Core Concepts-L23-Antibody Function

key antibody effector functions(5)

1. neutralisation- bind to virus/bacteria to stop them from entering cells

2. opsonisation- coat pathogens making them easier for phagocytes. Fc receptors on phagocytes bind to the Fc on antibodies

3. complement activation-IgM/IgG via C1q binding and make membrane attack complexes

4. ADCC- Nk recognise antibody coated and targets Fc receptors III to kill the cell by granzymes

5. ADCP- macrophages and neutrophils bind opsonised targets via Fcgamma R

6. recycling and internalisation- can be recycled via Fc neonatal receptor- fern

function of the Fc receptors- especially in IgG? structure of an Fc receptors

allows immune cells to recognise antibodies bound to antigens

• Fc gamma receptors for IgG- Fcgamma RI/IIa/b, IIIa/b- heavily glycosyated and triggers cell activation/inhibition depending on the receptor type

• mechanism: antibodies cluster on pathogens surfaces- Fc receptors clusters on immune cells transduce signals

• FcRn- recycles IgG

Fcgamma RI- high affinity for IgG

fcgamma RIIA- activating

Fcgamma RIIB- inhibitory

Fcgamma R IIIA- NK cells for ADCC

Fcgamma R IIIB- neutrophils

Types of Fc receptors and their roles

• Fc alpha- IgA- induce phagocytosis and microbe killing- mucosal

• Fc epsilon- IgE- on B cells/basophils/eosinphils- trigger histamine release and protect against parasites

• Fc gamma-IgG- 5 types- many phagocytes- induce phagocytosis, inhibitory Fcgamma RIIb- prevents overreaction and tolerance

• low affinity binding but high avidity when antibodies form immune complexes

activator vs inhibitory Fc receptor signalling

activating Fc

• ITAM- tyrosine based motif: propagate activating signals inside the cell- degranulation, phagocytosis, ADCC, cytokine

• Fcgamma RI,IIA,IIIA, Fc epsilon R

inhibitory Fc receptors

• ITIM- tyrosine based inhibitory motif

• suppresses activation and prevnts overactivation

• recruits phosphates and inhibits downstream signalling

• Fcgamma RIIB

discuss therapeutic antibody case studies

1. rituximad- targets CD20 on B cells in tumours. Fc recruits NK cells for ADCC and macrophages and complement

2. Herceptin in breast cancer- bricks HER2 dimerisation and stops uncontrolled cell growth. Fc recruits NK cells

limitations: only effective in patients with high HER2 expression only 20-30%

describe antibody dependent cellular cytotoxicity

1. recognition- NK cell expresses a FcR IIIa receptor and binds Fc receptor of IgG that coats target cell

2. activation-clustering of Fcgamma RIIIa triggers ITAM mediated signalling and becomes cytotoxic

3. perforin and granzymes- target for apoptosis

4. immune complex assisted apoptosis- M6P helps deliver granzymes

how are antibodies recycled- what does it do and what is the mechanism

via the neonatal Fc receptor

• stops them from being degraded and prolong shelf life and found on epithelial cells and APC

mechanism

1. binds igG in acidic endosome after internalisation

2. normally: proteins in endosome go to the lysosome for degradation

3. FcRn rescues IgG and returns it to the cell surface

complement system overview- who discovered it? how does it work? functions?

1890s Ehrlich

• plasma proteins circulate in inactive form and form a cascade once activated

• opsonisation, recruit immune cells and make chemokine signals(C3a/C5a), make membrane attack complex

name the 3 complement pathways

1. classical pathway

2. lectin- mannose binding pathway

3. alternative pathway

describe the classical pathway

triggered by antibody-antigen complexes

1. c1q complex binds to Fc portion of antibodies

2. C1 cleaves C4 and C2

3. C4 and C2 make C3 convertase and cleaves C3

4. C3b binds to pathogens for opsonisation

5. and MAC formation- CD5-C9 for MAC

describe the lectin MBL pathway

mannose or other sugars on pathogen surfaces binding to the MBL

1. MBL binds sugars on pathogen

2. activates MASPs

3. MASPs cleave C4 and C2 and makes C3 convertase and make C3b

AB INDEPENDENT

describe the alternative pathway

triggered by pathogen surfaces

1. spontaneous hydrolysis of C3

2. binds factor B which is cleaved by factor D and makes C3 convertase

what does the neonatal Fc receptor do?

protects the IgG from degradation- extends the serum Half life

• binds IgG at acidic pH inside the endosome

• keeps igG levels high

• transports IgG across the placenta

immune cells and their types of Fc receptors

macrophages: Fcgamma RI/R IIb(inhibitory), R III

neutrophils: Fcgamma RI/ IIA/ IIB/ IIIB

monocytes: Fcgamma RI/ RIIIB

B cells: Fcgamma RIIB- inhibitory- limit antibody production

NK: Fcgamma RIIIA-ADCC