Core Notes Immunology Year 1 PDF

IMMUNOLOGY  Introduction to Immunology - Roles of the Immune System 1. Defense against infections- vaccinations boost immune defenses while protecting against infections 2. Defense against tumours- immunotherapy for cancer 3. Control of tis...

IMMUNOLOGY  Introduction to Immunology - Roles of the Immune System 1. Defense against infections- vaccinations boost immune defenses while protecting against infections 2. Defense against tumours- immunotherapy for cancer 3. Control of tissue regeneration & scarring- reparation of damaged tissues 4. Injuring cells and inducing pathologic inflammation- immune responses cause allergic reactions and inflammation 5. Recognizing and responding to tissue grafts and newly introduced proteins- barriers to transplantation and gene therapy Microbes are constantly evolving and developing rapidly using new techniques like hijacking cellular machines to replicate and spread Problems with the Immune System 1. Immunodeficiency- failure to respond (major leading cause is malnutrition) 2. Allergy- inappropriate response to foreign substance 3. Autoimmune disorders- inappropriate response to self by body attacking itself (eg. Lupus) 4. Transplant rejection- appropriate but unwanted response to foreign substance 5. Cancer- altered self causing evasion 6. Pregnancy- causes toleration of non-self Physical & Chemical Barriers B-defensins and cathelicidins in the skin (produced by keratinocytes and stored in lamellar bodies) are secreted as an antimicrobial agents (kill/prevent growth) Barrier Functions 1. Production of chemical substances that are microbicidal (kills) 2. Defensins (anti microbial peptides secreted by epithelial cells and phagocytes) attack cell membrane of diseases (bacteria, fungi, viruses) Immune Responses Our immune system has tissues, organs, cells, etc responsible for protection from diseases 1. Innate defences: an immediate response that is there before the infection occurs. It recognizes the infection because of receptors that recognize common structures of pathogens 2. Adaptive Response: This response is very slow and is stimulated by exposure to specific pathogens. It reacts to a large number of structures. JOIN THE DARKSIDE Overview Steps 1. Barrier function (if it fails then) 2. Innate immunity (if it fails then) 3. Adaptive immunity Types of Immune Cells Leukocytes, neutrophils, macrophages, T cells, B cell each have a specialised function INNATE CELLS Macrophages Patrols tissues Macrophages in different tissues have their own unique names They are not found in the blood and are not specialized Function: engulf bacteria through phagocytosis, clean up debris, and present antigens on their surface Neutrophils (granulocyte) Most abundant WBC Not normally found in tissues but can be recruited Short lifespan Functions: engulf by phagocytosis and activates bactericidal mechanisms Eosinophil (granulocyte) Rare in blood Granules have enzymes that attack cell wall of parasites (causes damage to host tissue) Functions: kills antibody coated parasites (involved in allergic diseases) Basophil (granulocyte) Rare in blood Granules have inflammatory mediators that defend against parasites Functions: promotes allergic responses and recruits other cells for anti-parasitic immunity Mast cells (granulocyte) Found in tissues Contain granules that have inflammatory mediators Involved in allergic responses Functions: release granules that have histamine (sends signals by causing allergic reactions) and active agents Monocyte (agranulocyte) 10% of WBC in blood Has a kidney bean shaped nucleus Functions: phagocytosis, production of inflammatory mediators, recruited to tissue Natural Killer Cells (NK) (lymphocyte) Can kill host cells Opsonisation Produces chemical mediators (cytokines) Since some microbes are hard to phagocytose the process Functions: releases granules that kill virus infected cells of opsonisation is used What is phagocytosis? (A form of Endocytosis) Opsonisation is coating of a microbe with proteins so that it It is the internalization of a substance by engulfment is easier for the phagocyte to capture it Example= C reactive protein (CRP) Steps of phagocytosis 1. Microbes bind to phagocyte receptors Which cells use phagocytosis 2. Phagocyte membrane surrounds the microbe 1. Macrophages 3. Microbe is ingested in 2. Granulocytes: neutrophils, eosinophils, basophils 4. lysosomes fuse with phagosome creating a phagolysosome 3. Immature dendritic cells (their primary function is 5. Lysosomes break down the microbe activation of adaptive immunity) JOIN THE DARKSIDE Phases of NK Cell Activation 1. NK cell activation 1: CD16 is a receptor on NK cells that binds to antibodies which then activates the NK cell to kill the antibody-coated cell (process is called antibody-dependent cell cytotoxicity (ADCC). NK2D on NK cells bind to NKG2D ligands on target cells and kills them 1. NK cell activation 11: MHC class 1 is a ligand that inhibits Killer Immunoglobulin-like receptors (KIR) on NK cells. When its missing the NK cell activates and destroys the host cell JOIN THE DARKSIDE  Innate Immunity Innate and adaptive systems are different Innate immune cells use identical mannose (sugar on bacteria) receptors that bind to different microbes Adaptive immune cells use distinct antibody molecules that bind to different microbes Pathogen Associated Molecular Patterns (PAMPs) are structures shared by most pathogenic bacteria and some viruses Pattern Recognition Receptors (PRR) are receptors on innate cells that recognize PAMPs They can be located in the cell surface, endosomal membranes or cytosine - Focus on Toll Like Receptors (TLRs) There are many types of TLRs (in humans TLR 1-TLR 9) When PRRs detect PAMPs they release immune responses that: 1. Aid in phagocytosis 2. Activates innate cells 3. Promotes inflammatory mediators Danger Associated Molecular Pattern (DAMPs) are self proteins (in host) that are released during cell injury which activates immune system. It can activate the same way as PAMPs Complement (found in blood) is a collection of soluble proteins that help in Complement: Inflammation the immune system by: promoting phagocytosis and Opsonisation, C3a and C5a are fragments released by complement activation that promote inflammatory responses, directly killing pathogens vasodilation (increasing diameter of BV) and increase vascular permeability Many are proteases (enzymes that can act on proteins) C5a is a chemotactic factor (moves leukocytes from low to high They basically follow a domino effect concentration) JOIN THE DARKSIDE Complement: Opsonisation C3b attaches to the outside of a microbe and is then recognized by CR1 (complement receptor 1) located on phagocytes (leads to phagocytosis and destruction of pathogen) n Complement: Membrane Attack Complex Pathogen Occurs late in activation C5b, C6, C7, C8 all bind together then multiple copies of C9 start binding around forming a hole This results in lysis of the cell Cytokines can be: Cytokines 1. Pro inflammatory (IL-1, IL-6, TNF alpha Soluble proteins made by a bunch of cells 2. Anti inflammatory (TGF beta, IL-10) Their actions can be autocrine (acts back on cell 3. Cell growth and differentiation (CSFs) that made it), paracrine ( local), endocrine 4. Chemotaxis (CCL3, CXCL1) (through blood) Types t cytokine networks : complex cytokine networks. Inflammation Localised Intended to eliminate or wall off the injury and any dead cells to promote tissue repair Suffix -itis= inflammation Symptoms: Redness Heat Swelling Pain Functional impairment Steps: 1. Detection of PAMPs or DAMPs 2. Release of mediators that results in vasodilation, increased vascular permeability, recruitment of more immune cells (neutrophils, then monocytes, then lymphocyte) 3. Elimination of trigger 4. Repair JOIN THE DARKSIDE Inflammation: Vascular Changes 1. Blood vessel diameter increases (blood flow increases causing redness and warmth ) 2. Increased permeability (more fluid leading to swelling) 3. Reduced blood velocity (blood moves slow which is good because mediators can hop out of blood) 4. Accumulation of immune cells Recruitment Steps: 1. Neutrophil Rolling: first cell recruited. Activated by inflammatory cytokines (TNF alpha and IL-1) that induces E-selection on endothelium (receptors). Then low affinity interactions between carbs on neutrophil and E-selectin causes the rolling motion. 2. Neutrophil Adhesion: molecule on neutrophil (LFA-1) changes shape to bind to ligand (ICAM-1) on blood vessel wall. Then CXCL8 (a chemokine) causes the neutrophil to migrate down the concentration gradient. 3. Monocyte Recruitment: they are recruited hours after. CCL2 and CCL7 bind to CCR2 receptor and recruit monocytes. Systemic Effects JOIN THE DARKSIDE  Adaptive Immunology Terminology - Antigen: molecule that is specifically recognized by lymphocytes or antibodies that trigger the immune response - Naive lymphocytes: mature B or T cells that haven’t been in contact with an antigen & Activation: initial response of a cell to a signal from an antigen or cytokine I Proliferation: process of cell division leading to more of them Differentiation: cells develop specialized functions and ↑ characteristics Phases of Adaptive Immunity 1. Recognition 2. Clonal expansion 3. Differentiation 4. Antigen elimination 5. Apoptosis of T and B cells 6. Memory cells Functions of Adaptive Immunity B cells: produce antibodies ~ Helper T cells: interact with other immune to create an immune & response Cytotoxic T cells: kill host cells that are infected (similar to NK & cells) Difference between NK cells and cytotoxic T cells is that CT cells - need to recognize a specific antigen while NK cells only detect absence of MHC class 1. NK cells are also quicker with response time because they don’t need to be activated beforehand. STRUCTURES Recognition of Antigen B Cell Receptors (BCR) can directly recognize antigen - T Cell Receptors (TCR) cannot directly recognize antigen. Instead the - antigen has to be processed and shown on MHC before T cell recognition. This helps T cells differentiate between infected and normal cells. Antigen Presentation of T cells 1. Since T cells cannot directly recognize antigen the antigens must be chopped up (processed) 2. Then they have to bind to MHC There are 2 classes of MHC: MHC Class 1 pathway: type of molecule found on the surface of almost ↑ all cells on the body and presents antigens from inside of the cell MHC Class 11 pathway: found on certain immune cells and presents - antigens from the outside of the cell JOIN THE DARKSIDE  MHC Class 1 MHC Class 1 Pathway 3 genes in humans on chromosome 6 1. Protein (antigen) made in infected cell HLA-A 2. Gets chopped up · HLA-B 3. Binds to MHC class 1 molecule HLA-C 4. MHC molecule recognized by CD8 (co receptor for MHC - Different variants denoted by numbers ↑ class 1) on cytotoxic T cells and they all have different 5. Infected cell dies characteristics All cells are capable of MHC Class 1 MHC Class 11 Pathway 1. Foreign antigen gets engulfed by cell (infected) 2. Gets chopped up 3. Antigen binds to MHC class 11 molecule 4. MHC molecule recognized by CD4 (co receptor for MHC class 11) on helper T cell 5. Helper T cell activated leading to clonal expansion and MHC Class 11 differentiation & Expressed only by antigen presenting cells & Dendritic cells, macrophages, B cells & 6 main genes: HLA-DPA1, HLA- DPB1, HLA-DQA1, HLA-DQB1, HLA-DRA, HLA-DRB1 BCR/Antibody Structure & 2 identical heavy chains F 2 identical light chains ↑ Held together by disulphide bonds C Each chain has constant and variable domains TCR Structure - 2 chains (alpha beta) held together by disulphide bonds - Each chain has 2 domains (one constant and one variable Negative Selection - This process gets rid of a receptor that recognizes a self molecule ↑ In the thymus, immature T cells undergo apoptosis In bone marrow, B cells can undergo receptor editing or apoptosis & JOIN THE DARKSIDE  T Helper Cell Activation Needs to pass through 3 steps to activate 1. Antigen recognition 2. Co stimulation 3. Cytokines release & The result is clonal expansion and differentiation HAVE TO GO THROUGH ALL THESE STEPS FOR EFFECTIVENESS & B Cell Activation 1. Antigen recognition 2. Co stimulation from Helper T cell 3. Cytokines release Lymphoid Tissue & Primary (generative) lymphoid tissues: immune cells are generated and mature (bone marrow and thymus) - Secondary (peripheral) lymphoid tissues: where lymphocytes interact with antigen and activate (lymph nodes, spleen, mucosal associated lymphoid tissue (MALT)) A Note: T cells have to go to thymus to mature Antigens from tissue head to lymph node & Antigens from blood head to spleen S Terminology Lymph nodes: encapsulated organs found throughout body & (antigens are moved here by antigen presenting cells) Lymphoid follicles: a collection of T and B cells that will ↑ proliferate when encountering with specific antigen. This creates a germinal centre that creates mature effector (ready to do job) T and B cells Spleen: encapsulated vascular organ that filters blood. Eliminated & blood borne pathogens Antibody Isotypes It has follicles like lymphoid follicles 5 classes IgG (4 genes) IgA (2 genes) IgE IgM (first antibody produced) IgD JOIN THE DARKSIDE  Antibody Isotype Switching - B cells can undergo isotype switching - From IgM to either IgG, IgE, or IgA ↑ Signal 1 alone makes IgM Role of Antibodies Antibody Neutralization Opsonisation Cytotoxic T cell T cell Function JOIN THE DARKSIDE  T Helper Cells During activation different types of effector cells can be generated & & Treg cells produce IL-10 and TGF Beta (maintain self tolerance) Memory After the lymphocytes do their job most of them die. Some & activated antigen specific B and T cells stay after the antigen is eliminated. The next time something like that occurs these B and T cells be be reactivated much quicker In the secondary response less antibody is required and a higher & more efficient response is generated JOIN THE DARKSIDE