Antibody mediated effector functions
four main types
neutralization
complement fixaiton
opsonization and phagocytosis
ADCC = antibody dependent cell mediated cytotoxicity
Antibody neutralization
Neutralizing antibodies prevent pathogens from initating an infection
=bind pathogen surface and prevent receptor interaction
=bind receptor and prevent pathogen interaction
=block requisite interaction between pathogen and endosomal membrane proteins
=interfere with conformational changed required for viral-host membrane fusion
=inhibit release of progen pathogens
igg and antibody neutralizaton
prevent toxin/ microbe by coating it with antibodies
prevents receptor interaction
note: not all igg is strong enough to completely coat the microbe
Protection from toxins with antibodies
toxins of bacterial orgin = tetanus
toxins of venom = snake bites
serum therapy remains the only specific treatment against envenoming, but anti-venoms are still prepared by fragmentation of polyclonal antibodies isolated from hyper-immunized horse serum
Agglutinatiion
clumping of particles/ pathogens
agglutination and enchained growth of pathogens can facilitate their clearance
-> slgA in teh intestinal tract can lead to pathogen removal
immune complex
molecule formed by binding multiple antigens to antibodies
complement fixation
complement fixation elicits formation of the membrane attack complex (MAC)
This forms a pore in the target cell or viron membrane, causing influx of extracellular fluid
lysis of target
antibody binds and triggers C1 = makes pores aftera signal cascade
Complement cascade
CDC= complement dependent cytotoxicity
c5a is a chemoattractant for inflammatory cells
c5a upregulated activatihng FcRs and down regulated inhibitory FcRs
ADCC antibody dependent cellular cytotoxicity
ADCP antigody dependt cellular phagocytosis
outcomes of Fc receptors = more activation Fc and less inhibitory Fc
CDC
complement dependent cytotoxicity
ADCC
antibody dependent cellular cytotoxicity
ADCP
antigody dependt cellular phagocytosis
Fc receptors
a single antibody will not activate an FcR
-> requires multiple FcRs to be cross-linked (oligomerizeds) by binding complexed antibodies
FcR signalling is similar to Bcr signaling
-> Syk, Lyn and Btk signalling cascade
There are many types of FcRs
each ohave specific antibody isotypes that bind them
select cells express different types of FcR
Fc signalling leads to specific cell functions
-> sytokine produciton, enhancement of phagocytic activity etc
Opsonization - to make tasty
opsonization refers to the ability of antibodies to enhace the engulfment of pathogens by phagocytes
- > antibodies interact with FcR on the surface of phagocytes
- > induces antigen internalization and destruciton by phagocyte
mark with antibodies or complement
C3B in complement cascade
oposonation -> complement -> bind FcR
Antibody dependent cell madiated cytotoxicity
ADCC
antibody antigen complexed are bound by FcR on the surface of NK cells and granulocytes
- > allows cells to adopt antigen specificty
- -> once coated, NK or T cells recognixe coated FcR and mecdiate cytoxicity
Promotes direct cytotoxicity towards target cell
-> Release of cytoxic mediators such as perforin and granzyme B
(think about how this could be used theraputically or agaisnt cancer?)
Cytotoxic effector responses
cytotoxic responses trigger apoptosis in the target cell
- > clearance of virus and bacter infected cells
- > elimination of tumor cells
mediated by: CD8 (MHC1 endogenous antigen) NKT cellls (CD1 lipid antigen) NK cells (no MHC)
how to Th cells assist in the activaiton of CTLs?
bro isk
CTLS for immunologic synapse to mediate target cell killing
microtubule ortganizing cener MTOC, golgi apparatus and secretory granulers containing peroforin and serine proteases (granzymes) are polarized toward the immunological synapse and target cell
contraction of teh granules and extrusion of contents into the synaptic cleft
CTL activity agaist neruron
CTLS can mediate aconal transection of neruons
results in deirupstion of neural signalling
wallerian degeneration of axon
neuronal death
Central tolerance
deletion of b cells and T cells before they are allowed to mature
occures in the primary lymphoid oragns
second chance = receptor editing (with b cells)
-> autoreactive t cells can become Treg
central tolerance is not perfect
weakly/ moderatly bind to self become Treg cells
self-reactive lymphocytes find their way to the periphery and secondary lymphoid tissues
Read
ch 16 central tolerance
p 594-600
Peripheral tolerance
regulates autoreactive cells in circulation
backup control mechanisms
- > regulation by Tregs
- > anergy ( when a t cell sees its antigen but does not recieve CD86 costimulatory signals)
- > apoptosis
nTreg
natural regulatory T cells
inhibit the proliferation of CD25- T cells (non-activated)
iTreg
inducible populations of regulatory T cells secrete IL-10 and or TGF-beta to supress the activity of T cells
Treg
once in the periphery, they can inhibit the activation of other T-cells
If a Treg anda CTL are activated from the same antigen on a DC, the activated Treg can inhibit the CTL
IL-109 and or TGF-beta`
downplays CTL activity
CTLA-4
is a crucial inhibitory molecule expressed on Tregs
multiple modes of activation to inhibit effector T cell activaiton
has a much higer affinity (can outcomplete CD28 for CD80/86 binding)
BLocks actrivation of fellow T cell with the same APC
- > metabolic starvation (low tryptophan)
- > secreation of inhibitory cytokines - TGFb and IL10
Cd28
inhibitory singnal for T cells
Rheumatoid arthritis
autoimmunity manifests with the production of antigoes specifc for IgG (known as rheumatoid factors) or specific for cyclic citrullinated peptides
-> recall IgG leads for formation of large immune complexes
risk factors = smoking and DR4+ individuals ( RA in HLA)
after onset of clinical disease, inflamed synovium invades adjacent cartilage and promotes articular destruction
-> articular damage likely generates a rich source of neo-antigens ro promote further autoimmune reactivity
Immune cell infiltration in rhumatoid arthritis
(usually not a ton of immune cells ins the joints)
- > normally hypocellular synovial membrane becomes hyperplastic
- > cellular infiltrate includes synovial fibroblasts, macrophages, mast cells, CD4, CD8, NK, NKT, B and plasma cells
invades adjacent cartilage and promotes articular destrucion, which is mediated by the activities of osteoclasts, chondrocytes and synovial fibroblasts
Priming defects occur in the thymus
autoreative T cells dont become T regs
can subsue self reactive cells in the periphery
Cell-mediated immunity in RA
Th17 cells may orchestrate synotitis and damage
->funciton of tregs is impared in RA
macrophages secrete pro-inflamatory mediators
synovial fibroblasts secrete matic metalloprotinases (MMP) and cathepsisn via activation by the inflammatory microenvrionment but subsequently take on a semi-autonomous auasi-malignant phenotype
bone damage is caused by differentation and maturation of osteoclasts
Proposed mechanism of induction of autoimmunity
failure to control self reactive lymphocytes (even with AIRE)
release of sequestered antigens and breaak of self rolerance
-> ag that was never presented in the first place
or endogenous retroviruses
compare and contrast the following anti-body mediated responses
neutralization
complement fixation
opsonization
ADCC
describe the steps CTLs take to destroy their target
???
what is the difference between central and peripheral tolerance
???
How is CTLA-4 involved in Treg activity
???`
CD28 / CD80/86 thingy
Give and example of dysregulated cell-mediated immunity in Rheumatoid arthritis
and why is leads to pathogenesis