Topic 2 Adaptive immune system part A.pdf

Foundations in Pharmacology PHRM2005 Dr. Ricky R Lareu Adaptive Immune System – part A 2 Information See Lecture Outline document for Key Concepts, Learning Outcome and Lecture Summary Reading and reference material: Mim’s Medical Microbiology 5th Ed.: Chapter 10 3 Divisions of the immune system Fea...

Foundations in Pharmacology PHRM2005 Dr. Ricky R Lareu Adaptive Immune System – part A 2 Information See Lecture Outline document for Key Concepts, Learning Outcome and Lecture Summary Reading and reference material: Mim’s Medical Microbiology 5th Ed.: Chapter 10 3 Divisions of the immune system Features of the Adaptive IS Generates a specific response to any biochemical determinant Immune mechanisms are receptor-driven – receptors on surface of immune cells Provides a mechanism for immune recognition that can evolve as rapidly as the pathogen The ‘Specificity’ means ‘ability to discriminate among different molecule’ – even previously unseen molecules Present at birth but not functional i.e. not educated yet Changes throughout life – following exposure to antigens (Adaptive) Only present in vertebrates (that we presently know of?) Lag phase to response – takes days/weeks to develop a specific response Features of the Adaptive IS There is rapid amplification of a response ‘Memory’ is produced (anamnestic response) – the response is remembered after exposure Adaptive immune responses can detect cells that evade Innate immune mechanisms or cause a weak response i.e. re-engage and re-direct back to Innate immune mechanisms Adaptive immune cells are lymphocytes: B- and T-cells Antigens & Immunogens Foreign material is commonly referred to as antigens (not strictly correct) A pathogen has many antigenic regions Antigenic regions are recognised by immune system components and are said to be immunogenic Not all antigens are immunogenic i.e. produce and immune response Chemical make-up of antigens: Most antigens are proteins: complex, degradable Carbohydrates – poor antigens, flexible, repeating units Lipids – rarely immunogenic 7 Antibody Structure Antibodies are immunoglobulins produced by activated and differentiated B cells called plasma cells (see in Part B) The plasma cell secrete specific and identical immunoglobulins into plasma The ‘specific’ refers to binding only to one antigen type Antibody structure: 8 Antibody Functions Antibodies bind to antigens on pathogens and draw them in to further contact with Innate IRs. This can overcome mechanisms by pathogens to evade detection and destruction Activities of antibodies 1) Antibodies Activate complement 2) Activate phagocytic cells – opsinisation 3) Activate an acute inflammatory response 4) Blocks microbial reactions Figure 10.2 MMM p85 9 1) Antibody Activate Complement Antibody binding to antigen activates the Classical complement pathway (“Classical” because identified first) (C1 protein) Produces another enzymatic complex that cleaves and activates C3: Activates the membrane attack complex Releases C3a Various pro-inflammatory complement molecules 10 1) Antibody Activate Complement cont. 11 2) Antibodies Activate Phagocytic cells Binding of antibodies to microbe activates phagocytic cells to engulf microbe (see Innate IS lecture Part A for details) Two or more antibodies are necessary to trigger phagocytosis Therefore, the specific recognition of antigen (on microbe) by antibodies and activate different phagocytic cells e.g. neutrophil, macrophage Figure 10.6 MMM, p86 12 3) Abs. Activate Acute Inflammatory Response Antibody type E can activate mast cells and induce an acute inflammatory response (responsible for allergic reactions) Activate at site of infection Results in the degranulation of mast cell and release of inflammatory mediators ▪ Attract other immune cells to the area, called chemotaxis (polymorphs e.g. neutrophils, macrophages) ▪ Increases vascular permeability – increase access to immune cells and leakage of plasms Figure 10.5 MMM, p86 proteins e.g. Abs, complement 13 4) Antibodies Block Microbial Reactions The small size of antibodies allows them to interact with microbial molecules and block their activity, some examples: a) Block virus ligand binding to host cell receptor and stop entry e.g. Influenza b) Block essential transport molecules on bacterial cell wall and stop nutrients from entering bacteria c) attachment of antibody to toxins will limit-stop host cell damage Figure 10.7 MMM, p87 14 Summary – Ab Integration with Innate IS Mech. 15 Intracellular Destruction of Pathogens So far looked at the killing of extracellular microbes Many are intracellular, including bacteria, viruses and protozoa Adaptive IS cells, generally called lymphocytes, are involved in activating and carrying-out intracellular killing [We looked at the product of the B cell lymphocyte, the antibody] Intracellular killing is enabled and carried out by: T Helper (Th) cells – activate other cells T Cytotoxic (Tc) cells – carry out killing of infected cells Th and Tc recognise antigen only when complexed with MHC (see next slide) Natural Killer (NK) cells – carry out killing of infected cells, part of the Innate immune cell armament, and not MHCdependent 16 Surface Molecules - MHC class I and II MHC – Major Histocompatibility Complex Two types: Class I and II MHC-I found on nearly all cells MHC-II only on antigen presenting cells (APC), mononuclear macrophages and B cells Cell surface molecules used by immune system to recognise self, infected cells and communicate Self – every person has a unique MHC I combination making it difficult to transfer organs, need careful matching Identify infected cells – protein fragments from microbe attached to ‘peptide binding site’ and are ‘presented to immune cells’ Communicate – allows Th cells to interact and active macrophages and B cells 17 Surface Molecules – T Cell Receptor Like cells of the Innate IS, cells of the Adaptive IS have receptors ▪ T cells have T cell receptors (TCR) ▪ B cells have B cell receptors (BCR) They are analogous to antibodies, having a specific region that bind to an antigen, but are bound to the cell surface membrane Each lymphocyte can only recognise one type of antigen They can only detect the antigen if bound to an MHC molecule on the other cell: bind and recognise self (site on MHC) and at same time foreign peptide (blue) 18 T Helper Cells (Th) Cells Activate Macrophages Sometimes microbes can evade immune mechanisms and live inside other cells, e.g. Listeria, M. tuberculosis in macrophages Macrophages process internal microbe proteins: ▪ degrade and combine with MHC-II, complex migrates to cell surface Telling other immune cell “I am infected. Kill me!” Th TCR interacts with MHC-II+ foreign peptide and releases activating factors e.g. IFNγ This activates locked killing mechanisms in macrophage to kill intracellular invader, in particular nitric oxide 19 (NO) radicals Cytotoxic T Cells (Tc) Kill Virus-inf. Host Cells Body cells infected with viruses use MHC-I surface proteins to display virus protein fragments on their cell membrane Cytotoxic T cells (Tc) interact with MHC-I and recognise foreign peptide Tc is in contact with infected cell and releases killing substances Usually in early stage of infection, therefore virus replication halted 20 Natural Killer Cells (NK) Kill Virus-inf. Host Cells Natural Killer Cells (NK) have a similar function to Tc but don’t use the MHC molecule recognition system, have other receptors (e.g. PRR) Therefore, chance of binding effectively to infected cells lower than Tc ▪ Antibody However, NKbinding bindingto enhanced by: foreign peptide ▪ Th cells , Tc and infected cells release IFNγ ▪ IFN γ also renders uninfected cells resistant to infection Strength – NK cells kill intracell. pathogens in absence of MHCs, and foreign mammalian cell 21 Activity of NK Cells By Cacofonie - Own work, CC BY-SA 3.0, https://en.wikipedia.org/w/index.php?curid=14795148 Extracellular Killing of Large Microbes Some parasites that invade tissues are too large to be phagocytosed e.g. helminths Killing can occur through a mechanism called ‘antibodydependant cellular cytotoxicity’ (ADCC) Specific antibodies bind to surface of microbe and then immune cells can bind to Fc region of antibody, activating cellular killing mechanisms Mechanisms: Macrophages, reactive oxygen intermediates; NK, granzyme; eosinophils, perforins 23 Local Defence at Mucosal Surfaces Antibody type IgA is a secreted antibody, and found in mucus of membranes When microbes persist on mucosal surfaces (i.e. are not flushed away), IgA binds, specifically, and can stop further attachment of microbe to cells of epithelium If microbe does manage to penetrate mucosa, specific IgE antibodies on the surface of mast cells can initiate an acute inflammatory reaction This increases capillary permeability (complement, antibodies) and mobilises other immune cells (blood polymorphs and macrophages) 24 Innate and Acquired Immunity are Integrated 25 Summary Antigens are smaller components of pathogens, and not all antigens are immunogens i.e. cause an immune response. Antibodies (immunoglobulins) identify and bind to extracellular parasites: activate complement, enhance opsinisation, activate acute inflamm. response and block microbial reactions, and engage innate immune responses. Intracellular killing is carried out by T cells and NK cells. MHC surface molecules enable immune cells to recognise “self” and foreign antigens. Large parasites (e.g. helminths) are destroyed through antibody-dependent cellular cytotoxicity (ADCC) which recruits immune cells to release chemicals and enzymes. 26