Immune Response Flashcards
What are the three ‘components’ of the innate immune response?
- Cellular response (by the innate immune system)
- Chemical response (by cytokines and complement)
- Acute inflammatory response (initiated by the above)
What cells are involved in the innate cellular immune response?
Phagocytes (dendritic cells, blood monocytes, tissue macrophages, neutrophils)
NK cells
How do phagocytes recognise pathogens?
Via PAMPs (pathogen-associated molecular patterns).
They bind PAMPs using PRRs (pathogen recognition receptors), e.g Toll-like receptors (TLRs).
What are the stages of phagocytes’ immune response?
- identify PAMPs of pathogens via PRRs
- internalise pathogen, kill and digest it
- present protein antigens to the cells of the adaptive immune system via MHC (major histocompatibility complex)
- binding of PAMPs to PRRs triggers activation of NFKB, a transcription factor which upregulates the release of proinflammatory cytokines and initiation of the inflammatory response.
How are NK cells involved in the innate immune response?
- respond immediately when exposed to a pathogen
- target cells which do not express surface MHC I
- target cells are killed by release of toxic granules, which trigger apoptosis
- MHC I expression is suppressed in virus-infected and tumour cells; NK cells kill these
What are the components of the innate chemical immune response?
- complement system
- proinflammatory cytokines
Pathways of complement activation?
- Classical pathway (activated by antigen-antigen complexes on pathogen surface).
- Mannose-binding lectin pathway (lectin binding to mannose on pathogen surface triggers activation).
- Alternative pathway (C3 reacts directly with pathogen surfaces).
What complement protein is generated in all three pathways?
C3 convertase.
It cleaves C3 into C3a and C3b.
Role of C3a, C4a and C5a?
- Inflammatory mediators.
- Trigger maste cell degranulation, causing release of histamine (anaphylotoxins)
Role of C3b?
Opsonisation - coats pathogens, marking them for phagocytosis.
Role of C5b?
Memrane Attack Complex (MAC).
Osmotic lysis of bacterial cells.
Role of proinflammatory cytokines?
Released by immune cells in response to infection.
Mediate the acute inflammatory response.
IL-1,4,5,6,8,10,12,13; TNF-alpha, INF-gamma
Il-1 ?
activates lymphocytes and causes fever (systemic effect)
Il-6?
- Causes fever
- stimulates CRP production by the liver
- activates lymphocytes
Il-8?
causes chemotaxis of neutrophils
Il-12?
activates NK cells and TH1 cells
TNF-alpha?
increases vascular permeability, allowing immune cells to access tissues
Il-4, Il-5 and Il-13
promote IgE production
IFNγ
activates cell-mediated immunity in viral infections
Il-10
anti-inflammatory effect
What are the triggers of the acute inflammatory response?
innate immune cells’ activity
proinflammatory cytokines
complement
Occurs 4-96h after onset of infection.
What are the main effects of the acute inflammatory response?
vasodilation
increased vascular permeability (swelling/oedema)
pain sensitisation (by bradykinins and prostaglandins)
neutrophil chemotaxis
microvascular coagulation (confines the infection)
Fever, CRP, ferritin(systemic)
What are the main cells responsible for Antigen Presentation?
Dendritic cells
They carry digested antigens to lymph nodes, where they present them to naive T helper cells (TH0).
How is inappropriate activation of the immune system by antigens prevented?
- MHC restriction: antigens have to be presented in complex with MHC II to activate T helper cells.
- second signal: B7 proteins from Dendritic cells must bind CD28 receptors on T helper cell surface.
What cell types do activated T helper cell differentiate into?
TH1 cells (promote cytotoxic T cells and cell-mediated immunity)
TH2 cells (promote B cells and humoral immunity)
What is humoral immunity?
Specific adaptive immune response activated by TH2 cells, which leads to the production of B cells and antibodies.
What infections does the humoral immunity fight?
extracellular infections (bacteria, fungi, protozoans) parasitic worms
Structure of antibodies?
- two heavy chains (determine the Ig type)
- two light chains (kappa or lambda)
- connected by disulfide bonds
- constant and variable regions in all 4 chains
Which part of the antibody confers its specificity?
The variable regions
IgM?
- pentameric structure
- expressed on B cell surfaces
IgG?
- monomeric
- found in circulating blood and tissues
- crosses the placent to provide passive immunity to the foetus
IgA?
- forms dimers
- found in mucosa (GI respiratory) and urinary tracts
- secreted in saliva, tears and milk
IgE?
- forms monomer
- mediates allergic reactions
- provides immunity against parasitic worms
IgD?
- monomeric
- interacts with basophils and mast cells
What mechanisms enable B cells to create the vastly diverse array of specific antibodies?
B cells manipulate their own genome:
- VDJ recombination (shuffling of gene segments encoding the varable regions)
- imprecise joining of VDJ segments
- isotype class swithching (generates different antibody types)
- somatic hypermutation (generates variants of antibodies with the same specificity and varying affinity - high affinity antibodies are selected)
How do antibodies fight extracellular infections?
- they neutralise toxins by direct binding
- bind to antibodies on pathogen surface (opsonisation and agglutination)
- antibody-antigen complexes activate teh classical complement pathway
- directly activate dendritic cells, NK cells and cytotoxic T cells
What are the 3 stages of humoral immunity?
- activation of B cells by T helper cells
- maturation of activated B cells into plasma cells (these produce antibodies)
- dormant memory B cell formation
How do T helper cells activate B cells?
- activated naive Th0 cells differentiate into TH2 cells
- TH2 cells idenitfy the correct antigen bound to the MHC II on the B cell’s surface.
- the CD40 ligand is provided as the second signal to the B cell
- TH2 cells also release cytokines (IL-2, IL-4, IL-5). These promote B cell development.
What is Isotype class switching?
- IgM antibodies are produced first
- then different Ig classes,as required
What is Cell-mediated immunity?
A specific adaptive immune response activated by TH1 cells, which leads to activation of antigen-presenting cells and a cytotoxic T cell response.
What infections does Cell-mediated Immunity fight?
- intracellular infections (viral, bacterial)
- protozoans (Plasmodium)
Why is T Cell Receptor diversity important?
It needs to cover all possible infection-derived antigens, just like B cells.
How is diversity of T cell receptors achieved?
- VDJ recombination
- junctional diversity
- addition of N regions
Where do T cells maturate?
in the thymus gland
To what selective processes are immature T cells subjected to in the thymus gland?
- immunological tolerance (removal of T cells with receptors recognising self cell antigens)
- must express CD3 and CD4 or CD8
- must bind to self MHC complexes
How are antigen-presenting cells (APCs) activated?
- TH1 cell recognises the antigen presented on MHC II
- it activates the APC with a CD40 ligand and IFNγ
- activated APCs produce NO and superoxide radicals, enhancing their pathogen-killing abilities
What is the cytotoxic T cell response?
The killing of infected cells, recognised by antigens displayed on MHC I on their surfaces.
How are cytotoxic T cells activated for an antigen-specific response?
- activated APCs present their MHC I-bound antigen to the specific cytotoxic T cell receptor
- second signals must be present
- IL-2 enhances this process
What killing mechanisms do cytotoxic T cells use?
- perforin released into an immunological synapse makes a hole in the bacterial cell wall. Apoptotic agents are released through that hole.
- apoptosis can also be triggered by Fas ligand interactions
- IFNγ from cytotoxic T cells can block viral replication without killing the infected cell
What signals are needed to activate the cytotoxic T cell response during re-infection?
-MHC + antigen only
Thus can be activated by any antigen-presenting cell.
Adaptive immune response against extracellular infections?
Humoral immune response.
-TH2-mediated activation of B cells, clonal expansion and Ig production
Adaptive immune response against intracellular infections?
Cell-mediated immune response.
-TH1-mediated activation of the antigen-presenting cells and cytotoxic T cells.
