9: Immune receptors and Signal Transduction 2 Flashcards
what are BCRs
transmembrane form of an antibody
what antibodies are expressed by naive mature B cells
IgM and igD
how are antibodies other than IgM and IgD expressed on B cells
class switching or with memory cells
what are the signaling molecules for BCR
Iga and IgBeta
how are Ig a and IgB linked
disulfide bonds to each other and noncovalent with BCR
what makes Iga and IgB signaling molecules
have ITAMS in cytoplasmic tails
what is better about BCR compared to TCR
has two binding sites
co- receptors for B cells that associate with BCR complex
CD21, CD32, CD 19
which co receptors positively regulate B cell activation
CD21 and 19
What does CD 32 do for B cell activation
has an ITIM for negative regulation of BCR
how do the coreceptors link for BCR
to antibody Fc portion or through complement
Another name for CD 32
FcyRII
signal one for BCR complex
Ag to Ig receptor
signal 2 for BCR
CD 19, 21, 32 for signal 2 and signal transduction
what initiates B cell signaling and what does it cause
BCR- Iga/B complex with phosphorylation of ITAMS
what happens after ITAM phosphorylation in BCR
activation kinases and phosphatases
what controls the cascade of signals from B cell activation
co-receptors
what is the role of second messengers in BCR
activate TFs for effector function
what is effector function of BCR
Ab production
TcFs change B cells from
naive to mature/ active cells
what is activated by Ag binding to a BCR complex
Src-Syk activation
how must ag bind to BCR complex
As cross linked dimers
what is activated by 2 Src- 1 syk activation
PLCy and RAS/ RAC GTP
what transcription factors are activated as a result of BCR activation
NFAT, NF-kB and AP1
what do activated PLCy and RAS turn on in B cell activation
genes for Cell growth, differentiation and survival
what activates Syk in BCR
SRC phosphorylates ITAM of Iga and Ig B that allows SYK activation with SH2 domains
What is activiated by Syk specificaly
PLCy that in turn activates Grb2/SOS thorugh SLP 65
NFAT means
nuclear factor activate T cells
what are examples of Src kinases
Lyn, Fyn, and Blk
what connects Src kinases to plasma membrane
lipid anchors
where do cross liked BCRS go for adaptors and signaling molecules
lipid rafts
what type of domains do Syk kinases have
SH2
what activates Syk tyrosine kinases
Src kinases
what is activated by Syk
BLNK and other adaptor proteins
besides RAS, RAC and PLCy, what else is activated by SYK
BTK, bruton tyrosine kinases.
what pathways do BRC activate
Ras-MAP, PLC and PKC-B
what does IP3 bind to release Ca2+ from ER
IP3R receptor
PLCy activated by Syk leads to
PIP2 hydrolyzed into DAG and IP3
DAG leads to
PKC activation for RAS-MAP resulting in AP-1 and NF-kB
what happens after Ca2+ reaches the level it needs
activates calmodulin-calcineurin pathways
what does calmodulin-calcineurin activate
NFAT
how do TCR and BCR compare
same end result but different starts
what is needed for B cell activation of complement
a complex of CR2, CD 19, and CD 81
what part of complement binds and how
C3d bound to bacteria binds CR2 while the bacteria binds IgM with an antigen
what does the combo of BCR and CR2 complex lead to
enhance B cell activation
what is another name for CR2
CD 21
complement activation is part of what type of immunity
innate immunity
how does C3d become involved with the BCR complex
C3 is cleaved by C3b that binds the microbe then degrades into C3d that remains bound to microbe
BCR recognizes what part of the microbe
Ag
what part of the microbe does CR2 recognize
C3d
what makes up the B cell co-receptor complex
CR2-CD19- CD 81
what does the binding of Cr2 and C3d cause
CD 19 gets moved close to BCR associated kinases
what do BCR kinases do to CD19
phosphorylate the tyrosines
why are do the tails of CD 19 need to be phosphorylated in BCR activation
recruits lyn to amplify BCR so ITAMS of Iga and IgB can be phosphorylated
what does phosphorylated CD 19 activate
Pi3 kinase
what does PI3 kinase do
activates Btk and PLCy for greater activation of B cells
what is important for the immune system to work properly
balance between stimulatory and inhibitory signals
why is B cell activation so tightly controlled
avoid collateral damage in host tissue
what happens without inhibition
uncontrolled inflammation and lymphoproliferation that could lead to self antigens
what runs the inhibitory signaling of lymphocytes
inhibitory receptors and E3 ubiquitin ligases
what is the role of inhibitory receptors
recruit and activate phosphatases to counter kinases from Ag receptors
what are immune cells that have the biggest need for inhibition
NK cells, T cells and B cells
what are the parts of inhibitory receptor
ligand binding and ITIM on cytosolic tail
what happens when ligands bind inhibitory receptor
ITIM phosphorylated by SRC kinases
what does this phosphorylation of ITIMS result in
SH2 domains with tyrosine phosphatase bind for activation and lead to the dephosphorylation of substrates.
key B cell inhibitory receptors
FcyRIIB and CD 22
what does FcyRIIB cause
attenuation of signaling in activated B cells, DCs and macrophages
what is CD 22 an inhibitor for
B cells only.
two common phosphatases recruited by pITIMs
SHP and SHIP
what is SHP
SH2 domain containing phosphatases
what is SHIP
SH2 domain containingh inositol phosphatases
what is one of the main molecules that SHP and SHIP work on
PIP3 to inhibit PI3 kinase activity
what types of cells does PI3 kinase work with
lymphocytes, NK, and innate immune cells
what is ubiquitin
protein that is transferred to lysine residues based on E3 u ligases
how does ubiquination usually happen
poly ubiquitin chain by multiple ubiquitins
what is important for a ubiquitin chain
the shape and depends on which lysine residue was targeted.
what does lysine 48 ubiquitin chain lead to
proteasome degradation
lysine 63 leads to
no degradation
what is E3 ubiquitin ligases important for
non-canonical NF-kB signaling.
what leads to production of T reg cells
IL2 and TGFB
what leads to TH17
IL6 and TGF B
what leads to TH2
IL4
what leads to TFH cell production
IL6, IL 21, TH1, TH2, TH17
what leads to T H1 cell prodution
IL12, IFNy
what is the effector mediators for T reg cells
IL 10
what does IL 10 cause
regulation and suppression of inflammatory response
what results from Th17 cells
IL 17 A, F, and IL22
what are IL 17 A, 17 F, and IL22 for
inflammation
what do TH2 cells lead to
IL 4, 5, 13
what is the role of Il 4,5, 13
allergic and helminth response
What is produced by TFH cells
IL 4 and 21
what is the role of IL4 and 21
Germinal centre help
what is produced by TH1
IFNy and TNF
what are IFN and TNF responsible for
macrophage activation and inflammation
what cytokines lead to class switching to IgG
IFNy
what Cytokine leads to IgE
IL4
what leads to IgA
cytokines produced in mucous tissue such as TGF B and Baff
what is IgM for
compliment activatioin
what is IG 1 and 3 for
Fc receptor dependent phagocytes, compliment and neonatal placental transfer immunity
what is Ig E for
helminth immunity or allergies, Mast Cell degradation for hypersensitivity
what is IgA for
mucosal immunity
what is the structure of cytokine receptors
transmembrane proteins with EC domain for cytokine binding and tail for signaling
what activates signaling pathways for cytokine receptors
ligand- induced receptor clustering
what does cytokine binding and clustering activate
non-receptor tyrosine kinases
what is the classification of cytokine receptors based on
structural homologies, cytokine binding and shared intracellular signaling domains
how many classes of cytokine receptors are there
5
what are the 5 classes of cytokine receptors
Type I, Type II, Chemokine, TNF, IL1
what is different about chemokine receptors compared to others
has more than a single pass transmembrane protein
example of type I cytokine receptor
Jak STAT
ligands for type 1
IL 2, 3, 4, 5, 6, 7, 9, 11, 12, 13,15, 21, 23, GMCSF, G CSF
ligand of type 2
IFN a/b/y, IL 10 and 22
ligands for TNF
TNF a, B, LT, CD 40, FasL, BAFF, April, Ox40, GITR, nerve growth factor
ligand for IL1 receptor
IL 1, 18, 33
describe a type 1 receptor
unique ligand binding chains, one or more signal tranducing chains shared by several receptors for different cytokines
subgroups of type I cytokines are due to
shared signaling domains
what are the key players in Type I and type II cytokine receptors
JAK STAT
what does STAT stand for
signal transducers and activators of Tc
what does JAK stand for
Janus Kinases
what is the role of JAK
phosphorylates tyrosines on STAT
what type of TF are STATs
latent TFS that translocate to nucleus to induce gene expression
structure of JAK and STAT pinding
homo or heterodimers
what is also activated for STAT
MAPK pathway
how are MAPK and STATs related
MAP K phosphorylates Serine residues in STAT 1 and 3 to enhance their Tc activity
another name for type II receptors
interferon receptors
structure of type II
one ligand binding chain and one signaling chain
what signaling is used by Type II
JAK-STAT alone or JAK STAT with Tyk-STAT
TNF receptor structure
trimer
what can TNF receptors cause
gene expression or apoptosis
most important TNF receptors
TNFR1, TNFRII, CD40, Fas, TNF-B receptor and BAFF receptor
ligands of TNF receptors are
formed in trimers and can be membrane bound or soluble
what can be activated by TNF receptors
NF-kB and MAP Kinase or apoptosis
what is BAFF
B cell activating factor
TNF receptor bound by ligand leads to
TRADD adaptor protein binding to activate TRAF, E3, and RIP1 kinase
What MAP kinase pathway is activated by TRAF
JNK to FOS for AP1
what is activated by TRAF for apoptosis
Caspase 8
Another name for TNF receptors
CD 40
structure of IL1 receptor family or TLRs
conserved cytosolic sequence with TIR domain
TIR means
Toll-like/ IL 1 receptor domain
what happens when TLRs are active
receptor dimerization or recruitment of one or more of 4 adaptor proteins to TIR
What to TIR adaptors do
Link the TLR to IRAK
IRAK means
IL-1R associated kinases
what does IRAK do w/ TLR
links adaptors to TRAF6
what is TRAF6
E3 ligase needed for NF-kB activation
what is also signaled by TLRs
MAP kinase activation, phosphorylation of IRF3 aand 7
IRF3 means
interferon regulatory factor
what do IRF 3 and 7 do
induce type I interferon Tc
what happens when chemokines bind their receptor
adhesion, migration, chemotaxis, change shape, reorganize cytoskeleton, up regulate integrin expression, integrin activation
what is usually used with chemokine receptors
GPCR for G protein activation as chemoattractant
what is activated by GPCR in chemokine signaling
Ras and PLCy
what does RAS lead to
Protein K B
what does PLCy lead to
PKC
what is inhibited by GPCR
cAMP concentration and production
What inhibits adenylyl cyclase for reduced cAMP by GPCR
alpha subunit
what activates RAS and PLCy
By complex
