Immune System PDF

**IMMUNE SYSTEM**: Three barriers with increasing specificity: 1. **Surface barrier**: skin, eyelashes - Chemical (low pH of the stomach), Mechanical, Biological - Respiratory: coughing + sneezing - Flushing away of tears + urine - Lysosomes: antibacterial -- in tears - Phospholipa...

**IMMUNE SYSTEM**: Three barriers with increasing specificity: 1. **Surface barrier**: skin, eyelashes - Chemical (low pH of the stomach), Mechanical, Biological - Respiratory: coughing + sneezing - Flushing away of tears + urine - Lysosomes: antibacterial -- in tears - Phospholipase A2: breast milk, saliva + tears 2. **Innate Immune System**: no memory, rapid, non-specific, cell mediated & humoral - Effective from birth - 1^st^ line defence - Determined by an individuals genetic makeup, hormones + age 3. **Adaptive Immune System**: memory, slow, specific, cell mediated & humoral **INNATE IMMUNE SYSTEM**: 1. Recruitment of cells to area of infection/inflammation through cytokines (chemical mediators) 2. Complement Cascade Activation 3. Identification and removal of foreign substances in organ tissues, blood + lymph 4. Activation of adaptive immune system through antigen presenting cells **INFLAMMATION**: 1. **INCREASED BLOOD FLOW**: dilation of arterioles in response to histamine from mast cells + basophils 2. **INCREASED VASCULAR PERMEABILITY**: retraction of endothelium + increase vascular blood pressure in capillary bed -- allows antibody + complement to enter 3. **INCREASED CELL RECRUITMENT**: from venules into tissues signalled by cytokines **COMPLEMENT SYSTEM**: 9 PROTEIN SYSTEM: C1-C9 - Initiate recruitment of inflammatory cells - Label pathogens for destruction - Disrupt the plasma membranes of infected cells leading to cell lysis - Remove the neutralised antibody-antigen complexes **CELLS OF THE INNATE IMMUNE SYSTEM**: +-----------------------------------+-----------------------------------+ | NK CELLS | - Approx. 15% of lymphocytes | | | | | | - Innate ability to kill | | | tumor + viral cells | | | | | | - Receptors detect MHC | | | molecules + complement | | | cytotoxic T cells in their | | | destruction | | | | | | - CYTOTOXIC: contain perforin + | | | granzymes like protease | | | | | | -PERFORIN: causes holes | | | within the cell membranes | | | which allows proteases to | | | enter | | | | | | - Causes APOPTOSIS: cell | | | destruction not cell lysis | | | | | | (cell lysis will only release | | | the virion whereas apoptosis | | | destroys the virus and cell) | | | | | | - Activated by interferons or | | | cytokines released from | | | macrophages | | | | | | - MAIN ROLE: Limit viral | | | infection whilst the adaptive | | | immune response builds up its | | | response | +===================================+===================================+ | Mast Cells | - Reside in connective tissue + | | | mucous membranes (not in | | | blood like other cells) | | | | | | - Associated with allergy + | | | anaphylaxis | | | | | | - Releases histamine + heparin | | | when activated: | | | | | | - Vasodilation | | | | | | - Recruits macrophages + | | | neutrophils (phagocytes) | +-----------------------------------+-----------------------------------+ | Phagocytes | | | | | | Swallow the pathogen and form a | | | phagosome | | +-----------------------------------+-----------------------------------+ | Macrophages | - Derived from blood monocytes | | | | | | - Present throughout the body | | | | | | - Can phagocytose foreign | | | bodies in the blood + tissues | | | | | | - Can remove damaged or old | | | cells | +-----------------------------------+-----------------------------------+ | Dendritic Cells | - ANTIGEN PRESENTING CELL | | | | | | - Can process foreign material | | | and present to lymphocytes | | | and move from periphery to | | | lymphoid tissues to present | | | to TH cells | | | | | | - ALSO phagocytose foreign | | | substance found in blood + | | | peripheral tissues | +-----------------------------------+-----------------------------------+ | Neutrophils | - Short lived phagosome | | | | | | - Contains hydrolytic lysozymes | | | | | | - Produce oxide +super oxide | | | molecules which are toxic to | | | many micro-organisms | | | | | | - Important in defence against | | | **EXTRACELLULAR BACTERIA** | +-----------------------------------+-----------------------------------+ | Basophils + Eosinophils | - Related to neutrophils | | | | | | - Release histamine | | | | | | - Important in defence against | | | **PARASITES** + **ALLERGIC | | | REACTIONS** | +-----------------------------------+-----------------------------------+ **THE ADAPTIVE IMMUNE RESPONSE**: - Enhances the innate immune response, takes longer to develop (mins to hours) - Only present in vertebrates - Not fully functional at birth -- unlike innate immune system - Immunity is only acquired when it the system is encountered by a pathogen that has been failed to be cleared the innate immune system: Repeat encounter initiates a memory-induced response: 1. Lymphocytes activated 2. Antibody + cytokines produced 3. Memory cells develop **[CHARACTERISTICS OF THE ADAPTIVE IMMUNE RESPONSE]**: - Specific to a foreign agent - Responds to previously unseen foreign molecules - Antigen specific receptors of lymphocytes recognise the foreign molecules - Subsequent exposure to antigen causes the response to be more rapid and to a greater extent: **MORE EFFECTIVE** **[CELLS OF THE ADAPTIVE IMMUNE SYSTEM]**: B CELLS + T CELLS - 20-40% of WBCs - Peripheral blood has 20-40% lymphocytes, other remaining is in the lymphatic system - **Lymphatic system**: - Carries a clear fluid called plasma or lymph - Central lymphoid tissue: BONE MARROW: lymphocytes undergo differentiation to B-cells or T-cells - Peripheral lymphoid tissue: LYMPH NODES (lymph filter organs: 2-25mm in diameter) + SPLEEN+ADENOIDS (2-25mm in diameter): lymph/plasma travels through Antigen are presented to the immune system via the APCs at the lymph nodes - In the primary lymphoid tissue -- stem cells in the bone marrow produces three types of cells: 1. RBCs 2. Granulocytes: neutrophils, eosinophils, mast cells + basophils 3. Mononuclear leukocytes: monocytes, B-cells, T-cells - **[CLONAL SELECTION]**: each lymphocyte has its own receptor with antigen specificity - During differentiation in the **[primary lymphoid tissues]** -- the genes which encodes the antigen receptors diversify enormously - Lymphocytes that do not generate an antigen receptor: **UNDERGO APOPTOSIS** - **[CLONAL EXPANSION]**: lymphocytes divide rapidly as only a small number of lymphocytes can identify a particular pathogen -- this happens in the **[secondary lymphoid tissues]** - Can take a few days **[TWO PHASES OF IMMUNE RESPONSE]**: 1. **[Initiation phase (afferent phase]**): activation of lymphocytes- in the mucosa or in local lymph nodes near site of infection 2. **[Effector phase (efferent phase)]**: lymphocytes + phagocytes enter the site of infection **[TWO MAIN TYPES OF ADAPTIVE IMMUNE SYSTEM]**: 1. HUMORAL MEDIATED: B-CELL 2. CELL MEDIATED: T CELL +-----------------------------------+-----------------------------------+ | **HUMORAL MEDIATED: B-CELL | **CELL MEDIATED: T-CELL | | MEDIATED** | MEDIATED** | | | | | **Bone marrow derived (start off | **Thymus derived (mature in the | | and mature in the bone marrow of | thymus but start off in the bone | | primary lymphoid tissues)** | marrow of primary lymphoid | | | tissues)** | +===================================+===================================+ | - Extracellular microbes | - Intracellular microbes | | | | | - B-cells are the secreted form | - IMMATURE: from bone marrow to | | of antibodies | thymus | | | | | - **IMMATURE**: bone marrow | - MATURE in the thymus | | | | | - **MATURE**: peripheral | - 60-70% of lymphocytes | | blood + lymphatic tissues | | | | - Destroy viral-infected cells | | - B-cells identify pathogens | -- cytotoxic T-cells -- CD8+ | | when the antigen binds to an | glycoprotein | | antibody -- the | | | antigen-antibody complex is | - Control the type of immune | | taken up by the B-cell | response -- helper T-cell: | | | CD4+ glycoprotein | | - B-cells processes the complex | | | and processes it into | - **TH1**: activates | | peptides | macrophages + | | | cell-mediated response | | - The B-cell displays the | | | antigenic peptides on the | - **TH2**: promote antibody | | surface MHC Class 2 molecules | responses | | | | | B-Cell + Antigen on MHC 2 surface | - Responsible for recognising | | molecules = attracts a T-helper | antigens originating inside | | cell which released lymphokines + | other cells of the body + | | activates B-cell | which are presented on the | | | cell surface: **ANTIGEN | | - Activated b-cell begins to | PRESENTING** | | divide -- differentiate into | | | antibody forming cells which | | | secrete millions of copies of | | | antibodies that recognise | | | this specific antigen -- | | | DAUGHTER CELLS (memory cells) | | | | | | - Antibodies circulate in blood | | | plasma + lymph and mark | | | pathogens for destruction by | | | complement activation + | | | phagocytosis -- therefore | | | antibodies are only effective | | | on extracellular pathogens | | +-----------------------------------+-----------------------------------+ | - | **[CYTOTOXIC | | | T-CELLS]**: | | | | | | - Defence against intracellular | | | pathogens mediated by NK | | | cells + Cytotoxic Tcells | | | | | | - Class 1 MHC -- normal cell | | | identification | | | | | | - Many intracellular pathogens | | | attempt to evade Tc cells by | | | causing the cell to reduce | | | its level of Class 1 MHC | | | molecules -- which then | | | becomes targets for NK cells | +-----------------------------------+-----------------------------------+ - **LYMPHOID FOLLICLES**: area in which B-cells proliferate, develop + mature antibody responses - **PARACORTEX**: APCs present antigen to T-cells which may then migrate to the lymphoid follicles to activate other B-cells Few days after the immune response has developed the lymphocyte generated in the lymph node leave vis the efferent lymphatic to enter other lymphoid tissues **[MUCOSA ASSOCIATED LYMPHOID TISSUES]**: - Secondary Lymphoid Organs: spleen + lymph nodes + MALT - MALT -- protects mucosal surfaces - Mucosal tissues are a major site of pathogen entry -- have more lymphocytes in normal mucous membranes than in all the lymph nodes + spleen put together - Even in normal, non-inflamed conjunctiva: there are many leukocytes which enter by crossing specialised blood vessels: high endothelial venules or via the lymphatics - Normal epithelium: no plasma cells + mast cells - Normal conjunctiva: no eosinophils + basophils MALT: specific arrangement of lymphoid tissues within mucous membranes - Collections of lymphocytes + APCs located beneath the mucosal epithelium - Particularly high proportion of IgA producing B-cells and T-cells that promote IgA production **[Controlling Immune Responses]**: - TH1: secretes cytokines that activates macrophages + cell mediated response - TH2: secretes cytokines that promote B-cell division (antibody response) - BALANCE BETWEEN TH1 + TH2 RESPONSES: maintained via a network of interacting cytokines + type of response depends: 1. The pathogen 2. How it was encountered by the immune system 3. Genetic makeup of the individual TH1 responses: seen typically in Type 1 hypersensitivity -- hayfever -- macrophages present antigen to TH1 cells TH2 responses: seen typically in Type 4 hypersensitivity -- contact dermatitis -- antibodies present antigen to TH2 cells **[MHC Molecules + Antigen Presentation]**: - Class 1: present on all cells in the body - Class 2: present only on APCs -- macrophages, dendritic cells, B-cells - Class 1 + Class 2 differ between people - Gene locus in humans: HUMAN LEUKOCYTE ANTIGEN - Everyones immune system works in different way **[ANTI-BODY MEDIATED RESPONSE]**: - Basic four-chain structure: a. Two light chains b. Two dark chains c. Fab: antigen binding site d. Fc: binds to various receptors on cells or to the first component of the complement system **[5 DIFFERENT CLASSES OF ANTIBODIES -- DEPENDENT ON THE STRUCTURES OF THEIR HEAVY CHAINS]**: +-----------------------------------+-----------------------------------+ | IgG | - Most abundant in the blood, | | | lymph fluid + CSF | | | | | | - Transferred across the | | | placenta to provide | | | protection in neonatal life | | | | | | - Opsonising antibody: allows | | | macrophages + neutrophils to | | | bind to antibody coated | | | bacteria + engulf and destroy | | | it | | | | | | - NK cells to infected target | | | cells | | | | | | - Activates Complement cascade | | | | | | - Neutralises viruses by | | | targeting the virus protein | | | coat required for attachment | | | to the host cell | | | | | | - Clumps insoluble antigens | | | together like bacteria | +===================================+===================================+ | IgA | - Antibody protecting mucosal | | | surfaces | | | | | | - Found in high secretions such | | | as saliva, tears + breast | | | milk | | | | | | - Primary defence against local | | | respiratory or GIT infections | | | | | | - Prevents microbe from | | | attaching to + penetrating | | | the epithelial surface | | | | | | - Clumping antibody | +-----------------------------------+-----------------------------------+ | IgM | - First antibody produced in an | | | immune response | | | | | | - Activates Complement | | | | | | - Elevated IgM indicates recent | | | infection or exposure to | | | antigen | | | | | | - Causes clumping | +-----------------------------------+-----------------------------------+ | IgE | - Binds to receptors on mast | | | cells + basophils | | | | | | - Causes release of vasoactive | | | agent histamine | | | | | | - Important in Type 1 | | | hypersensitivity reactions | +-----------------------------------+-----------------------------------+ | IgD | - Not fully understood | +-----------------------------------+-----------------------------------+ **[Immune defences against bacteria]**: 1. Releasing toxins 2. Invading tissues, parasitising + killing ccells 3. Combination of 1+2 - Specific antibodies can bind + neutralises toxins -- prevents it from binding to its target + promotes uptake by phagocytes 4. Restrict macrophage chemotaxis 5. Prevent phagocytosis 6. Resist the macrophages' killing mechs - Most important immune defence against bacteria: phagocytosis by macrophages - Success of macrophages depends on type of bacteria - Deficiencies of C3/alternative pathway: Gram-positive bacteria - Deficiencies of **lytic pathway**: Gram-negative pathway **[Immune defences against viruses]**: - Vital anti-viral defence: interferon (cytokines) - Cytokines are activated by: 1. Virally infected cells: interferon alpha + interferon beta 2. T-cell activation: interferon gamma - Cytotoxic cells ability to kill targets -- varies: Neurones + CNS cannot be generally replaced from stem cells + are unable to divide: Therefore virus maintains and is contained -- esp in herpes virus **[Immune mediated disease]**: - Protect against invasion by foreign organisms -- BUT under certain conditions can cause injury: 1. Hypersensitivity Reactions 2. Autoimmune disorders -- immune system mistakes itself as foreign 3. Immunodeficiency ***[HYPERSENSITIVITY REACTIONS]***: Immune response that lead to tissue injury or disease: can be classified based on immune response +-----------------+-----------------+-----------------+-----------------+ | TYPE | DESCRIPTION | MEDIATORS | | +=================+=================+=================+=================+ | 1 | Allergy | - Localised | IgE | | | | or | | | | | generalised | | | | | reaction | | | | | | | | | | - Occurs | | | | | within mins | | | | | after | | | | | exposure to | | | | | antigen | | | | | | | | | | - Variability | | | | | in | | | | | susceptibil | | | | | ity | | | | | to Type 1 | | | | | reactions | | | | | depends on | | | | | genetics | | | | | | | | | | - Typically | | | | | involve IgE | | | | | binding to | | | | | receptors | | | | | on mast | | | | | cells + | | | | | basophils | | | | | | | | | | - Repeat | | | | | exposure | | | | | makes more | | | | | IgE | | | | | | | | | | - IgE + MAST | | | | | CELL/BASOPH | | | | | IL + | | | | | Antigen -- | | | | | release of | | | | | histamine, | | | | | leukotriene | | | | | s, | | | | | prostagland | | | | | in + | | | | | thromboxane | | | | | from the | | | | | cell | | | | | membrane | | | | | | | | | | - 50% of | | | | | population | | | | | makes IgE | | | | | in response | | | | | to airborne | | | | | allergens | | | | | but only | | | | | 10% show | | | | | symptoms of | | | | | allergy | | +-----------------+-----------------+-----------------+-----------------+ | | | Histamine | | | | | Actions: | | | | | | | | | | - Contraction | | | | | of smooth | | | | | muscle | | | | | | | | | | - Vascular | | | | | dilation | | | | | | | | | | - Increased | | | | | permeabilit | | | | | y | | | | | of venules | | | | | | | | | | - Increased | | | | | secretion | | | | | of nasal, | | | | | bronchial + | | | | | gastric | | | | | glands | | | | | | | | | | - Hives | | | | | | | | | | - Wheal + | | | | | flare | | | | | reactions | | +-----------------+-----------------+-----------------+-----------------+ | | | Ocular Clinical | | | | | Manifestations: | | | | | depends on site | | | | | of exposure + | | | | | extent of | | | | | sensitisation | | | | | | | | | | - Vasodilatio | | | | | n | | | | | | | | | | - Vessel | | | | | permeabilit | | | | | y | | | | | | | | | | - Fluid | | | | | leakage | | | | | | | | | | - Conjunctiva | | | | | l | | | | | hyperaemia | | | | | | | | | | - Chemosis | | | | | | | | | | - Lid oedema | | | | | | | | | | - Eyes are | | | | | dark + | | | | | puffy due | | | | | to reduced | | | | | blood flow | | | | | due to | | | | | swelling | | | | | | | | | | -rubbing eyes | | | | | will make more | | | | | mast cell | | | | | degranulation | | | | | -- more itching | | | | | | | | | | **[Anaphylaxis] | | | | | ** | | | | | -- systemic | | | | | immediate | | | | | hypersensitivit | | | | | y | | | | | shock | | | | | | | | | | -vascular shock | | | | | | | | | | -widespead | | | | | oedema | | | | | | | | | | -Difficulty in | | | | | breathing: | | | | | contraction of | | | | | bronchioles, | | | | | laryngeal | | | | | oedema, | | | | | abdominal | | | | | cramps, | | | | | vomiting and | | | | | death | | +-----------------+-----------------+-----------------+-----------------+ | 2 | Cytotoxic -- | - Mediated by | IgG | | | | antibodies | | | | antibody | -- | IgM | | | | targeting | | | | | antigen on | Complement | | | | cell | | | | | surface or | | | | | ECM | | | | | | | | | | - IgG/IgM | | | | | activate | | | | | complement | | | | | -- NK | | | | | cells/chemi | | | | | cal | | | | | mediators | | | | | are | | | | | activated | | | | | | | | | | - Example | | | | | Ocular | | | | | Pemhigoid: | | | | | membrane | | | | | breakdown, | | | | | bullae of | | | | | conjunctiva | | | | | , | | | | | subepitheli | | | | | al | | | | | fibrosis, | | | | | loss of | | | | | goblet | | | | | cells + | | | | | formation | | | | | of | | | | | symblepharo | | | | | n | | +-----------------+-----------------+-----------------+-----------------+ | 3 | Immune complex | - Antigen + | | | | | antibody | | | | disease | combine and | | | | | circulate | | | | | in the | | | | | circulation | | | | | | | | | | - Antigen may | | | | | be a drug, | | | | | micro-organ | | | | | ism | | | | | or self | | | | | component | | | | | | | | | | - The Immune | | | | | complex is | | | | | deposited | | | | | in the cell | | | | | wall and | | | | | causes | | | | | tissue | | | | | damage by | | | | | inflammatio | | | | | n | | | | | | | | | | - May be | | | | | generalised | | | | | or | | | | | localised: | | | | | | | | | | | | | | | | | | | | - Kidney: | | | | | glomerulone | | | | | phritis | | | | | | | | | | - Joints: | | | | | arthritis | | | | | | | | | | - Small blood | | | | | vessels of | | | | | the skin | | | | | | | | | | - Eye: | | | | | episcleriti | | | | | s | | | | | or | | | | | scleritis | | | | | | | | | | Architecture of | | | | | the limbal | | | | | vasculature may | | | | | play a role in | | | | | deposition of | | | | | antigen-antibod | | | | | y | | | | | complex | | | | | deposition | | | | | | | | | | TREATMENT: | | | | | topical | | | | | corticosteroids | | | | | , | | | | | NSAIDs, | | | | | systemic | | | | | corticosteroids | | | | | , | | | | | immunosuppressi | | | | | ve | | | | | +/or | | | | | immunomodulator | | | | | y | | | | | mediators | | +-----------------+-----------------+-----------------+-----------------+ | 4 | Delayed type | - Activated | T CELLS | | | | by | | | | | antigen-act | | | | | ivated | | | | | T-lymphocyt | | | | | es | | | | | | | | | | - Examples: | | | | | contact | | | | | sensitivity | | | | | | | | | | - APCs -- | | | | | activate | | | | | CD4+ T | | | | | cells which | | | | | secrete | | | | | cytokines | | | | | | | | | | - Cytokines | | | | | recruit | | | | | lymphocytes | | | | | , | | | | | monocytes + | | | | | fibroblasts | | | | | | | | | | - Peak | | | | | response: | | | | | 24-48 hours | | | | | | | | | | - Antibodies | | | | | not | | | | | involved in | | | | | this type | | | | | of response | | +-----------------+-----------------+-----------------+-----------------+ **[Autoimmune disorders]**: - Reaction of the immune system against the body's own tissues - Represents the breakdown of the normal mechanisms of self tolerance - Organ specific: Grave's Disease - Multi-organ: Systemic Lupus Erythematosus - Often genetic related - Autoreactive T Cells -- CD4+ responsible for initiating tissue damage - Pathogenic role of autoantibodies -- via a type 2 hypersensitivity reaction **[Immunodeficiency]**: - Ability to fight infections is compromised - Most are acquired but you can be born with in