34 - B cells: Distribution & function of antibodies Flashcards
It is well documented that antibody affinities for an immunizing antigen continue to increase upon successive rounds of immunization (i.e., secondary, tertiary, etc.).
This is because:
At each round of immunization, new naive B cells are recruited into the response.
At each round of immunization, the expression of AID increases, leading to
higher rates of somatic hypermutation.
Memory B cells express higher levels of AID than naive B cells, leading to
higher rates of somatic hypermutation.
Memory B cells can re-enter germinal centers and undergo additional somatic hypermutation.
Memory B cells can re-enter germinal centers and undergo additional somatic hypermutation.
-increases affinity for Ag, specificity stay the same
Antibodies mediate …
Each Ab isotype has …
…clearance & destruction of pathogen in variety of ways
…has distinct properties & traits that enable it to do so
Key Ab functions: 5
- Virus & toxin neutralization
-Prevents pathogen host binding - Opsonization
-Phagocytosis - Complement fixation & formation of MAC (membrane attack complex)
-Phagocytosis/lysis - Antibody-dependent cell mediated cytotoxicity (ADCC)
-NK-induced apoptosis - Bind Fc receptors on granulocytes =Ag binding to Ab triggers degranulation (like ADCC)
-Granulocytes: mast cells, eosinophils, basophils - Transport
-Not an Ab function to clear infection but they are transported to exert their function
Fc receptors important for
Ab functions
Fc receptors help Igs to… & how?
How do Igs opsonize?
How do Igs act on cells?
How do they get across walls?
o FCR bind to FC fragments of Ab
FcR
Family of cell surface (transmembrane) receptors that binds to Fc portion of Igs:
-Expressed on macrophages, granulocytes, DCs, mast cells, B cells, epithelial cells, NK cells etc…
-Binds Igs in a class specific manner
–Different class of FCR bind to specific isotope FC
–Fc𝛾RI binds IgG1, FcεRI binds IgE, etc
NOT one fits all
Each Fc receptor is specific for the…
3 examples:
constant Fc region of one class of Ig
o Fc𝛾R - R binds Fc region of IgG
o FcεR - R binds Fc region of IgE
o Fc⍺R - R binds Fc region of IgA
Fc receptors mediate…
many effector functions of antibodies
Crosslinking FcRs
more important for triggering signalling
-When FC receptors bind their specific Ab that are bound to their specific Ag
-If Ab not bound to Ag but bount to FcR = not signalling
Functions of Fc receptors
- Degranulation
- Opsonization
- Transportation & maintenance of serum levels
- ADCC
Using FcRs allows
non-specific immune cells (mast cell, macrophages) to take advantage of Ag-specific Ab
Opsonization
Promotes and/or enhances phgocytosis of Ag
- Free IgG doesn’t crosslink FcRs
-IgG not bound to Ag but bound to macrophage = no intracellular signaling - Aggregation of binding can allow crosslinking of FcRs
Ab binding to their Ag and their FcR -Trigger intracellular signaling – pseudopodia – phagocytosis
IgG effector function
Include several subclasses, each with distinct effector capabilities
-Some IgG subclasses = effective at complement fixation
-Some IgG subclasses = good at mediating ADCC by NK cells
All IgG subclasses bind to Fc receptors on macrophages/phagocytes – enhancing phagocytosis by macrophages-opsonization
all classes of IgG lead to opsonization
ADCC
antibody dependent cell mediated cytotoxicity
Activates killing activity of several types of cytotoxic cells (NK cells)
ADCC: NK cells
- NK cells have FcᵧRs
- Can recognize Fc region of IgG Ab
- If these FcRs bind to Ab on a cell - crosslinking trigger signaling- NK cell releases toxic granules- target cell dies by apoptosis
ADCC vs. innate
Same toxic granules are released in both cases, but activating signal sent to NK cell is NOT the same
Innate: balance between activating/inhibitory signal
Fc receptors & granulocytes
Antibody dependent degranulation from granulocytes – like ADCC
IgE effector function
- BEST Known for role in allergy & asthma
- Role in protection against parasitic helminth & protozoa
- Made in very small quantities – but induce potent effects
-Degranulation of eosinophils/basophils
-Release of molecules such as histamine to damage large pathogens
Review: TH2 response: Eosinophils & mast cell activation
TH2 cytokines activate eosinophils & mast cells
Mast cell granules contain histamine & other molecules
Eosinophils & mast cells express receptors that recognize the Fc portions of IgE-Eosinophils & mast cells can then specifically target pathogen & degranulate
-Baseline for mast cells to express FcεR, free-flaoting IgE can bind to it, but if its not bound to its Ag, nothing will take place. If it is bound to its Ag = release of granules
Neutralization
Protects against viral/bacteria infection, or against the damaging effects of toxins
Binding of Ab to toxins/pathogens (Anti-) to prevent them from binding their targets & exerting their effects
Different targets can be neutralized
o Toxins
o Viruses
-bacteira – not as much
toxisn & viruses are the mian ones, because they like to bind on human cells & enter the human cells to exert their function
Ig class most important for neutralization
IgG & IgA antibodies
IgA major isotype found in
secretion
o Mucus in gut
o Milk from mammary glands
o Tears
o Saliva
Complement activation
Results in generation of MAC (membrane attack complex), inflammation and/or opsonization
Classical pathway recap
C1q binds pathogen surface
-Can bind pathogen directly
-Can bind Ab that are bound to pathogen surface
Connects adaptive to innate
Once C1q binds
-Triggers signaling cascade on pathogen surface
C3 convertase generated
-C3 cleaved= C3a & C3b
Antibodies important in complement activation:
Both IgM & IgG can trigger complement cascade
IgM most effective = pentamer = good landing pad for C1q
-1st Ab produced in primary response
-Tend to be lower affinity
-Pentavalent
-10 total Ag binding sites (bc its pentamer)
-Very good at activating complement cascade
-Efficient at forming dense Ab-pathogen complexes efficiently englulfed by macrophage
FcRs allow
targeting of different Ig classes to different parts of body
Transport: Different Ig classes in differen parts of body
o IgA - selectively found in mucosal tissues
o IgE - found near epithelial surfaces
o IgM - found in blood (not a lot)
o IgG - widely distributed (mainly in blood)= including to developing fetus
-Newborns have maternal IgG in circulation
-Example of passive immunity
FcRs are involved in
transporting Igs across barriers
Antibody mediated effector functions: IgD
IgD = minor component of blood (0.2% of circulating Ab)
-But present at higher levels in secretion of upper respiratory tract
Effector functions:
-Bind basophils & mast cells – prompting them to release AMPs (antimicrobial peptides), cytokines & chemokines
-Not well understood – not easily found in body
Which statement is false?
Transporting antibodies requires Fc receptors on epithelial cells
The classical pathway of the complement system relies on C1q binding to IgG and IgA antibodies O
Mast cells can have IgE antibodies bound to their Fc receptors at baseline
Antibodies must be cross-linked in order for them to trigger an Fc receptor-mediated signal
The classical pathway of the complement system relies on C1q binding to IgG and IgA antibodies O
IgA - found in, effective in
Found in secretion, effective in neutralizing toxins & pathogens
IgM, shape & main role
1st Ab produced in primary response, pentavalent
IgG, many…, some good at…
Included several subclasses, some of which particularly good at complement fixation
IgD, promotes… that does…
Promotes basophil & mast cell release of AMPs
IgE, known for…
Best known for roles in allergy, asthma, parasitic worm infection
Neutralization & Ig class involved
Most effective mode of protection from toxins & viruses
IgG & IgA
Opsonization & Ig class involved
Enhances engulfment of Ag by phagocytes
IgG
Complement activation & Ig class involved
Results in formation of MAC
IgG & IgM
ADCC & Ig class involved
Activated killing activity of cytotoxic cells including NK cells
IgG
Degranulation of granulocytes, Ig class involved?
IgE
IgD - function
AMPs, cytokines & chemokines from basophils & mast cells
