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
