CGIER (CA 1)

• the immune response depends on the ability of the organism to distinguish between itself (self) and foreign matter (non-self)
• an antigen is any substance that can be recognised by the immune system

  • they can be proteins, peptides, polysaccharides, lipids or nucleic acids
• antigens can be derived by the host organism (self) or a foreign organism (non-self)

  • they can be bound to a group of cell surface proteins called major histocompatibility complexes (MSCs) which display the antigen to the immune system
• in humans, the MSCs are referred to as human leukocyte antigens (HLAs)

  • self antigens promote immune tolerance (no activation of immune response), while non-self do the opposite
• non-specific immune responses are very fast, automatic responses

  • also known as innate responses
  • this is independent of antigens
• non-specific immune responses is an immediate maximal response but has no immunological memory
• non-specific immune responses include barriers (e.g. skin, lining of GI tract), pattern recognition receptors (these recognise viral DNA that has been injected in cells), NK cells, dendritic cells, macrophages, cytokines and complement
• specific responses require several hours to days to develop, and they are adaptive responses that are learnt over time.

  • these responses are antigen specific
  • there is a lag time between exposure and maximal response
  • divided into cell-mediated and antibody-mediated immunity
• the first line of defence includes:

  • skin
  • mucous membranes
  • secretions of skin and mucous membranes
• the second line of defence includes:

  • phagocytic leukocytes
  • antimicrobial proteins
  • inflammatory response
  • fever
• the skin and mucous membranes provide a physical barrier against pathogens but also provide secretions in sweat and sebum which destroy some bacteria with lysozyme

  • microorganisms entering lungs are trapped by the mucous lined bronchi and bronchioles
• cytokines are special proteins that help regulate and coordinate the immune response

  • they activate immune cells and can also be released by them (i.e. immune system)
  • they have 3 mechanisms of action
• the 3 mechanisms of cytokines are:

  1. Autocrine i.e. act on cell that releases cytokines
  2. Paracrine i.e. act on nearby cell (preventative measures e.g. making more antiviral proteins)
  3. Endocrine i.e. released in bloodstream and act on a distant cell
• interferons are a group of cytokines that are released in response to viral infections

  • they are released by infected cells to act as a warning system
  • they trigger nearby cells to increase synthesis of anti-viral genes, and stimulate anti-viral responses from the immune system
• interleukins are a group of cytokines and are secreted primarily by macrophages and lymphocytes

  • they regulate interactions between various parts of the immune system
  • some important interleukins include IL-2 (activate T cells to proliferate) and IL-4 (released by T-cells and mast cells to produce IgE and promote B-cell proliferation)
• there are three main types of phagocytic cells in the non-specific immune system: neutrophils, macrophages (monocytes) and dendritic cells

  • they are very important as they initially control infection by destroying and reducing the number of pathogens in the body
• some phagocytes can present antigens from destroyed pathogens on their MHC proteins, resulting in further activation of the immune system

  • some bacteria (e.g. tuberculosis bacilli) can resist phagocytes
• macrophages are formed in tissues and are most numerous in the gut wall and lungs

  • they release IL-1 to stimulate T cells and antigen-presenting cells (APCs) as well as promoting B cell growth and antibody production
• NK (natural killer) cells are large granular lymphocytes that have a rapid response to viral infected cells and tumour surveillance

  • they don't need antigens to be presented in order to kill an infected cell
  • if a target cell is infected, it will present normal MHC I antigens which inhibit the NK cells but also activating ligands, which activate NK cells to kill the infected cell
• NK cells are:

  • inhibited by MHC I proteins on surface of cell
  • activated by activating ligands on surface of cell
• when a NK cell looks at a target cell, 3 things can happen:

  1. Inhibition of NK cells
  2. Activation of NK cells (reduced inhibition)
  3. Activation of NK cells (strong activation)
• 1. Inhibition of NK cells

  • there are enough MHC I proteins present to produce a strong inhibitory signal in NK cells
  • these cells are protected from NK cells attack
• 2. Activation of NK cells (reduced inhibition)

  • unhealthy cells often downregulate the production of MHC I molecules
  • this means that the inhibitory signal from target cell isn't strong enough to protect from NK cell and that cell is therefore killed
• 3. Activation of NK cells (strong activation)

  • transformed or infected cells can increase expression of molecules that are recognised by activating NK cell receptors (activating ligands)
  • therefore there is a much stronger activating signal from the target cell which allows NK cells to kill them
• Mechanism of Action : NK cells

  • NK cells release granules that contain perforin and granzyme
  • perforin creates holes in the target cell's membrane, which allows granzyme to enter the target cell
  • granzyme triggers the death of the target cell by activating apoptotic enzymes
• Inflammation is triggered when pathogens invade tissues.

  • damaged cells release histamine, serotonin and other substances to cause vasodilation
  • increased capillary permeability causes oedema in tissues (oedema causes pain)
  • increased blood flow to that region brings more monocytes and neutrophils to fight infection
• Fever occurs when neutrophils and macrophages release endogenous pyrogens (incl. IL-1 and prostaglandins) which reset the body's thermostat (hypothalamus) to a higher temperature

  • the higher temperature increases the effectiveness of the immune system and can decrease pathogen replication
• in cell mediated specific defence, there is 2 main cells involved:

  • T-lymphocytes
  • B-lymphocytes
• immature T-cells are produced by lymphoid progenitor cells in the thymus

  • only a small amount actually mature and leave the thymus
• Activation of T-cells

  • each T cell has a unique T cell receptor (TCR) which is produced by mutation of the TCR gene which leads to millions of different TCRs, all recognising a different antigen
  • T cells recognise antigens through binding of TCR with MHC-presented antigens on an APC
  • only t cells with receptors that can bind to that specific antigen can respond
• Types of T cells

  1. Cytotoxic T cells
  2. Helper T cells
  3. Suppressor T cells
  4. Memory T cells
• 1. Cytotoxic T cells

  • recognise and destroy cells with foreign antigens
• 2. Helper T cells

  • enhance the immune response
  • T-helper 1 release IL-2 to stimulate other T cells
  • T-helper 2 release IL-4 to stimulate proliferation of B-cells
• 3. Suppressor T cells

  • turn off immune response when fewer antigens are present
  • release suppressor cytokines
• 4. Memory T cells

  • remain in lymphatic tissue for many years
  • responsible for secondary immune response if reinfected
• T-Cell Action [1]

  1. An APC phagocytoses the pathogen and breaks down surface antigens which are then presented on the APCs surface by MHC-2 proteins
  2. Helper T cells are activated by specific foreign antigen-MHC complex
  3. Activated helper T cells increase in size and divide by mitosis which then differentiate and migrate to other tissues
  4. Activated helper T cells also release cytokines to act on other T cells and on macrophages
• T-Cell Action [2]

  1. Cytotoxic T cells are activated by foreign antigen-MHC complex displayed by infected cells
  2. These activated cytotoxic t cells then form clones and migrate to infected tissues
  3. They then release proteins that destroy infected cells
• The first exposure of the body to a new pathogen elicits a primary immune response, which can take between 3 and 14 days to develop

  • subsequent exposure results in a rapid and more dramatic reaction called a secondary immune response
  • this rapid response is due to the presence of memory cells
• in a secondary immune response, much less antigen is required, the latent period is shorter, there are more antibodies produced and the pathogen is destroyed before it can get established

  • there is 3-4x more immune response in secondary response
• vaccination illicits an immune response by administering a much smaller amount of an attenuated pathogen (cannot cause disease)

  • the body produces antibodies against the pathogen and memory cells are produced
  • reinfection now causes a secondary response, which leads to a reduced likelihood of disease