Immune Receptors And Signal Transduction II Flashcards
(111 cards)
1
Q
What are Ig alpha and Ig beta?
A
They are signaling molecules for the BCR and are also required for assembly and expression of the Ig receptor.
2
Q
What co-receptors associate with the BCR complex, especially when both the BCR and one or more of the co-receptors arelinked through an antigen complement or antibody complex?
A
CD21, CD32 and CD19
3
Q
What provides signal 1 (ag-receptor)?
A
Binding of the lymphocyte to an Ag via a receptor.
4
Q
What are requird for cell-cell interaction and the signal transduction events lading to the generation of signal 2?
A
Costimulatory molecules
5
Q
What is B cell signaling initiated through?
A
The BCR-Ig alpha/Ig beta complex.
It results in phosphorylation of tyrosine motifs (ITAMS)
6
Q
What is the signaling cascade modulated by?
A
Signals from co-receptors.
7
Q
In BRC signaling, second messengers are responsible for what?
A
The activation of transcription factors, followed by activation of the effector function.
8
Q
What are the regulatory molecules of a B cell?
A
CD19, 22, 29, 40, 80, 86
9
Q
What does the B cell receptor complex consist of?
A
It consists of the Ag receptor in association with Ig alpha and Ig beta.
10
Q
True or false: the BCR is a transmembrane form of an Ab molecule
A
True
11
Q
What do naive mature B cells express on their surface?
A
IgM and IgD
12
Q
What Igs do class-switchd B cells and memory B cells express?
A
IgG, IgA or IgE classes
13
Q
What is the BCR associated with?
A
Invariant signaling Ig alpha and Ig beta molecules
14
Q
How are Igs linked to one another.
A
Through disulfide bonds.
They are non-covalently associated with the BCR.
15
Q
What is found in the cytoplasmic tails of Ig alpha and Ig beta?
A
ITAMs.
ITAMs mediate signaling functions.
16
Q
What does Src-Syk activation lead to?
A
The activation of PLC gamma and Ras and Rac small GTPase, which are followed by the activation of several transcription factors:
NFAT
NF-KB
AP-1
17
Q
What occurs when PLC gamma and Ras are activated?
A
They turn on genes involved in cell growth, differentiation and survival.
18
Q
Signal initiation by Ag occurs how?
A
By cross linking of the BCR. This is facilitated by the coreceptor for the BCR.
19
Q
In BCR signaling, what does Ag binding facilitate?
A
It facilitates a conformational change in BCR-associated ITAMs, making them accessible to Src kinases such as Lyn, Fyn and Blk which are linked by lipid anchors to the inside of the plasma membrane.
20
Q
What do activated Src kinases phosphorylate?
A
The ITAMs of Ig alpha and Ig beta.
21
Q
What occurs at lipid rafts of cross-linked BCRs?
A
Where many adaptors and signaling molecules are concentrated.
22
Q
What do phosphoryylated ITAMs of Ig alpha and beta provide a docking site for?
A
The tandem SH2 domains of Syk tyrosine kinase.
23
Q
What is Syk kinase activated by?
A
Lyn, fyn and Blk kinases
24
Q
What does activated Syk phosphorylate?
A
Tyrosine residus on BLNK and other adaptor proteins.
25
Once activated Syk phosphorylates tyrosine residues on BLNK, what do recruited enzymes do?
They activate Ras and Rac, PLC gamma 2, and the Btk.
26
In the Syk pathay, what does the recruitment of enzymes result in?
The activation of downstream effectors, each generally contributing to the activation of distinct signaling pathways:
Ras-MAP kinase pathway
PLC pathway
PKC-beta pathway
27
What is the pathway downstream of the BCR identical to?
It is identical to the downstream pathway of T cell activation.
28
What is the result of the Ras MAP kinase activation?
The phosphorylation of various transcriptional factors and regulators culminating in changes in gene transcription.
29
What are the steps of the Ras MAP kinase activation?
GTP/GDP is recruited to BLNK
An inactive GDP bound Ras is the convertedby SOS from an active GTP-Ras
Once activated, GTP-Ras activates an enzymatic cascade of MAP kinases.
This results in the phosphorylation of various transcriptional factors.
30
What does Ag recognition by the BCR activate?
Different protein kinases, such as Lyn, BLNK and Syk, which activate PLC gamma 2
31
What is the function of PLC gamma 2?
It hydrolyzes membrane bound PIP2 into small amounts of DAG and IP3.
32
What is the function of IP3?
It binds to its receptor IP3R located in the ER membrane and allows the release of stored calcium.
33
IP3 allows the release of stored calcium. To facilitate the extension of cellular responses, what other route of entry of calcium?
CRAC
34
What is the function of DAG?
It activates protein kinase C and the Ras-MAP kinases, which ultimately activate transcription factors AP-1 and NF-KB.
35
Once the increase in intracytoplasmic Ca levels is achieved, what pathway is activated?
The calmodulin-calcineurin pathway, with the final activation of NFAT
36
What do B cells express?
CR2, CD19 and CD81
37
What is the function of microbial Ags opsonized by C3d?
They can simultaneously engage both the CR2 molecule and BCR
38
What is the result of the signaling cascades from the BCR complex and the CR2 complex?
They greatly enhance B cell activation as compared with the response to Ag alone.
39
What does CR2/CD21 complement coreceptor enhance the activation of?
B cells
40
What results from the cleavage of C3?
It results in the production of C3b that binds covalently to the microbe or Ag-Ab complex.
41
What is the receptor that B cells express for C3d?
CR2 or CD21.
42
What does the complex of C3d and Ag bind to?
B cells, with the BCR recognizing Ag and CR2 recognizing the micro-bound C3d.
43
What two membrane proteins is CR2 expressed on mature B cells?
CD19
CD81
44
What is the CR2-CD19-CD81 complex often called?
The B cell coreceptor complex because CR2 binds to Ags through attached C3d at the same time that BCR binds directly to the Ag.
45
What does C3d-CR2 do?
It brings CD19 in proximitiy to BCR-associated kinases.
The CD19 cytoplasmic tail rapidly becomes tyrosine phosphorylated.
It follows the efficient recruitment of Lyn kinase that amplifies BCR signaling by greatly enhancing the phosphorylation of ITAM tyrosine in Ig alpha and Ig beta.
46
What does phosphorylated CD10 also activate?
PI3 kinase, which in turn further augments signaling initiated by Ag binding to BCR.
47
What does PI3 kinase activate?
Btk and PLC gamma 2 on the inner leaflet of the plasma membrane.
48
What is the net result of coreceptor activation?
The rsponse of the Ag-stimulated B cell is greatly enhanced.
49
How are the functional responses of all cells regulated?
By a balance between stimulatory and inhibitory signals.
50
Why is B cell activation tightly controlled?
To limit immune responses against microbes in order to avoid collateral damage to host tissues.
51
Why is inhibition of signaling essential?
It is essential to prevent uncontrolled inflammation and lymphoproliferation.
52
What is inhibitory signaling in lymphocytes mediated by?
Inhibitory receptors and also by enzyms know as E3 ubiquitin ligases.
53
What do inhibitory receptors typcially recruit and activate?
Phosphatases.
They counter signaling events induced by Ag receptors.
54
What do inhibitory receptors play a key role in?
NK cells, T cells and B cells as well as other cells of innate immunity.
55
What does an inhibitory receptor contain?
An extracellular binding domain and a cytosolic ITIM motif.
Ligand binding results in phosphorylation of the ITIM tyrosin by a Src family kinase.
56
What to p-ITMs recruit?
An SH2 somdain containing tyrosine phosphatase that can attenuate immune receptor signaling.
57
What are the key inhibitory receptors in B cells?
Fc gamma RIIB and CD22.
FC gamma RIIB is an important attenuator of signaling in activated B cells and, DCs and macrophages.
CD22 is an inhibitor receptor on B cells only.
58
What are ITIMS of inhibitory receptors phosphorylated by?
Src family kinases linked to lymphocyte activation.
59
What to p-ITMs recruit?
SH2 domain-containing tyrosine phosphatases such as SHP and SHIP.
60
What are the functions of SHP and SHIP?
They remove phosphates from PIP3 and inhibits PI3 kinase activity in lymphocyts, NK cells and inante immune cells.
61
What is ubuquitin?
A protein that is transferred to lysine residues on specific substrates that are recognized by E3 ubiquitin logases.
62
What can a polyubiquitin chain be generated by?
Attachment of other ubiquitin molecules.
63
What is the shape of ubiquitin chain dependent on?
It is dependent on which lysine residue on the preceding ubiquitin molecule in the chain is used.
If lysine in position 48 of the first ubiquitin is used, a lysine-48 type ubiquitin chain will be generated and protein will be targeted for proteasome degrdation.
64
Are lysine-63 type ubiquitin chain targeted for degrdation?
No
65
What is the ubiquitin ligase pathway important for?
NF-KB signaling.
66
What are features of the canonical pathway?
It is rapid and transient
Independent of protein synthesis
Responds to numerous stimuli
Has diverse functions
67
What are features of the non-canonical NF-KB signaling pathways?
Slow and persistent
Dependent on protein synthesis
Responds to a subset of TNFR signals
Specific functions
68
What are functions of the canonical pathway?
Inflammation
Survival
Proliferation
69
What are propertieies of the noncanonical pathway?
Chemokines
Lymphoid stroma
Survival
70
What are processes that the NF-KB family participates in?
The immune response and inflammation.
71
What is the NF_KB family composed of?
ReIA, ReIB, c-Rel, NF-KB1, NF-KB2
72
What are the NF-KB proteins normally sequestered in the cytoplasm by?
IK-B alpha.
It is triggered by signals mediated by innate and adaptive immune receptors.
It involves the actiation of IKK, IKB alpha phosphorylation and subsequent degradation.
It results in rapid and transient nuclear translocation of the prototypical NF-KB heterodimer ReIA/p50
73
What does the non-canonical pathway rely on?
Phosphorylation-induced p100 processing, which is triggered by sinaling via CD40-CD40L and a subset of TNF receptors.
74
What is the non-canonical pathway dependent on?
NIK and IKK alpha.
It mediates the persistent activation of ReIB/P52 complex.
75
NF-KB1 and NF-KB2 are traslate as precuros proteins p105 and p100. What are features of these precursor proteins?
They contain an IKB-like C terminal portion and function as NF-KB inhibitors.
76
What occurs with proteasome-mediated processing of p105 and p100?
It results in a disruption of the IKB-like funciton of these precursor proteins and producs the mature NF-KB1 and NFKB2 proteins.
77
What is the function of IgM?
Complement activation
78
What is the function of IgG?
Fc-receptor dependent phagocyte responses
Complement activation
Neonatal immunity
79
What are the functions of IgE?
Immunity against helminths
Mast cell degranulation (immediate hypersensitivity)
80
What is the function of IgA?
Mucosal immunity (transport of IgA through epithelia)
81
What do cytokine receptors consist of?
Transmembrane proteins.
The extracellular domains are responsible for cytokine binding whereas cytoplasmic tails are responsible for initiatio of intracellular signaling.
82
What activates the cytokine signaling pathways?
Ligand-induced receptor clustering.
Cytokine binding and clustering activates unique non-receptor tyrosine kinases.
83
What is the classification of cytokine receptors based on?
Structural homologies of the extracellular cytokine binding domains and is shared intracellular signaling mechanisms.
84
How many classs of cytokine receptors are there?
5
85
What are receptors for different cyotkines classified into families on the basis of?
Conserved extracellular domain structures and signaling mechanisms.
86
What do type I cytokine receptors consist of?
Unique ligand binding chains and one or more singal transducing chains, which are often shared by several receptors for different cytokines.
87
What are type I cytokine receptors divided into subgroups based on?
Structural homologies or the use of shared signaling chains.
88
What are some examples of type I cytokine receptors?
IL-2, IL-4 and IL-15
89
What do the type I cytokine receptors engage?
The JAK-STAT signaling pathways.
90
What are key players in type I and II cytokine receptor signaling?
Transcription (STATs) and Janus kinases (JAKs).
91
What is the function of JAKs?
They phosphorylate tyrosineon STATs which are latent transcription factors.
92
Where do STATs translocate to?
The nucleus to induce the expression fo genes.
93
What phosphorylates serine residues of STAT1 and STAT3, subsequently enhancing their transcriptional activity?
MAPK pathways.
94
What is another term for type II cytokine receptors?
The interferon receptor pathway.
95
What do type II cytokine receptors consist of?
One ligand-binding polypeptide chain and one signal transducing chain.
96
What pathways do the type II cytokine receptors engag?
JAK-STAT or JAK STAT and Tyk-STAT pathways.
97
What are the cytokine receptors in the type II cytokine family?
IFN-alpha/B, IFN-gamma, IL-10, IL-20. IL-22
98
What are features of the TNF receptor family?
They have conserved cysteine-rich extracellular domains and shared intracellular signaling mechanisms that stimulate gene expression.
99
What may the signaling of some TNF receptors lead to?
Apoptosis
100
What are the most important TNF receptors?
TNFRI and TNFRII, CD40 protein, Fas, TNF-beta, and BAFF receptors.
The ligands for these receptors also form trimers.
101
What can the TNF receptor signaling pathway result in?
The NF-KB and MAP kinase activation of in the induction of apoptosis.
102
What does ligationof the TNF-RI result in?
The recruitment of an adaptor protein (TRADD), which can activate TRAF molecules and the RIP1 kinase.
103
What are downstream consequences of the TNF receptor signaling pathway?
The activation of the NF-KB pathway and the JNK MAP kinase pathway or the induction of apoptotic death.
104
What is conserved among the IL-1 receptor family?
TIR domain
105
What does the engagement of the IL-1R or TLRs result in?
Receptor dimerizatio and the recruitment of one or more of the four known TIR-domain-containing adaptors.
106
What is the function of the TIR domain-containing adaptors?
They adaptors link TLRs/IL-1R to different members of the IRAK family.
IRAKs linke adaptors to TRAF6, an E3 uniquitin ligase required for NF-KB activation.
107
What does IL-1R signaling also induce?
MAP kinase activation and the phosphorylation of IRF3 and IRF7, inducers of type I interferon transcription.
108
What are some of the things that binding of a chemokine to its receptor can induce?
Adhesion, migration, chemotxis, cellular shape change, reorganization of the actincytoskeleton, upregulation of integrin expression, integrin activation.
109
What does the alpha subunit of some adenylyl cylase lead to?
A decrease of intracellular cAMP levels and cAMP dependent protein kinase activity.
110
What does the beta-gamma complex activate?
Ras, which induces the activation of PI3K-gamma.
111
What does the beta-gamma complex activate?
Phospholipase C (PLC).
It hydrolizes IP2 to generate IP3. IP3 mobilizes calcium fro non-mitrochondrial stores.
DAG activates protein kinase C.
