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Specific Immunity - Adaptive Immunity - Nursing
- 1. The Immune System AdaptiveImmunity
- 2. Specific Resistance: Immunity It is mediated by the combined actions of both T and B lymphocytes “THIRD LINE OF DEFENSE” Specific immunity differs from nonspecific defense mechanisms with respect to: Unresponsiveness to self - recognizes self cells vs. non-self cells/compounds Memory - second and subsequent encounters produce an even more vigorous response than the first encounter with the same foreign cell/compound Inducibility - the presence of specific, identifiable pathogens will induce/stimulate Clonality - Upon activation, the cells involved in specific immunity reproduce identical “offspring” Specificity - made against particular, recognizable, foreign molecules, cells, etc. response is directed against one and only one of these items
- 3. The Role ofT and B Cells in Specific Immunity T-cells mature in the thymus; responsible for the cell-mediated immune response effective against fungi, viruses, parasites, cancer, and tissue transplants Killer T-cells directly attack antigens = cytotoxic T-cells Helper T-cells co-stimulate T- and B-cells
- 4. B-cells maturein the bone marrow effective against extracellular pathogens such as bacteria antibody-mediated immune response plasma cells (activated B cells) that form antibodies and actively secrete them
- 5. The Lymphatic System The lymphatic system drains lymph from all areas of the body and sends it back towards the heart to be returned to the blood circulatory system. Once mature, the T and B cells migrate into the secondary lymphoid organs and lymphoid tissues such as lymph nodes, the spleen, tonsils, MALT (mucosa-associated lymphoid tissue),etc. As the lymph moves through the lymphatic system, it is under constant surveillance for the presence of pathogens by the various cells of adaptive immunity
- 6. Blood capillary From heart Tissue cell Intercellular fluid Lymph toheart via lymphatic vessels Gap in wall Valve Lymphatic capillary To heart Afferent lymphatic vessel Medulla Vein Artery Efferent lymphatic vessel Capsule Primary follicle Lymphatic nodule Valve (prevents backflow) Cortex Tonsils Cervical lymph node Lymphatic ducts Thymus gland Axillary lymph node Heart Breast lymphatics Spleen Abdominal lymph node Intestines Peyer's patches in intestinal wall Part of mucosa- associated lymphoid tissue (MALT) Appendix Red bone marrow Inguinal lymph node Lymphatic vessel
- 7. What is anAntigen? Molecules or bits of foreign material entire microbes, parts of microbes, bacterial toxins, pollen, transplanted organs, incompatible blood cells An antigen has: Immunogenicity = the ability to provoke an immune response by stimulating the production of specific antibodies &/or specific T- cells Reactivity = the ability to react to the cells or to the antibodies it caused to be formed
- 8. If antigensget past the body’s nonspecific defenses where do they go to next? They may: Enter the bloodstream to be deposited in the spleen Penetrate the skin & end up in the lymph nodes Penetrate mucous membrane & lodge in the associated lymphoid tissue
- 9. The Chemical Natureof Antigens/Epitopes Antigens are generally large, complex molecules, usually proteins, though some lipids and carbohydrates can be antigens If they have simple repeating subunits they are not usually antigenic (I.e. plastics or metals in joint replacements)
- 10. The smallpart of an antigen that actually elicits the immune response is called the epitope It is also referred to as an antigenic determinant because it is the portion of the molecule that allows your immune system to determine that the molecule itself is an antigen.
- 11. Epitopes (antigenic determinants) Cytoplasmic membrane Cytoplasm Antigen Epitopes (antigenic determinants) Nucleus Figure3a Antigens, molecules that provoke a specific immune response.
- 12. Extracellular microbes Exogenous antigens Endogenous antigens Intracellular virus Virally infected cell Autoantigens (normal cell antigens) Normal (uninfected) cell Exogenousantigens Endogenous antigens Autoantigens Figure 3b-d Antigens, molecules that provoke a specific immune response.
- 14. An antibody interactingwith the epitope on an antigen
- 15. Sources of Antigens Antigens can originate exogenously, as parts of microbial cells’ structure (i.e. cell walls, flagella, pili, plasma membrane), or as chemicals secreted/released by a microbe (i.e. toxins) Some antigens are referred to as being endogenous because their source is a microbe that reproduces inside the body’s own cells. Such microbes include viruses, protozoa, fungi and some bacteria.
- 16. How doesthe immune system detect endogenous antigens? The affected body cells must incorporate/add the antigen to the plasma membrane of that body cell so that it can be ‘seen’ or detected by cells of adaptive immunity Finally, some antigens are referred to as being autoantigens because they are molecules belonging to ‘self’. Normally, the immune system learns tolerance to these cells and ‘ignores’ them
- 17. Diversity of AntigenReceptors The immune system can recognize and respond to a billion different epitopes -- even artificially made molecules An explanation for the great diversity of receptors is that this diversity is produced by the genetic recombination of a few hundred small gene segments
- 18. Each Bor T-cell, by the time it has matured, has its own unique set of gene segments (produced through somatic recombination) that codes for its own unique antigen receptor, located in the B or T-cell’s plasma membrane Therefore, we have an enormously diverse population of immune cells ready to respond to foreign antigens
- 19. Major Histocompatibility Complex(MHC) Antigens They are a family of membrane proteins All of our cells have unique surface markers (1000s of molecules) These integral membrane proteins are called HLA (for human leukocyte antigen) antigens, or MHC-antigens/markers
- 20. While theseproteins are recognized as ‘self’ in OUR bodies, in another person, with different MHC-markers, these same molecules would stimulate a specific immune response Hence, they are usually referred to as MHC-antigens Reference to them as ‘markers’ in these notes is done to avoid confusion with use of the word ‘antigen’ as a reference to foreign molecules (i.e. from bacteria, virus, etc.)
- 21. The MHCmarkers allow our bodies to identify ‘self’ versus ‘non-self’ based on the precise nature of the MHC molecules on the cell surfaces MHC-I markers are built into the cell membrane of all cells except red blood cells Therefore, they are often referred to as being present on all nucleated cells in our bodies MHC-II markers are seen only on the membrane of specialized antigen- presenting cells (such as macrophages, B cells, and thymus cells) When antigen-presenting cells (APCs) (macrophages or B cells) ingest foreign proteins through phagocytosis, they will display them as part of (i.e. attached to) their MHC-II markers
- 22. This seriesof proteins is coded for genetically and involves a large number of alleles Only identical twins carry the same set of MHCs MHC markers are important in tissue transplantation since they identify ‘self’ versus ‘foreign’ tissue types to the recipient’s immune system MHC-I marker molecules also help cells display antigens from intracellular pathogens (i.e. endogenous antigens)
- 23. Polypeptide is catabolized. Epitopes MHC Iprotein in membrane of endoplasmic reticulum Lumen of endoplasmic reticulum Epitopes are loaded onto complementary MHC I proteins in the ER. MHC I protein– epitope complex Golgi bodies package MHC I protein–epitope complexes into vesicles. MHC I protein– epitope complexes on cell surface Cytoplasmic membrane MHC I protein–epitope complexes are displayed on cytoplasmic membranes of all nucleated cells. 5 4 3 2 1 Vesicles fuse with cytoplasmic membrane. Figure 12 The processing of endogenous antigens.
- 25. Phagocytosis by APC Exogenous pathogen with antigens MHCII protein in membrane of vesicle Epitopes in phagolysosome MHC II protein– epitope complex Vesicles fuse and epitopes bind to complementary MHC II molecules. Vesicle fuses with cytoplasmic membrane. MHC II protein– epitope complexes on cell surface Cytoplasmic membrane MHC II protein–epitope complexes are displayed on cytoplasmic membranes of antigen- presenting cell. 1 2 3 4 Figure 13 The processing of exogenous antigens.
- 26. MHC-II antigensthen bind to receptors on helper T cells The helper T cells are now activated by this interaction and will go on to activate cytotoxic T cells and B cells (the latter of which will produce antibodies to the foreign protein that was originally displayed)
- 27. Cell-Mediated Immunity Beginswith the activation of a T-cell by a specific antigen; recognition of that antigen is the FIRST signal in the T-cell activation process The T-cell will bind to the recognized antigen and only then will receive a SECOND signal; this signal is the co-stimulation of the T-cell by chemicals such as cytokines or by the plasma membrane molecules on both the T-cell and the antigen-presenting cell
- 28. Once theT-cell has received TWO signals it is activated The T-cell then proliferates (divides) and differentiates into identical effector cells (a clone) that are all capable of recognizing the SAME antigen
- 29. The activation,proliferation and differentiation of the various types of T-cells occurs in the secondary lymphatic organs such as the lymph nodes The result is the production of a population of T-cells capable of an immune attack against THAT antigen The elimination of the intruder occurs via a direct attack on the intruder by the T-cells
- 30. Types of T-Cells Helper T-cells; TH; also called CD4+ cells because they display CD4 protein Cytotoxic T-cells; TC; also called CD8+ cells because they display CD8 protein Memory T-cells; of both of above kinds; long-term ‘memory’ of encountered antigens that permits rapid, strong second response to that antigen
- 31. Helper T-cells Recognizeantigen fragments bound to the MHC-II molecules in the plasma membranes of APCs The MCH-II molecules also bind to and ‘activate’ the TH cells
- 32. Co-stimulation occursand leads to the TH-cell’s production of cytokines such as interleukin-2 (which stimulates further T-cell differentiation and further release of IL-2) Activated T-cell proliferates & differentiates into a population (clone) of active TH cells and long-lived memory TH cells
- 33. Figure 14 Activationof a clone of cytotoxic T (Tc) cells. Antigen presentation MHC II Epitope TCR Th cell Th differentiation Th1 cell IL-2R IL-2 IL-2R IL-12 DC IL-2 Active Tc cells MHC I Inactive Tc cell IL-2 receptor (IL-2R) Clonal expansion Memory T cell Self-stimulation IL-2 IL-2 Dendritic cell MHC I CD8 Epitope TCR Tc cell Immunological synapse Active Tc cells 1 2 3 4
- 34. The overallfunction of TH cells is to co-stimulate all other lymphocytes, including natural killer cells by: Secretion of cytokines (i.e. interleukin-2) The use of cytokines for the co-stimulation of more TH cells
- 35. The co-stimulationrole of cytokines is an autocrine function in that the cytokine co-stimulates the TH cell that secreted it, causing the TH cell to proliferate and secrete even more cytokines such as interleukin (this is a positive feedback effect that stimulates the formation of many more active helper T-cells)
- 36. Cytotoxic T-cells Knownas T8 or Tc or killer T-cells Recognize antigen fragments that are bound to MHC-I molecules; these would be found on: Cells infected with a virus Tumor cells Tissue transplants of non-matching tissue type
- 37. Co-stimulation ofcytotoxic T-cells is required for them to be active, and this is accomplished by the presence of cytokine chemicals that are produced by the helper T-cell population
- 38. Maximal activationof cytotoxic T-cells occurs when an antigen is presented in association with BOTH MHC-I and MHC-II molecules The TC cell then proliferates & differentiates into a population (clone) of active Tc cells and memory Tc cells This step occurs in the secondary lymphatic organs such as the lymph nodes
- 39. Memory T-cells MemoryT-cells are T-cells from a clone that did not turn into either active TH or active TC cells during a cell-mediated response These cells are available for swift response if a second exposure to the same antigen should occur These cells ‘remember’ which antigen to react to, therefore are termed ‘memory’ T-cells
- 40. Elimination of Invaders Activated TC cells migrate to the site of infection or tumor formation These cells recognize the specific antigen, attach to it & attack They ultimately kill the cell to which the antigen is bound by:
- 41. 1. Secretionof granules containing perforin that punches holes in the target-cell which will then permit the entry of a cytotoxin known as granzyme whose action is to induce apoptosis in the target cell 2. Secretion of a chemical called lymphotoxin that activates enzymes in the target-cell, causing its DNA to fragment; target cell dies
- 42. 3. Secretionof gamma-interferon to activate phagocytic cells, which engulf target cell and digest it Thus, foreign cells, cells infected with viruses or cells that have turned cancerous, will be killed
- 43. Active cytotoxic T (Tc) cell TCR Viralepitope MHC I protein Virally infected cell Intracellular virus CD8 Figure 15a. A cell-mediated immune response.
- 44. 44 Tc cell Perforin Granzyme Perforin complex(pore) Granzymes activate apoptotic enzymes Inactive apoptotic enzymes Active enzymes induce apoptosis Virally infected cell Tc cell CD95L CD95 Enzymatic portion of CD95 becomes active Inactive apoptotic enzymes Active enzymes induceapoptosis Virally infected cell Figure 15b-c A cell-mediated immune response.
- 45. Immunological Surveillance Acancerous cell displays weird/unusual surface antigens (tumor antigens) that are rarely, if ever, found on normal cells Surveillance = ability for the immune system to find, recognize & destroy those cells that are displaying tumor antigens
- 46. Immunological surveillanceis performed by cytotoxic T-cells, macrophages & natural killer cells It is especially effective at finding tumors that are caused by viruses Transplant patients taking immunosuppressive drugs are at the greatest risk of contracting viral-induced cancers
- 47. Graft Rejection Aftera tissue or organ transplant, the immune system may produce both a cell-mediated and an antibody-mediated immune response This response constitutes graft rejection
- 48. Having aclose match of MHC antigens will result in a weaker graft rejection response The chance of a graft rejection can also be reduced by the use of immunosuppressive drugs (such as cyclosporine); these drugs Inhibit the secretion of interleukin-2 by helper T-cells However, the drugs have little effect on B cells so the patient maintains some resistance
- 49. Antibody-Mediated Immunity Ourbodies contain millions of different B cells that can recognize different antigens and respond to them B cells sit still and let antigens be brought to them The B cells are specifically located in the lymph nodes, the spleen or in Peyer’s Patches (in the GI system)
- 50. Once activated,B-cells differentiate into plasma cells that actively secrete antibodies The antibodies circulate in the lymph and the blood The antibody combines with an epitope on the antigen, similarly to a key fitting a specific lock
- 51. B cellreceptors bind to an antigen – the response will be even more intense if the antigen is already on an APC A helper T-cell costimulates the B cell The stimulated B-cell then undergoes rapid cell division and differentiation to produce: 1. Long-lived memory cells
- 52. 2. Aclone of plasma cells (which will actively secrete antibodies against the antigen) The plasma cells will produce antibodies at a rate of 2000 Ab molecules/sec for 4-5 days The plasma cells secrete only one kind of Ab ( the one that is specific to the original Ag) The Ab enters the blood/lymph circulation to attack the antigen
- 53. Repertoire of Thcells (CD4 cells) CD4 TCRs APC presents antigen to Th cells for Th activation and cloning. APC Th cell TCR Epitope MHC II CD4 CD28 CD80 (or CD86) APC Th cell clones Th cell differentiates into Th2 cell. CCR3 CCR4 Th2 cell IL-4 MHC II proteins Repertoire of B cells Th2 cell TCR Epitope MHC II CD40 CD40L CD4 Th2 cell activates B cell. Clone of plasma cells Antibodies Memory B cells Th2 cell B cell 1 2 3 4 IL-4 Figure 18 A T-dependent antibody immune response.
- 54. Antibody Structure Antibodiesare glycoproteins that are also called immunoglobulins They contain 4 polypeptide chains -- 2 heavy & 2 light chains There is a hinged midregion that lets the Ab assume either a T or a Y shape
- 55. The tipsare the variable regions – these form the Ag-binding sites The remainder of the molecule is the constant region and is species-specific There are 5 different classes of antibody based on the structure of the constant region IgG, IgA, IgM, IgD and IgE
- 56. 56 Light chain Arm (Fab) Hinge Stem(Fc) Antigen-binding sites Variable region of heavy chain Variable region of light chain Constant region of light chain Constant region of heavy chain Arm (Fab) Hinge Stem (Fc) S S S S S S S S Heavy chains Figure 5 Basic antibody structure.
- 57. Antibody Actions Antibodieshave the ability to bind to and eliminate foreign invaders too; the techniques used include: 1. Neutralization of the antigen by blocking its effects as a toxin or by preventing its attachment to body cells 2. Immobilize the antigen, and therefore also the bacteria on which it is found, by attacking cilia/flagella
- 58. 3. Agglutinate& precipitate the antigens (and also, therefore, cells on which they are found) by cross-linking them; this causes the clumping & precipitation of the antigens/cells on which they are found 4. Complement activation 5. Enhancing phagocytosis through precipitation, complement activation or opsonization (coating of antigen with a special substance to stimulate phagocytosis)
- 59. Adhesin proteins Bacterium Toxin Virus Neutralization Agglutination Pseudopod ofphagocyte NK lymphocyte Fcreceptor protein Perforin allows granzyme to enter, triggers apoptosis and lysis Antibody-dependent cellular cytotoxicity (ADCC) Bacteria die Oxidation Opsonization Fcreceptor protein Figure 6 Five functions of antibodies.
- 60. Role of theComplement System This is a defensive system of plasma proteins that attack and destroy microbes specifically The system is activated by 2 different pathways to produce the same result 1. Activated via inflammation: dilation of arterioles, release of histamine & increased permeability of capillaries
- 61. 2. Activatedby opsonization of antigen: a special protein binds to the microbe, making it easier to phagocytize Activation of the complement system results in the cytolysis of the microbe: a complex of several complement proteins can form holes in the microbe’s plasma membrane, causing leakiness and cell rupture (which leads to cell death)
- 63. Immunological Memory Primaryimmune response Occurs on the person’s first exposure to that antigen The immune response produced is steady, slow The immune response includes the formation of memory cells that may remain for decades
- 64. A secondaryimmune response occurs upon the second exposure to that antigen In the immune memory there are 1000’s of memory cells that on the second exposure will proliferate & differentiate into plasma cells & cytotoxic T-cells specific to that antigen
- 65. The antibodytiter is a measure of the degree of immune memory (measures the amount of serum antibody) Ideally, immune recognition & removal of the foreign cells/molecules occurs so quickly that the person does not even become ill
- 66. Figure 19 Theproduction of primary and secondary antibody immune responses.
- 67. Self-Recognition & Immunological Tolerance T-cells must learn to recognize self cells (based on self MHC molecules ) & NOT react to self proteins This is referred to as self-recognition & immunological tolerance
- 68. T-cells maturein the thymus Any T-cells that can’t accurately recognize self cells, or T-cells that react to self cells, will be either destroyed by programmed cell death (apoptosis or deletion), or inactivated (anergy) -- alive but unresponsive As a result of the above processes, only 1 in 100 emerges as an immunocompetent T-cell B cells develop in the bone marrow in the same way
- 69. Figure 8. Clonal deletionof T cells. Stem cell (in red bone marrow) Thymus T cells TCRs with differently shaped binding sites MHC Epitope Thymus cells Recognize MHC? Thymus cells No Yes Receive survival signal Recognize MHC-autoantigen? Apoptosis No Yes Few Most Repertoire of immature Tc cells Regulatory T cell (Tr) Apoptosis 3 4 2 1
- 70. Stem cell (in redbone marrow) B cells Cell with autoantigens BCRs with differently shaped binding sites Cell with autoantigens Apoptosis Blood vessel To spleen 1 2 3 4 Figure 9 Clonal deletion of B cells.
- 71. Aging and Immunity As we age, we are more susceptible to all types of infections and malignancies Our response to vaccines is decreased We produce more autoantibodies
- 72. We experiencereduced immune system function because: The T-cells become less responsive to antigens; this is due to the age-related atrophy of the thymus and also to a decreased production of thymic hormones B cells become less responsive, and therefore production of antibodies is slowed
- 73. TYPES OF IMMUNITY ACTIVE; this involves a person's OWN immune system being involved in producing a response to Ag This lasts longer than passive immunity PASSIVE; This is a situation in which immunity is transferred from another individual, whose own immune system was involved with Ag This provides immediate protection
- 74. NATURAL Naturalimmunity results from unintentional exposure to antigen It is an everyday event (i.e. when you unintentionally are infected with a disease) ARTIFICIAL This involves an intentional exposure to a pathogen or a vaccine which produces intentional immunization and is used as a preventive measure
- 75. Combinations ofthe above four categories are possible. For example, babies receive collostrum from their mothers, which provides natural, passive immunity; when you are immunized with an attenuated virus you will form an artificial, active immunity to that pathogen.