Graduate Accelerated BVetMed Infections & Responses - Immunology PDF

Graduate Accelerated BVetMed Infections & Responses Unit 1: Immunology Principles of Adaptive Immunity Brian Catchpole BVetMed MSc PhD FRCVS  Learning Objectives Discuss the role of T cell-mediated immunity in the host response to infection Discuss the role of B cells, p...

Graduate Accelerated BVetMed Infections & Responses Unit 1: Immunology Principles of Adaptive Immunity Brian Catchpole BVetMed MSc PhD FRCVS  Learning Objectives Discuss the role of T cell-mediated immunity in the host response to infection Discuss the role of B cells, plasma cells and antibody in the immune response to viruses, bacteria and parasites Describe the ways in which innate and adaptive immune systems act synergistically  The lymphocyte family tree Differentiation in bone marrow Lymphocytes Differentiation in thymus T cells B cells Differentiation CD4 T cells CD8 T cells in secondary lymphoid tissues Effector HELPER REGULATORY KILLER PLASMA cells: T cells T cells T cells cells (memory lymphocytes)  Antigen receptor Antigen receptor The Laws of Immunology B T Lymphocytes detect antigen in different ways – B cell receptor detects whole antigen (protein) on the surface of pathogens in the extracellular fluid – T cell receptor detects digested antigen fragments (peptides) ‘displayed’ on the surface of other cells in association with MHC molecules Antigen Lymphocytes respond in different ways – B cells secrete ANTIBODIES Antigen MHC fragment – T cells secrete CYTOKINES B (immunological hormones) T T cell-mediated immunity Antigen is brought to lymphoid tissues by dendritic cells, where it is processed and presented Epithelial surface Afferent lymphatic Pattern-recognition receptors  Recognition of antigen by T cells T cells enter lymphoid tissues via HEVs and examine the dendritic cells present in the paracortex T cells express TCRs that can recognise foreign peptides displayed by carrier molecules known as Major Histocompatibility Complex (MHC) The ‘immunological synapse’  The Laws of Immunology MHC Class I molecules present peptide fragments of antigen from the cytoplasm – i.e. ICF/cytoplasmic antigens intracellular antigen MHC Class II molecules present peptide fragments of antigen from the tissue fluid – i.e. ECF antigens extracellular antigen Compartmentalisation of antigen presentation  Antigen presentation: is what is recognized by T cells MHC Class I how viral peptides are presented Plasma membrane cell surface Viral protein synthesis PROTEASOMAL ER DEGRADATION TAP Antigen in Peptide MHC I cytoplasm fragment  Antigen presentation: MHC Class II Antigen in ECF Plasma membrane Endocytosis LYSOSOMAL DIGESTION Peptide MHC II fragment FROM ER  The Laws of Immunology CD8 T cells are only allowed to interact with MHC Class I : peptides – Detect intracellular infection CD4 T cells are only allowed to interact with MHC Class II : peptides – Detect extracellular infection  When naïve T cells are first activated they proliferate: CLONAL EXPANSION Frontline troops Reserve troops T cells then differentiate into their mature effector forms CD8 T cells differentiate into KILLER T cells – aka cytotoxic T lymphocytes (CTL) (marines) CD4 T cells have a choice: – HELPER T cells (infantry) – REGULATORY T cells (military police)  Naïve T cells are in ‘SURVEILLANCE MODE’. They move around the body in search of antigen which is trapped in the secondary lymphoid organs Activated T cells are in ‘ATTACK MODE’. They move around the body in search of pathogens in infected tissues  T cells… …are like tanks. They must leave the lymph node to go and engage the enemy  Activated T cells alter their homing receptors NAÏVE T CELL EFFECTOR T CELL High endothelial venule Inflamed endothelium LYMPH NODE INFECTED TISSUES  T cell-mediated immunity CD8 KILLER T cells – Recognise MHC I-peptide (intracellular infection) – Seek out and destroy virus infected cells CD4 HELPER T cells – Recognise MHC II-peptide (extracellular infection) – TH1 help macrophages – TH2 help B cells make antibody CD4 REGULATORY T cells – The ‘military police’ of the immune system  CD8 Killer T cells are important for virus infections Virus peptide presented by MHC Class I Recognised by CD8 T cells CD8 T cell KILLS virus infected cell CD8 killer T cells are the most important for fighting virus infections — they are the professionals amateurs Much more effective and efficient than NK cells  The ‘kiss of death’ cytotoxic cytokine and granzyme both enter the pathogen to kill it cytotoxic cytokine Killer T cell Cell death perforin Degranulation granzyme  CD4 T lymphocytes are HELPER T cells Some T helper cells make cytokines to activate macrophages the macrophages are normally like bruce banner, but when exposed to Other T helper cells make interferon gamma - they turn into killer cellls (like the hulk) cytokines to activate B cells  CD4 TH1 cells Important in vesicular infections where pathogens deliberately infect macrophages – e.g. mycobacteria such as TB – Interferon gamma is required to ‘hulkify’ your macrophages  CD4 TH2 cells are important for production of antibodies TH2 cells produce cytokines (such as IL-4) to tell the B cells which type of antibody to secrete – IgG vs IgA vs IgE  Regulatory T cells The ‘military police’ of the immune system Produce immunosuppressive cytokines such as IL-10 Ensure response is appropriate and minimise ‘friendly fire’ (collateral damage to host cells) Principles of Adaptive Immunity Part 2: B cells and antibody Antibody-mediated immunity  B cells recognise whole proteins (antigen) in the extracellular fluid Antigen B cell receptor Antibody binding to antigen Plasma cell  Early stage of infection NAÏVE B CELL IMMUNE SURVEILLANCE PLASMA CELLS ANTIBODY  Later on... IMMUNE SURVEILLANCE Eventually undergo apoptosis Long lived cells MEMORY CELLS Antibody wanes  Plasma cells Plasma cells are antibody secreting factories They develop in germinal centres in lymph node secondary follicles They migrate to medullary cords of LNs where they secrete antibody into efferent lymph > blood Some migrate to the bone marrow and produce antibody directly into bloodstream  Plasma cells… …are like missile launchers They can remain in the lymph node and fire antibody out into the circulation to act far away at the site of infection Basic structure of antibody Light chain x2 Heavy chain x2 Basic structure of antibody BINDS TO ANTIGEN (Fab) fragment antigen binding allow it to bind to antigen BIOLOGICAL EFFECTS (Fc) decides what happens next  important against Basic biological functions viruses bc viruses have to attach to be able to attack of antibody Once the antibody missiles find their target: Types of immunoglobulin  surface immunoglobulin B cell receptor (IgD/IgM) Antigen Antibody (IgM, IgG, IgA, IgE) Plasma cell  Immunoglobulin M (IgM) default antibody that is made First antibody produced in the immune response Pentamer – binds 10 antigens at once Agglutinin Good at triggering the complement cascade J  Immunoglobulin G (IgG) Produced after receiving TH2-cell help only occurs if receiving signal from TH2 cell – CLASS-SWITCHING Neutralising antibody in viral infection Enhances phagocytosis of bacteria Triggers complement activation less potent — need at least 2 IgG to activate and they have to be close together  Immunoglobulin A (IgA) Produced by B cells in the MALT and secreted onto mucosal surface as a dimer most outside of your body as it’s on the surface of MM Important neutralising antibody for protection of GIT and respiratory tract Important component of colostrum and milk for neonatal health  Immunoglobulin E (IgE) Produced by B cells in response to parasite infections Binds to receptors on the surface of mast cells Enhances parasite killing response assists eosinophils and mast cells — to make them more effective parasite hunters Mast cells have receptors for IgE (FceR) Y Recognition triggers degranulation of cell multiple eosinophils/mast cells have to gang up on the parasite (as the parasite is usually really big) to be able to overtake it (cannot just it like macrophages) once they all gang up on it - they can degranulate it by releasing the toxic material to kill it the presence of IgE makes this process easier  Antibody isotype summary IgM is the first antibody produced (agglutination and complement activation) IgG is produced to neutralise viruses and aid in response to bacteria (enhanced phagocytosis and complement activation) IgA is produced for mucosal defence (neutralising antibody) IgE is produced for anti-parasite defence to aid mast cell response (assist degranulation) Kinetics of antibody response LAG LOG PLATEAU Recovery Immune Antibody negative during LAG phase (first 5-7 days) IgM > IgG = recent exposure (7-14 days previously) PLATEAU phase of IgG can last months/years