L9. Humoral and Cell-Mediated Immunity 1 Flashcards
What is the overall role of antibodies?
Antibodies Label pathogens –> elimination/ destruction
What does 1) Affinity 2) Avidity mean?
1) Affinity= binding of one Fab arm to antigen
2) Avidity= whole Antibody binding to a pathogen (if more than one arm)
What are 5 roles of the Fab arms of an antibody, and how does it do each, and which antibody heavy chain class does each?
1) Immobilise pathogens (IgM)
>Bind to flagella and stop movement.
2) Agglutinate particles e.g. bacteria (IgM, IgA)
>More easy to remove clumps from the body
3) Form “immune complexes” with soluble antigen
>Cross linking
4) Block binding of pathogens to host cells (IgG, IgA)
>IgG and IgA go through affinity maturation so bind with high affinity.
>e.g. antibodies to bacterial adhesins or viral receptors
5) Neutralize toxins e.g. tetanus, diphtheria, cholera (IgG, IgA)
>IgG and IgA bind with high affinity to toxins, stopping them causing damage
What is the role of the Fc section of an antibody?
Invoke destruction of labelled pathogens
What are 2 ways the Fc region of an antibody Invokes destruction of labelled pathogens?
1) Activate complement (IgM, IgG)
2) Bind Fc receptors on leukocyte surfaces (IgG, IgA, IgE)
What is required for the activation of complement from the classical pathway?
Requires Antigen/Antibody, C1, C2 and C4
What 3 factors about infection will determine the effector mechanism which act on it?
1) Site of infection (e.g. in secretions or gut will be IgA)
2) Type of infection (if is parasite will be IgE)
3) Stage of the immune response (primary or secondary uses different classes for flexible response)
What makes up C1 in complement?
> C1 is made up of 3 proteins, linked together
> C1 = C1q +C1r + C1s
> C1s and C1r are serine proteases when activated (cleave proteins).
What interaction must occur to trigger the start of complement activation by the classical pathway?
C1q must interact with 2 Fc regions (of IgG or IgM) for activation of complement by classical pathway to occur
What is the structure of C1q?
6 globular heads joined together by collagen stalk, 2 of these heads must bind to Fc antibody for stable binding
Why is valency important in the binding of C1q to Fc regions?
Down to valency as needs interaction with 2 heads (of C1q) to get stable binding.
What antibody is most efficient at activating complement by the classical pathway and why?
> IgM is the best at activating complement
> As would require two IgG molecules at the perfect distance between to interact while IgM is a pentamer so has 2 adjacent IgM
How does IgM not constantly activate complement in the blood (as two Fc regions are adjacent before binding)?
IgM doesn’t bind complement in blood due to its confirmation blocking binding to Fc regions
How can complement bind to IgM once bound to antigen, and what allows this?
Before binding to antigen Fc region is not accessible by C1q to bind but once bound the Fc region extends out for binding to complement due to flexible functional hinge region (forms crab like shape)
What IgG type is best at activating complement and which is the worst?
IgG3 > IgG1 > IgG2 > IgG4
IgG4 doesn’t activate complement at all but IgG3 is the best out of IgG.
Describe the classical pathway of activation for complement in 5 steps
- When antibodies bind to antigen, can interact with C1q causing conformational change associated with the serine proteases C1r and C1s
- When C1r is activated, it cleaves a bit of C1s, acting C1s
- C1s is now a protease, acts on C4 and C2 (cleaves)
- This generates the C3 convertase which cleaves C3 into C3a/ C3b
- This generates the C5 convertase which can cleave C5 into C5a and C5b leading to formation of membrane attack complex on bacterial cell.
What are the roles of complement?
Complement activation can result in phagocyte recruitment, inflammation, opsonization and direct bacterial killing
What receptor on phagocytes allows interaction with antibodies?
Fc receptor (FcR)
What antibodies does Fc receptors (FcR) on phagocytes best recognise (opsonisation)?
> IgG (IgG1 and 3 are both good, IgG4 is okay but IgG2 cannot opsonize)
> Monomer IgA
What are the 2 roles of Fc receptors on phagocytes?
1) This facilitates the uptake of immune complexes (soluble antigen + antibody), can be important for presenting processed antigen to T cells or just the destruction of pathogen.
2) OPSONIZATION - phagocytosis and destruction of antibody-coated pathogens
What occurs if a pathogen cannot be phagocytosed?
Frustrated phagocytosis
What is frustrated phagocytosis?
> If pathogen cannot be phagocytosed, frustrated phagocytosis occurs where it spits out lysosome contents onto surface of pathogen/ Release lysosomal contents (“frustrated phagocytosis”, for pathogens too big to phagocytose)
> As they would eb large pathogens, many leukocytes e.g. eosinophils surround it and release lysosomal contents (e.g. ROS).
What is the role of Fc receptors on NK cells?
Mediate antibody-dependent cell-mediated cytotoxicity (ADCC)
What are NK cells good at defending against?
NK cells good for dealing with intracellular infections
What antibodies can mediate antibody-dependent cell-mediated cytotoxicity (ADCC)?
Only IgG1 and IgG3 in humans.
Describe the process of antibody-dependent cell-mediated cytotoxicity (ADCC) in 4 steps
1) IgG1 and IgG3 binds antigen on surface of target cells.
2) Fc receptors on NK cells recognise bound IgG1 and IgG3
3) Cross-linking of Fc receptors signals the NK cell to kill the target cell.
4) NK cells release granzymes and perforin from cytoplasmic granules to cause apoptosis to host cell.
What receptor does IgE bind to with high affinity and what cells are these found on?
IgE binds with high affinity to FcεR on mast cells and basophils
What do FcεR on mast cells and basophils mediate?
> Mediate allergy/defence against large parasites
> Mast cells secrete inflammatory mediators and cytokines, Setting up strong inflammatory response.
How does an allergy be formed?
- Allergen which gets through tissue leads to IgE produced against this allergen and binds to mast cell tightly
- If the allergen gets through tissue again, activates IgE (immediate hypersensitivity) where mast cells undergo degranulation releasing inflammatory mediators. (good for dealing with large parasite)
What are “NUDE” mice?
Have no thymus and therefore no T cell responses
Why were “NUDE” mice good to study on?
Still survived if kept in germ free environment as still have innate and some B cell responses, allows us to study immune responses without T cells.
What is a common property of thymus independent antigen and give an example
> Lots of repeated epitopes (shapes) that B cells recognise which is enough to trigger B cell differentiation
> e.g. bacterial polysaccharides
What response is produced from thymus independent antigens (e.g. bacterial polysaccharides)?
- Induce a rapid response and production of IgM antibodies(agglutination and activating complement).
- Memory cells are not generated, as no class switching or affinity maturation can occur.
What usually is a thymus dependent antigen and why?
> Most proteins
> As these are processed into peptides and presented to T cells to recognise (only T cells can recognise peptide + MHC complex and has adaptor proteins CD3).
Why are T cells required for a response against thymus dependent antigens?
Require T cells for differentiation of B cells into plasma cells.
What response is produced from thymus dependent antigen?
- Long-lived memory B cells may also be generated.
- Responses can involve somatic hypermutation (allows for affinity maturation) and class switching.
