable of recognizing the displayed shape (antigen). Once an antigen presenting cell with an expressed antigen migrates through the lymph and comes in contact with a naïve T-cell with a receptor that recognizes the same antigen, the T-cell will be stimulated to differentiate into different types of specialized T-cells: helper T-cells, cytolytic T-cells (CTC’s), and memory T-cells. These specialized T-cells then proliferate to produce many thousands of clones of the helper and cytolytic cells and memory cells. The helper T-cells and CTC’s will live for several days to a few weeks while the memory cells can live in the lymph for many decades. The CTC’s will kill any cell which displays the same antigen that stimulated the original T-cell to divide and proliferate while the helper T-cell is necessary to help stimulate the production of antibody-producing B-cells. The memory cells stay circulating in the lymph and when they bump into the original pathogen again (many weeks, months, or years later) they are immediately stimulated to proliferate and differentiate into many thousands of helper cells and CTC’s. These cells then initiate an extremely aggressive attack against the pathogen and it is often completely destroyed before any symptoms of disease can start.

13. B Lymphocytes • Express Ig M and D receptors on cell-surface • Antigen-presenting cells such as macrophages digest invading pathogens and express specific antigens on their cell surface • Macrophages present antigens to naïve B-lymphcytes and the lymphocytes, with the co-stimulation by helper T lymphocytes, are then stimulated to proliferate and differentiate into antibody producing B lymphocytes and memory B lymphocytes • Antibody producing B lymphocytes secrete large amounts of IgG antibodies which bind to the specific antigenic sites of the invading pathogen • Memory B lymphocytes remain in circulation for many years to provide a swift response to a subsequent infection

14. Antibodies (IgG) produced by B-lymphocytes bind to the antigenic sites on the pathogen

15. B-cells also express antigen receptors on their cell-surface which interact with the antigen-presenting cells and are stimulated to differentiate into antibody producing B-cells and memory B-cells. The catch to this process is that it won’t happen without the participation of the helper T-cells that recognize the exact same antigen. The helper T-cells must interact with a APC-stimulated B-cell before the newly stimulated B-cell can differentiate into antibody-producing B-cells and memory B-cells and proliferate through clonal expansion. The resulting antibody-producing B-cells release huge numbers of antibodies but only live for several days to a few weeks. Each antibody is identical and binds only to the antigen on the original pathogen that stimulated the B-cell in the first place. When antibodies bind to pathogens they greatly stimulate any neutrophils, NK cells, and macrophages to destroy them. The antibody-activated neutrophils, NK cells, and macrophages also produce large amounts of inflammatory signals to attract more killer cells to the region to enhance the killing response. A full-blown immune response usually can occur within one to three weeks of the first exposure to an antigen resulting in an adaptive immune response for the (hopefully) elimination of pathogens before they can cause mortal damage The way the pathogen is destroyed often involves compliment proteins and the antibodies. The antibodies bind to the antigens and then the compliment proteins bind to any membrane coated with antibodies and destroy the membrane. Complement is actually a group of proteins produced (in part) by the liver. When they come in contact with foreign cells which are incapable of inhibiting them, they will assemble into complex tube-like structures which penetrate the membrane of these foreign cells and open up a large pore. Thus the pathogens are destroyed by complement through the process of membrane rupture; leading to cellular necrosis. The process of complement binding and assembly into membrane-destroying proteins is greatly enhanced when they bind to those antibodies which are already bound to the pathogen. The memory B-cells and memory T-cells stay circulating in the lymph and when they bump into the original pathogen again (many weeks, months, or years later) they are immediately stimulated to proliferate and differentiate into many thousands of cytolytic T-cells and antibody-producing B-cells and even more memory cells. Stimulation of memory cells can initiate a full-blown response within hours. In this way a sub-clinical infection with a previously “seen” pathogen will be wiped out long before any symptoms of infection can occur. Pathogens which cause disease are, of course, very numerous. They range from viruses and bacteria to various yeasts, fungi and parasites. As already mentioned, viruses are often the cause of many seriously deadly diseases.

16. In essence, the adaptive immune response leads to the production of antigen-specific (pathogen-specific) antibodies which greatly enhances the ability of neutrophils, macrophages, NK cells, and compliment to do their job of removing pathogens from the body.