Flashcards in The Immune Response Deck (27):
What occurs during an immune response when everything is working as it should?
1. Challenge & Inflammation: e.g. a Tumour or an infection
2. Pathogen clearance:
Induction of inflammation. Innate response kicks off as it sees non self antigens; releasing neutrophils and macrophages into circulation. After 5-6 days the adaptive response begins to aid the innate, resulting in pathogen clearance.
3. Resolution-wound healing:
During their action neutrophils will have released ROS, chemokines will have been released by macrophages and keratinocytes, and fibroblasts and other non-haemopoetic cells at the injury site will also have released harmful species. So we require a further resolution, wound healing process to heal and close the lesion (outside) or fix the barrier on the inside.
This can result in scar formation driven by the immune response. This is acute inflammation, though it is very hard to put a time limit on this as if you don't always just get acute inflammation - ie if the innate response can't resolve the inflammation it will lead to chronic inflammation.
What is the difference between acute and chronic inflammation?
- causative agent
- major cells involved
Acute: Pathogen, Injured tissue
Chronic: Persistent acute inflammation due to non-degradable
pathogens, viral infection, persistent foreign bodies (eg a
splinter), autoimmune reactions
MAJOR CELLS INVOLVED:
Acute: Immediate and direct from blood stream; Granulocytes
(neutrophils, eosinophils, basophils), Mononuclear cells
Chronic: Mononuclear cells, Lymphocytes, Fibroblasts; Adaptive immune
response continues with no regulation
Acute: Days (could be weeks in certain diseases)
Acute: Resolution, abcess (often with bacteria), chronic inflammation if
Chronic: Tissue destruction, Necrosis, fibrosis (can lead to cirrhosis etc,
C. Diff - mucosal tissue destruction driven by a pathogen)
How is the resolution of inflammation achieved naturally?
Reduction in antigen as pathogen removed, so inflammation resolves.
Short life span of innate cells - fast and stupid (eg neutrophils undergo phagocytosis more than once but ultimately are engulfed by other macrophages).
Often we can be infected and not even realise it.
Control of protein response:
- Short lived mediators that work locally rather than systemically
- Decoy receptors (eg IL1RA)
- Post-translational modification (enzymatic cleavage eg IL33, IL18)
Expression of inhibitory cytokines (eg IL-10 and TGFbeta - First found to produce an activate t reg cells, key for regulation of immune response)
- Production / activation of T regulatory cells
What is IL1RA?
Receptor on cell that IL1 binds too. If there is a soluble IL1 receptor in the periphery it will bind to it and prevent IL1's signalling action further. So even if you have a constant signal requesting IL1 (one of the first cytokines seen in acute inflammation, but who's concentration never goes down to zero). So if the body decides that IL1RA is necessary when and it is time to resolve, the pathogen signals are starting to decline then the downstream signals of ILR1A will also decline.
What is IL33?
Type 2 cytokines important in allergies. Has many cleavage sites that can be cleaved by extracellular proteases and pathogens. Depending where it is cleaves determines how active it is. This is post translational modification.
How are regulatory T cells produced?
Thymus produces niiave T cells that can then be induced with antigen to become reg T cells with the right signals.
T reg cells can also come direct from thymus - these are native t regs e.g. Th0.
But you can also get induced t regs that are antigen specific, these come from CD8+ or CD4+ cells that have been produced in the thymus and exposed to antigens
How do regulatory T cells exhibit their control?
T regs can inhibit both Th1 and Th2 immune responses:
IL10 and TGIF-b control the polarisation of the Th1 and Th2 cells; they have a direct effect on dendritic cells which help with this polarisation process. This stops the inflammation where it starts (at the dendritic cell).
The homeostasis controlled by regulatory T cells is key to regulating inflammation caused by chronic diseases.
How can helminth’s be used to generate an immune response as a treatment for IBD?
Th1/Th2 driven - mixed immune response of both. We know t regs can inhibit both so if we can promote an immune response that would make them produce t regs they could initiate their own immune response. Helminths are worms that live in the gut and produce t regs - could they be used to generate tgfbeta?
Can ‘natural’ exposure to a challenge regulate inflammation through ‘natural’ generation of Tregs that can then 'dampen' the immune response?
How do T regulatory cells promote Tumour progression?
Tumour cells are Self cells hiding from the immune response.
Cancer cells in pink. CD4 T cells can help cancer cells proliferate. But t regs cal downregulate this, as they dampen the immune response. So if the immune response is trying to kill tumour cells (good) the t regs stop it!
What is overactive healing?
When the immune system isn’t ready to restore homeostasis and thinks the ‘pathogen’ is still out there. Leads to hypersensitivity type I-IV (allergies!)
Which immune reactant (antibody) is responsible for each type of hypersensitivity?
Type I: IgE
Type II:IgG (cytotoxic antibodies)
Type III: IgG (immune complexes)
Type IV: a: TH1
b: TH2 } cell-mediated
What type of antigen is targeting in each type of hypersensitivity?
Type I: soluble antigen
Type II: cell or matrix-associated antigen
Type III: soluble
Type IV: a: soluble
c: cell-associated antigen
What effector mechanism is used by each type of hypersensitivity?
Type I: mast cell activation
Type II: FcR+ cells (phagocytes, NK cells)
Type III: FcR+ cells complement
Type IV: a: macrophage activation
b: eosinophil activation
What is an example of each type of hypersensitivity reaction?
Type I: systemic anaphylaxis, allergic rhinitis, asthma
Type II: some drug allergies (eg penicillin)
Type III: serum sickness, Arthur reaction
Type IV: a: contact dermatitis, tuberculin reaction
b: chronic asthma, chronic allergic rhinitis
c: contact dermatitis
What is an allergy?
TYPE I HYPERSENSITIVITY
First exposure – generation of antibody
Second exposure – allergic reaction
Involves antigens of the allergen binding to IgE’s attached to the surface of the mast cell
Immediate response of mast cell is to release histamine
eg allergic rhinitis
Clinical effects include:
- Vascular permeability (histamine)
- Smooth muscle contraction (histamine, leukotrienes)
- Mucus production (goblet cells, IL13)
- Vasodilation (histamine, PAF (endothelium & neuts)
What is atopy?
Linked to the overproduction of IgE
Can be symptomatic or asymptomatic
Patients with an above normal amount of IgE production have greater type I hypersensitivity
What is the pathology of asthma?
Only 30% of asthma incidence is thought to be due to atopy
(with a large variation across different populations), and the genetic risk factors are linked but not the same. For example infection, eg fungal, can cause asthma symptoms.
IgE driven asthma is most likely to be caused by pets and dust, possibly pollen mould and cockroaches, this is due to danda (protein and polysaccharides) that drive an immune response
What is anaphylaxis?
Same principle as allergy, but time window and severity is different.
Extreme allergic reaction
- Very rapid onset
- Common triggers: peanut, insect bites, latex
- First exposure has no symptoms so people tend not to know
what it was they are reacting to
Massive histamine and TNFα release resulting in drop in blood pressure, swelling of throat and mucus membranes – respiratory collapse
Rescued with epinephrine injection
Why do we develop allergies to non-harmful species, such as pollen?
Pollen contains proteins that mirror proteins in pathogens so if we're not exposed to the correct pathogens our body will respond as if they are dangerous.
IgE also responds to extracellular infections, eg helminth infection
What is type II hypersensitivity?
The immune system responds with antibody driven response exactly how you want it to, but not towards what you want it to!
Complement dependent red blood cell lysis:
eg incompatible blood transfusion (remember it like: II cells that don’t complement each other)
Antibody dependent red blood cell degradation:
eg Rhesus incompatibility
Autoantibodies destroy host cells:
A: Mechanism 1: Autoantibody-mediated activation of complement
B: Mechanism 2: Autoantibody-mediated and complement opsonization of a host target cell
C: Mechanism 3: Autoantibody-mediated and complement attraction of neutrophils
D: Mechanism 4: Autoantibody-dependent cell-mediated cytotoxicity
E: Mechanism 5: Antireceptor autoantibodies
What is type III hypersensitivity?
An antibody driven immune complex formation that causes tissue damage. Eg rheumatoid arthritis ‘serum sickness’
1. Antibody-antigen complex formation
2. Phagocytes remove most of the complexes but some lodge in blood
3. This causes activation of complement
4. Antigen-antibody complexes and activated complement attract and
activate neutrophils which release inflammatory chemicals
5. Inflammatory chemicals damage underlying blood vessel walls
Normally antigen antibodies complexes are recognised by complement, perform their function and are destroyed. But when there are lots of antigens the complexes made are too small so aren't recognised by complement.
why do immune complexes lead to disease?
In the early stages of the immune response there are very few antibodies and therefore an excess of target antigens. In the presence of excess antigen small immune complexes are formed with IgG. They are too small to fix complement and so are not cleared from circulations, instead they are taken up by endothelial cells and deposited in tissues. (One antibody to several antigens, several free antigens left over)
In the intermediate stages there are comparable amounts of antigen and antibody, so large complexes can form involves several antibodies bound to the same antigens. These large immune complexes can fix the complement and be cleared from circulation. (Lots of antibodies bound to lots of antigens = clumps)
In the late stages of response there is an excess of antibody compared to antigen so medium sized immune complexes are formed that fix complement and are cleared from circulation (lots of antibodies bound to only one antigen, lots of free antibodies)
Hence, since in the early stages complexes are deposited in tissues, clinical presentation depends on site of complex deposition and if it is overwhelmed.
What are examples of immune complexes leading to disease?
When immune complexes are deposited in the synovial tissue,
When immune complexes are deposited in the kidney glomeruli,
They cause glomerulonephritis.
When immune complexes are deposited in the endothelium of the blood
Vessels of the skin, they provoke vasculitis.
SLE, immune complexes are deposited anywhere! Particularly in joints, skin and glomeruli.
What is the Arthus reaction?
Used to be a very common inflammatory reaction following immunisations.
1. Antigen is injected into immune individual with IgG antibodies
2. Local immune complexes form
3. Complex formation activated FcyRIII on mast cells causing them to
4. Local inflammation, increased fluid and protein release, phagocytosis
and blood vessel occlusion (area appears red and swollen)
*process takes 1-2hours*
5. Induction of complement factors C3a C4a and C5a
This is now rare!
What is hypersensitivity type IV?
The only type of hypersensitivity mediated by T cells.nit is also known as cell-mediated or delay-type hypersensitivity.
Antigen-specific effector T cells caused a delayed response due to being part of the adaptive immune system. You may have seen it more than once before if they were all in this initial time it takes for adaptive response to form. Lag time before clinical presentation (1 to 3 days).
Need a large dose - not many antigens can do this.
1. Sensitisation phase: initial contact with antigen.
Picked up by an antigen presenting cell, eg a macrophage, this releases
IL-1 attracting and activating T helper cells (Th1). Th1 releases
IL-2 which allows proliferation and differentiation of T memory
2. Effector phase: secondary contact with antigen.
T memory cells are already in circulation from phase 1. Bind to
antigens presented on macrophages by stimulation from IL-1 and 2.
T helper cells release IL-8, MIF and MCP (cause chemotaxis of
macrophage), IFN-y and TFN-b (activate macrophage to increase
phagocytic and microbicidal activities), IL-3 and GM-CSF (induct
myelopoeisis of macrophage and neutrophil precursors). The
macrophages produces IL-8, TNF-a and MIP (cause chemotaxis and
extravasation of macrophages)
Is diabetes a type II or type IV hypersensitivity reaction?
Antibodies to beta islets are a marker of disease. This suggests a Type II hypersensitivity?
The body recognises antigen on beta islets as foreign and generates an antibody response. CTL and NK cytotoxic activity destroys insulin producing cells.