immunoglobulin effector function Flashcards
how does each b cell produce an Ig of single antigen specificity
Ig gene rearrangement is tightly conserved
ensures only 1 light and 1 heavy chain is expressed, allelic exclusion
where are Igs first made
in a membrane bound form that is present on b cell surfaces
b cell receptor is made up of cell surface IgM with invariant proteins Ig-alpha and Ig-beta
invariant chains are important for signalling once antigen binds to IgM
Ig heavy chains have hydrophobic sequence near c terminus that anchors them in the membrane
how do plasma cells secrete antibodies of the same specificity as the membrane bound immunoglobulin expressed by their b cell precursor
resting b cell with membrane bound Ig, bacteria encounters an antigen
this stimulates b cell to give rise to antibody secreting plasma cells
the pathogen is neutralised by secreted antibodies
first Ig class secreted is always IgM
how are membrane and secreted form generated
by alternative RNA processing of the heavy chain
transmembrane Ig have a hydrophobic transmembrane domain around 25 aa that acts as an anchor in the plasma membrane
secretory Ig has a hydrophilic secretory tail
2 carboxyl termini are encoded in separate exons and selected by alternative RNA splicing
all Igs have a transmembrane type and a secreted type
during differentiation from the naive b cell to antibody producing plasma cell, b cells go from producing only membrane bound form to only producing secretory form
how does the b cell immune response work
b cells require help from t cells to respond to most antigens
b and t recognise the same antigens:
- b cells bind through viral protein coat
- viral particle is internalised and degraded
- peptides from internal protein of the virus are presented to the t cell which activates the b cell
- activated b cells produce antibodies against viral protein coat
t cells provide help in 2 ways:
1. co-stimulatory signal through ligation of CD40 and CD40L
2. secretion of cytokines which aid the induction of isotype switching
how long are diseases present in primary and secondary responses
primary response - disease is still present after 10 days
secondary response no disease present after 4 days
Ig heavy chain locus in class switching
IgG, A and E isotypes are generated by irreversible change in DNA in a process known as isotype switching or class switching association of the Vh exon with different Ch genes keeps antigen specificity the same occurs throughout non homologous DNA recombination guided by stretches of repetitive dna called switch regions which are located upstream of Ch genes switch regions contain repeats of GAGCT and GGGGGT sequence
class switching from Igm (and IgD) to IgG1 expression
recombination to excise a previosly expressed c gene and juxtapose another on with the Vh
depends on the action of enzyme named ‘activation-induced cytidine deaminase’ (AID) which is only found in proliferating b cells
AID targets switch regions causing nicks in both DNA strands
nicks facilitate recombination between switching regions leading to excision of intervening DNA
what is the distribution of antibody classes throughout the body
IgG, A and M are predominant in circulation to protect internal tissues
dimeric IgA is predominant in secretion and protects mucosal surfaces
IgG and A (monomeric) are major isotypes in extracellular fluid
there are no Igs in the brain
IgE is found mainly in connective tissue beneath the skin, respiratory tracts and GI tracts - provides mechanism for rapid ejection of pathogens from a body
how do mothers provide protective antibodies to their young before and after birth
IgG from maternal circulation is transported across the placenta delivered directly into foetal circulation
at birth human babies have IgG levels as high as their mother
IgG has a wide range of antigen specificities
the IgG help protect the baby until the can make their own antibodies
after birth the GI tract of babies is protected by dimeric IgA in breast milk through passive transfer of Ig
in 1st year of life infants have a transient decrease in IgG levels - their own production of IgG doesnt begin until 6 months
how do high affinity neutralising antibodies prevent viruses infecting the host cell
adults with influenza virus IgA antibodies stop the virus from infecting cells
without anti-influenza antibodies, haemagglutinin on the viral cell surface binds to sialic acid on cell surface and is internalised into the endosome
viral lipid envelope fuses with the endosome membrane and viral RNA is released into the cytoplasm
how do neutralising antibodies prevent bacterial infections
antibodes prevent the attachment of bacteria to the tissue pharynx
if antibodies arent present, bacteria stay in the pharynx and multiply
antibodies prevent attachment to fibroconectin in the ECM
neutralisation of toxins
toxins bind to cellular receptors
toxin-receptor complexes are endocytosed
dissociation of the toxin to release the active chain poisoning the cell
OR
antibodies block binding of the toxin and protect the cell
IgG and A are efficient at binding soluble toxins preventing them from binding to cell surface receptors neutralising antibodies
how do antibodies have a dual function?
recognition function - binding antigens mediated by fab arms
effector function - clearance of mechanisms mediated by interaction of the fc region with effector molecules
IgG
most abundant in plasma
IgG1-4 differ in sequence of the heavy chain constant regions
only Ig to cross the pacenta
the predominant Ig of secondary response
IgG4 in humans undergo fab arm exchange
- exchange half molecules constantly
- in circulation they become functionally non-covalent
flexibility of IgG is crucial to function of binding simultaneously to pathogens, effector molecules and receptors of the immune system
IgM
only present in plasma secretions
5 monomer units joined by j chains and disulphide bridges, mu chain has an extra domain in place of a hinge
has 10 binding sites for antigens
predominant Ig in primary response
undergoes a conformational change on binding to antigenic surface - prevents inappropriate complement activation by free IgM
binding of IgM to antigen on pathogen surface activates complement in a classical way
activation of classical compliment pathways by IgG
requirement for interaction with 2 or more IgG molecules simultaneously prevents inappropriate compliment activation by free IgG
what is FcRn
a neonatal Fc receptor
structurally similar to MHC class 1
site that binds to IgG fc region predominantly formed by alpha 1 and alpha 2 domains
maintains high levels of IgGin extracellular fluids
selectively protects IgG from degradation that turns over other plasma proteins
IgG molecules have higher half life than most plasma proteins
FcRn is in part responsible for transport of IgG across placenta
it transports IgG from blood stream into extracellular spaces
the human FcyR
y chains posesses a signalling motif (ITAM)
itam - immunoreceptor tyrosine-based activation motif
human ig subclasses have differing abilities to bind to and trigger via FcyR
high affinity for IgG1 and IgG3
binds to lower hinge and Ch2 of IgG3§
Fc receptor mediated clearance
free ig does not cross-link fc receptors - so no activation of macrophage
aggregation of Ig on bacterial surface results in cross-linking of Fc receptors which triggers activation of macrophage leading to phagocytosis and destruction of bacterium
how does Fc receptor ligation enhance the efficiency of phagocytosis
antibody binds to bacterium
antibody coated bacterium binds to fc receptors on cell surface
macrophage membrane surrounds the bacterium
macrophage membranes fuse creating a membrane bound vesicle - the phagosome
lysosomes fuse with the phagosome creating the phagolysosome
Antibody dependant cell mediated cytotoxicity
antibody binds antigens on the surface of target cells
Fc receptors on NK cells recognise the antigen bound antibody
cross linking of fc receptors signal nk cell to kill the target cell
target cell dies by apoptosis
fc receptors enable haematopoietic cells to bind and be activated by IgG bound pathogens
IgD
found at very low serum concentrations and on surface of lymphocytes
function is unclear but may be involved in the control of antibody response
produced in the upper respiratory tract
binds to respiratory bacteria and their products
binds to a specific receptor on circulating basophils
