Antibody functions Flashcards
In what 2 general ways can antibodies work/have their effect?
Label pathogens → elimination/destruction
antibodies flexible adaptors: 2 functions:
- bind antigen
- mediated by FAB arms variable regions
- trigger elimination
- effector functions mediated by Fc regions
Avidity vs affinity
-
NB! antibodies are at least divalent. Avidity vs affinity
- affinity is strictly the binding of 1 Fab arm to an antigen
- Avidity is the binding of a whole antibody molecule to antigen if it can bind more than 1 arm
- avidity usually greater than affinity
Through FAB arms: what 2 general ways can they carry their effect dependent on?
either requiring the innate immune response or without
Describe FAB arm function not requiring innate immune response (5)
- Immobilise pathogens (IgM)
- e.g. bacteria with flagella
- stop bacteria moving and spreading infection
- Agglutinate particles e.g. bacteria (IgM, IgA)
- makes them easier to remove from the body such as by paristalsis from the gut
- Form “immune complexes” with soluble antigen
- soluble antigen can form these complexes where they crosslink with eachother, this way its easier to get rid of and bind better to Fc regions
- Block binding of pathogens to host cells (IgG, IgA)
- e.g. antibodies to bacterial adhesins or viral receptors
- bind with high affinity because somatic hypermutation and affinity maturation
- Neutralise toxins (IgG, IgA)
- e.g. tetanus, diphtheria, cholera
- when disease is caused by the toxins the bacteria release, and not so much the bacteria themselves
In what 2 major ways can Fc regions have their effect? and which antibody class
Invoke destruction of labelled pathogens
- Activate complement (IgM, IgG)
-
Bind Fc receptors on leukocyte surfaces (IgG, IgA, IgE)
NB! effector mechanisms that operate will depend on:- Site and type of infection (where and type)
- Stage of immune response (primary or secondary)
To summarise, what are the antibodies main function?
label pathogen, interact with their Fc regions elements of the innate immune system
Describe the activation of complement by the classical pathway
- Requires Antigen to bind to antibody, + C1, C2 and C4
- C1 = C1q + C1r + C1s
- C1 consists of 3 proteins
- C1r and C1s associate with C1q
- C1s and C1r are serine proteases (cleave proteins)
- In order to get activation of complement in the first place:
- C1q must bind to adjacent antibodies on the surface of a pathogen
- C1q has 6 globular “tulips” joined together by a collagen like stalk
- C1q must interact with 2 Fc regions (through its globular “tulips” for activation to occur
- this is down to valency
- you need 2 to get stable binding.
Why is IgM a much better activator of compliment than IgG
- you need 2 IgG antibodies at the right distance form one another on the surface of a bacterium, for C1q to bind
- IgM is a pentamer, with 5 Fc regions, so its much easier for C1q to interact with at least 2 C1q regions
- problem: you don’t want IgM to activate complement when its just floating in blood… so how do tey solve this?
- when IgM binds to pathogen, it undergoes a conformational change
- Fab arms are normally in the same place as the Fc region, when it binds to antigen, the Fab arms can bend through the flexible hinge region to form a staple/crab structure. Only this structure can interact with C1q
- Efficient interaction with complement C1q
- IgG3 > IgG1 > IgG2
- IgG3 better than IgG1 which is better than IgG2
- IgG4 doesn’t activate complement at all
Describe in detail the activation of compliment
- C1q binds → conformational change in C1q which is associated with serine proteases C1r and C1s → C1r activated → C1s cleaved (by C1r) → C1s activated (becomes a protease)→ C1s can now act on C4 and C2 →
- C4 and C2 are cleaved → generate C3 convertase → cleaves C3 into C3a and C3b → C5 convertase generated → C5 cleaved → C5a and C5b → MAC activated on membrane of bacterial cell
- NB! complement activation can result in phagocyte recruitment, inflammation, opsonisation and direct bacterial killing! (look at lecture 2)
What other main function do FC regions have?
to interact with Fc receptors (FcR) on phagocytes
Which antibodies interact with FcR’s on phagocytes? and which are more effective
- IgG and monomer IgA
- effectiveness of IgG subclasses in opsonisation IgG1 = IgG3 > IgG4
In what 2 ways do Fc regions of antibodies interact with FcR’s on phagocytes?
- Uptake of immune complexes (soluble antigen + antibody)
-
Opsonisation - phagocytosis and destruction of antibody-coated pathogens
NB! following phagocytosis, pathogens can be destroyed as discussed previously in lecture 3
What happens if the pathogen is too big to be phagocytose
- results in frustrated phagocytosis → where phagocyte discharges its lysosomal contents on the pathogens surface. Same classes antibody involved
- e.g. Eosinophils attacking a large parasite → releasing their lysosomal contents onto the pathogen
Describe FcR’s on NK cells: function, which antibody subclasses etc.
- IgG : IgG1 = IgG3
- Fc receptors can enhance the activity of NK cells
- Fc receptors bind and recognise antibody on target cell → cross-linking of Fc receptors signals the NK cell to kill the target cell → target cell dies by apoptosis.
- ADCC
- Mediate antibody-dependent cell-mediated cytotoxicity (ADCC)
- Often when cell infected with virus, it will display viral proteins on the surface → antibody binds → FC receptor on NK cell now more efficiently recognises infected cell → ADCC
- NK cells produce perforin which perforate membrane of target cell → enzyme from granules enter target and cause it to call apoptosis
Describe FcR’s on mast cells and basophils: functions which antibodies etc.
- IgE
- mediate allergy/defence against large parasites
- Mast cells secrete inflammatory mediators and cytokines (sentinel cells often found underneath mucosal surfaces)
- When IgE is made in the first place e.g. in response to grass pollen
- at first, nothing happens other than IgE binds with high affinity to receptors on mast cell surface
- If individual comes across e.g. grass pollen allergen again → crosslinking of IgE bound to its Fc receptors → triggering a fast response (immediate hypersensitivity) with 5-10 minutes of inhaling allergen → mast cell release inflammatory mediators (degranulation) → symptoms
- Beneficial if you are trying to deal with large parasite…
Describe the functional activity of each antibody and where in the body they are distributed
