LMP299Y1 Lecture Notes - Nf-Κb, B-Cell Activating Factor, B-Cell Receptor

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Published on 3 Jun 2013
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LMP430 January 23, 2013
Cellular and humoral immune responses
B cells
How BCR produced, how diversity of receptor generated by rearrangement
How isotype switching occurs in B cells
B cell receptor somatic hypermutation increases diversity important for affinity maturation that
occurs in germinal centre of lymph noid and lymphoid tissues
Ig gene rearrangements in B cells
VDJ segments rearrange at DNA level joined to various constant regions to RNA splicing, etc.
Most B cells are born expressing IgM and IgD through stimulation with antigen and T cell help, that
other isoforms are made, IgA, IgG, etc.
TCR gene rearranemgent similar to B cell
NO SOMATIC HYPERMUTATION
Once selected for receptor the only receptor ever expressed
Presumably less diversity
Ig various classes and subclasses different effector functions KNOW THIS
IgE involved in allergic reactions, type 1
IgA for gut immunity
IgG key Ig for many things
IgM is largest Ig very active in certain kinds of immune responses especially effective at activating
complment
All the effector functions of Ig depend on Fc segment bind to Fc receptors that activate and turn off
immune cell depending on which
IgG five units
IgA dimer
All others are monomers
Antigen stimulation thymus dependent and Independent antigens
Most antigens, espeiclaly protein, won’t crosslink B cell receptor very much – so weak
But endocytosed when binding to BCR B cell acts as APC interact with Thelper cell, activate
Some antigens with multiple repeating units indepentn antigens can cross link B cell receptor
extensively activate B cells without T cell help
Precursor of B cells in bone marrow mnmigrate to lymphoid tissues lymph nodes Peyer’s patches
and so on in the lymph nodes, there is B cell zone, the cortex, where B cell meets antigen and then
migrate to inside follicles where they interact with T cells with different shapes; knockout mice made, if
knock out NFkappa B signalling, events in the spleen cannot occur CD40 knockout, no B cell maturation
B cells differentiate into plasma cells almost all Ig secreted by plasma cells; many of them go back to
Bone marrow
B cells mostly in the cortical areas; T cells
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B cells migrate to germinal centre and they interact with T cells cooperation and interaction with T
cells
Plasma cells go to lymphatic go all over body
CD40 key molecule for STIMULATING cell
BAFF receptor TNF family member; in some diseases like lupus, a lot of autoantibody production, BAFF
over produced, B cells overstimulated, apply drug to block interaction
CD40 and BAFF turn on NF kappa B pathway critical for B cell activation, survival, proliferation, etc
BAFF and APRIL (a proliferation inducing ligand) members of TNF family produced by all sorts of cell
produced by macrophages fibroblasts many cell types can make them in the tissue interaction
between tissues and immune system
Bind to BAFF R TAC BCM HSPG TACI BCMA stimulatory to B cells
Role of cytokines produced by Th cells mostly
Most of them influence the Ig isoform made
In IgE mediated disease, IL4 important to stimulate IgE allergy
IFN gamma induce
TGF beta produced by many cell types all cells in body have receptors; in immune system, inhibitory
Increase IgA production
Cytokines key to determine type of humoral response
Pentameric IgM
IgG molecule can also activate complement
C1q bind to two IgG molecule complement cascade to be activated
Can bind to receptors effector mechanism
Fc receptors found on macrophages, dendritic cells, polymorphonuclear lymphocotes
Two functions
Most are activated activate Fc receptor positive cells, increase function can activate macrophages so
their killer function is improved
One receptor which is Fc gamma R two B is inhibitory ITIM motif in cytoplasmic portion and turns
immune cells off
B cells only express the inhibitory receptor
If knock off inhibitory receptor, get production of autoantibodies autoimmune disease
On the B cells multiple inhibitory receptors FcR2B inhibits when it is crosslinked to B cell receptor
somehow (perhaps part of immune complex) to turn off B cell; CD72 is inhibitory receptor; PRB also
These inhibotyr receptors found on immune cells important to regulate immune response to keep and
dampen to prevent unwanted immune responses
Simplified classification of hypersensitivity reactions
Hypersensitivity any kind of immune reaction with tissue injury
Classical IgE mediated hypersensitivity is one type of hypersensitivity called type ONE
Antibody can mediate disease types two and three
Type 2 are cytotoxic antibodies bind to antigens on cell membrane or tissue; could be anywhere;
activate effector mechanism like complement system, phagocytes, killer cells
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Type 3 antibodies bind soluble molecule form soluble complex but may then precipitate in tissues
and activate complement and other effector mechanism causing inflammation
Delayted type 4 everything that does not require antibodies
Type 2 hypersensitivity easiest type to understand antibodies produced against infectious agents
Autoantibody reacting to cell normally if it were a bacteria or something like that, antibodies could
activate complement bind to phagocytes and macrophages Fc receptor
Engulfed and killed phagocytosis
B complement
F c receptor polymorphs are highly phagocytic cells with Fc receptors
When complement system activated can punch hole in membrane through MAC complex
Some split products released attract neutrophils and activate them and get acute inflammation
Complement activation usually associated with acute inflammation can cause tissue injury if in excess
Antibodies can cause disease through other means can bind to receptors and block their action
In m gravis, antibodies against ach receptor block signal, cause weakness; stimulate _________,
second way to damage junction
Block receptor can be stimulatory so antibodies against Tsh receptor which stimulates tyroid cells
these antibodies can duplicate hormone action and cause hyperthyroidism
Stimulatory autoantibodies cause grave disease, thyroid toxic disease
Goodpasture’s syndrome – antibody produced against basement membrane
Basement membrane of glomeruli and in the lung
IF stain of conjugated antibody linear stain along the end if look at this with regular histology
polymorphs present can destroy destroy the glomerulus and cause acute kidney failure
Red blood cells prime targets fo various lymph antibodies
Red cells coated with antibody lysed by
Lysed by complement system hemolytic anemia
Type 3 hypersensitivity
Soluble antigen
If antibody excess, small conmplexes
Equivalence large complexes
Serum sickness example horse serum injected to treat toxins at antigen excess, acute lymphomatic
reactions in many tissues (ex glomerulus, blood vessels, lungs) will clear up, but damage to tissues may
be permanent
Deposition of immune complex SLE disease where circulating immune complexes and targets include
DNA and other nuclear antigen
Immune complexes resembling
Glomerlus of SLE patients activation of complement acute glomulero
One of the most common target is blood vessels, especially small ones
Where complex forms - deposit in wall of vessel activate mechanisms
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