What are the 3 phases of immune response to a pathogen?
RECOGNITION of the pathogen
REACTION to eliminate it
RESOLUTION of the immune response
How are innate and acquired immunity linked?
Innate: Polymorhp and complement system
NK and Macrophages and Cytokines
Acquired: Antibody (humoral immunity, extracellular organisms)
T Cell (cell mediated immunity - intracellular organisms)
Describe the cell levels in the time after viral infection
(IFNs = interferons = soluble proteins)
Type 1 IFNs- Alpha and Beta involved with the first stage of the immune response
IFNs and NK cells try to keep the virus numbers under control until the adaptive immune response effectors begin to work
CTL - Cytotoxic Lymphocytes - very good adaptive response but takes a week to start
Explain the process of antigen processing and presentation
When APCs take up external pathogens, proteins (antigens) from the pathogens are broken down into short peptide chains. These are then displayed on the APC surface attached to special molecules called MHC II (Major Histocompatibility Complex II). They are displayed to lymphocytes.
Which cells act as antigen presenting cells?
Dendritic Cells => the BEST
(dendritic cells travel to the lymph nodes (an area rich in T cells - if the antigen is recognised it leads to the intiation of the adaptive immune response)
What are MHCs?
Major Histocompatibilty Complexes are structures that come from inside an APC, grab antigens and present it on the surface.
Two classes - MHC I and MHC II - are involved in immune recognition
What is TCR?
T CELL ANTIGEN RECEPTOR
Looks similar to structure of antibody, has variable and constant regions and is embedded in the cell membrane. Has a cytoplasmic tail which sends signals into the cell to determine whether it should react.
This is where the SPECIFICITY of the T-cell is determined, and why T cells react so rarely
Where are MHC I molecules expressed?
What recognises the antigen displayed on them?
On ALL nucleated cells
CD8+ cytotoxic T cells
But these cells need help to be activated
Where are MHC II molecules expressed?
What recognises the antigen presented on them?
ONLY on professional APCs (Dendritic cells, Macrophages, B cells)
CD4+ Helper T Cells
What are CD4+ cells?
What do they do?
Helper T Cells
Monitor Leukocytes and are ready to react to any that express foreign antigen fragments in their MHC II molecules
Initiates the immune response immediately
What are CD8+ cells?
What do they do?
Cytotoxic T Cells
Monitor ALL the cells of the body detecting foreign antigen fragments in their MHC 1 Molecules but
NEED HELP from CD4+ cells to react efficiently
These do the killing, but are managed by CD4+ cells
What are the steps in the activation of T Lymphocytes
What are the effector functions of
CD4+ (Helper) Cells
Activation of macrophages, B cells and other cells
(memory CD4+ cells produced)
When activated, starts to make IL2 - positive feedback on itself, cloning and expansion of many T cells with the same Receptor.
CD8+ (Cytotoxic) Cells
Killing of infected 'target cells', macrophage activation
(memory CD8+ cells produced)
These aren't as good at producing IL2 - so rely upon CD4+ cell
What effect does the Thelper cell have?
In this example, activated by macrophage, and has capacity for all of these effects
Immune response can be fine-tuned for a particular situation, the way in which the Th is activated determines the different type of response you get.
Under induction, what do Naive CD4+ cells differentiate into?
Distinct Helper and Regulatory Subsets which coordinate responses to extra and intracellular infections
Induced By Into
TGF-Beta1, IL-23 and IL-6 Th17
TGF-Beta1 Treg (switching off)
What are the effector functions of the Th1 cell?
- Activates macrophage to destroy engulfed bacteria (IF-gamma, and CD40 ligand)
- Kills chronically infected cells, releasing bacteria to be destroyed by fresh macrophages (Fas ligand or TNF-beta)
- Induces T-cell proliferation, increasing numbers of effector cells (especially CD8+ cytotoxic cells) (IL-2)
- Induces macrophage differentiation in the bone marrow (IL-3, GM-CSF)
- Activates endothelium to induce macrophage binding and exit from blood vessel at site of infection (TNF-alpha and beta)
- Causes macrophages to accumulate at the site of infection (MCP-1 => chemokine, attracts macrophages)
What are CD8+ cells?
What do they do?
Cytotoxic T cells (CTL)
They are the prinicpal defence against obligate intracellular microbes such as viruses and some bacteria which proliferate inside the host cells
Tc cells can directly kill infected cells by LYSIS
What is the CTL recognition mechanism?
Via MHC Class 1 - TCR allows virus infected cells to display the virus antigen so that it can be recognised and killed (reaction) by a Tc cell
What are the Cytotoxic T Cell effector functions?
Tc release proteolytic enzymes called granzymes and perforin
Perforin - punches holes in the target cell membrane
Granzymes - pass through these pores and activate the enzymes causing APOPTOSIS of the infected cell, by destroying its structural cytoskeleton proteins and by chromosomal degradation
The cell breaks into fragments and these are removed by phagocytes (resolution)
What is Fas-FasL mediated apoptosis?
Killer T Cell has Fas Ligand (L shaped) which interacts with Fas on surface of a virus infected cell
How to CTL cells go about apoptosis?
- CTL recognises and binds virus - infected cell
- CTL programs target for death, inducing DNA fragmentation
- CTL migrates to a new target
- Target cell dies by apoptosis]
- Cleared by macrophages (resolution)
What are the cytotoxic products of CTL cells?
Perforins - polymerase in the membrane of the target cell to form channels that cause cytosol leakage and toxic molecules to enter the cell
Granzymes - granules containing granzymes/fragmentins, break target cell DNA into oligomers
TNF-B - Inhibits protein synthesis in target cell
Serine Proteases - degrade cell membrane proteases
Nucleases - degrade DNA and RNA
Fas Ligand - Binds Fas on target cell surface to induce apoptosis
What are Natural Killer (NK) cells?
- These are nonB, non T lymphocytes that recognise and destroy certain infected cells and tumour cells
- Part of the INNATE immune response
- Do NOT require prior sensitisation
- MHC Class 1 molecules provide an INHIBITORY cue to NK cells, NK cells won't kill these.
- Recognise infected cells and tumour cells when they lack MHC Class I (many tumour cells do)
- They LYSE target cells with PERFORIN and GRANZYMES causing apoptosis of target cells
What happens to Antigen specific T cells with time after infection?
Contraction = most T cells die after infection is resolved
Some remain as memory cells, which can react within hours of reexposure - expand and kill before contracting to memory cells again
What are the Primary Lymphoid Organs?
What happens in them?
Bone Marrow, Thymus
Development and Selection of Naive Cells
All immune cells arise in the BONE MARROW
T cells then move to the Thymus to mature
What are the Secondary Lymphoid Organs?
What happens in them?
Lymph Nodes, Spleen, Mucosa-Associated Lymphoid Tissue (MALT)
Surveillance, Differentiation and Effector Function of Immune Cells
Foreign antigens are likely to be present in these secondary organs - allows close proximity between antigen-laden dendritic cells and lymphocytes so that recognition and activation can occur
How can lymphocytes migrate?
Lymphocytes stimulated by an antigen at one mucosal site can migrate via regional lymph nodes, thoracic duct and bloodstream to other mucosal sites using specialised homing receptors
nb. the example of Peyer's Patches - packed with lymphocytes and dentritic cells which send processes into the lumen of the gut wall and retrieve antigens
How is the adaptive immune response self-regulatory/self-resolving?
Can achieve this through Treg cells which can inhibit immune responses by:
- cell-cell contact (inhibition or apoptosis of leukocytes)
- Producing inhibitory cytokines (IL-1, TGF-B)
- Scavenging growth factors (eg IL-2)
Also important in preventing action of T cells which recognise self antigens (ie. preventing autoimmunity - could be a therapy for it)
(Can also repair tissue - very specialised cells involved in turning off inflammation)
What is there a selective evolutionary pressure for?
An effective immune system