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Basic Immunology- Module 1 > Generation of receptor diversity > Flashcards

Generation of receptor diversity Flashcards

1
Q

How are the variable regions for heavy and light chains in a mature B cell coded in DNA?

A

by a single exon-exon 2 but separated from each other within this coding sequence

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2
Q

What is exon 1 of the variable region?

A

antibody’s leader sequence

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3
Q

What is the function of hte antibody’s leader sequence?

A

directs the antibody into the ER for surface expression or secretion

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4
Q

What is the difference between the DNA sequence for the variable-region exon in immature vs mature B cells?

A

in immature- the exon is encoded by 2 separate DNA segments

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5
Q

How are hte separate DNA segments encoding the varibale region joined together?

A

spliced together during B cell development in the bone marrow

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6
Q

Which gene segment do CDR1 and CDR2 come from in the immature B cell

A

variable/V gene segment –also included beta sheets A-F

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7
Q

Which gene segment is CDR3 found in?

A

partly on V region and rest on J region–as well as beta sheet G

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8
Q

What is the exon encoding the complete variable region formed by the joining of the V and J segments in thel ight chain called ?

A

V-region gene

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9
Q

What is this rearranemgent of genes in a maturing B cell known as?

A

somatic DNA recombination

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10
Q

Why does the joining of the V and J segments in the developing B cell also bring hte V gene segment closer to the C segmen/t

A

J segment is located close to the C region

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11
Q

What separates the J gene segment from the C-region in the rearranged V region?

A

short intron

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12
Q

How many gene segments encode the V region in the heavy chain?

A

3

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13
Q

What is the additional gene segment encoding hte V region in the heavy chain?

A

diversity gene segment

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14
Q

Where is the location of the Dh gene segment in relation to the V and J segments of hte heavy chain?

A

foudn in between the Vh and Jh segments

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15
Q

What is hte process of recombination for a heavy chain?

A

2 stages: 1-D and J segments join; then V joins the DJ segment to complete the V region

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16
Q

How are the V regions and C regions joined up?

A

RNA splicing

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17
Q

What creates the great diversity of V regions in immunoglobulin?

A

there are multiple copies of the V, D and J segments which are combined randomly

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18
Q

What is a pseudogene?

A

gene segments which aren’t functional as have accumulated mutations

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19
Q

Why are there a large number of pseudogenes in hte V, D and J gene segments?

A

no single gene segment is essential

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20
Q

Which type of light chain has a greater number of unctional genes encoding the V segment?

A

kappa > lambda

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21
Q

What is the name for the immunoglobulin gene segement clusters?

A

genetic loci

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22
Q

Which chromosome is the labda light chain locus?

A

22

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23
Q

Which hcrosome is the kappar light chain locus found on?

A

2

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24
Q

How many constant regions does the kappa light chain have?

A

1

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25
Q

How many constant regions does the lambda chain ahve?

A

one for each joining region-4/5

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26
Q

Which chromosome contains the heavy chain locus?

A

14

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27
Q

Waht is the difference between the organisation of hte J segments in relation to the C regions between light and heavy chain?

A

in the heavy chain the C regions are all clustered together- each corresponding to a different immunoglobulin isotype

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28
Q

How does the expression of other isotypes aside from u and d take place?

A

thorugh DNA rearragments called class switching (after B cell activation)

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29
Q

what guides DNA rearragments?

A

conserved noncoding DNA sequences- recombination signal sequences

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30
Q

Where are the recombination signal sequences found in the chromosomes?

A

adjacent to the points at which recombination takes palce

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31
Q

What is the sequence of hte RSS?

A

heptamer- beside the coding sequnce; nonconserved region:spacer (12/23 base pairs); nonamer

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32
Q

What is the 12/23 rule?

A

a gene segment flanked by an RSS with a 12-bp spacer can only be joined to one flanked by a 23-bp spacer

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33
Q

What is the function of hte 12/23 rule?

A

prevents the wrong segments joining- in the heavy chain as V always has 23-bp so does J, which prevents them joining directly, however D has 12 on both sides

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34
Q

What encodes CDR3 in the heavy chain?

A

V, D, J segments

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35
Q

What is an exception to the 12/23 rule?

A

D-D joining can occur before joining to the J segment which gives greater diversity to the CDR3- accoutns for hte unusuaully long CDR3 loops in some heavy chains

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36
Q

How are sequences recombined by the RSS in 2 segments in the same transcriptional orientation?

A

looping out of the intervening DNA

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37
Q

How are sequences joined by recombination when they are not in the same transcriptional direction?

A

coiled configuration, inverting one of the segments and joined from there

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38
Q

What is hte signal joint?

A

the head-to-head ends of the heptamer sequences in the RSS where recombination occurs

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39
Q

how are the V regions connected with both m and d C regions in the immature B cell?

A

both C regions are transcribed in the priamry RNA transcripted which produces 2 different mRNAs through alternative RNA splicing

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40
Q

What enzyme catalyses the joining process?

A

RAG enzyme complex / V(D)J recombinase

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41
Q

what happens to the signal join when the joining segments are the same orientation?

A

contained in a circular piece of extrachromosomal DNA which is lost from the genome when the cell divides

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42
Q

What is junctional diversity?

A

as the coding joint junction is imprecise- nucleotides can be added or lost during rearrrangement process–increases varibility of the V region

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43
Q

What are the recomination activating genes responsible fro the VDJ recombinase in lymphoids?

A

RAG1 and RAG2

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44
Q

What pathway are the otehr proteins in the recombinase complex invovled in?

A

nonhomoloud end joining pathway of DNA repair: double-strand break repair

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45
Q

What is the function of double-strand break repair?

A

rejoining two ends at the site of a double-strand break in DNA

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46
Q

What is responsible for recognising and aligning the 2 RSSs that are the target of hte cleavage reaction?

A

a complex of RAG-1; RAG-2 and high mobility group chromatin protein- HMGB1/2

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47
Q

Which RAG specifically recognises the haptamer and nonamer of the RSS and conatins the endonuclease activity of the RAG compelx?

A

RAG-1

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48
Q

What is the endonuclease actvitiy of RAG-1 dependent on?

A

zinc

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49
Q

How si the double-stranded DNA break achieved?

A

RAG complex makes a single-strand DNA break at the join between the hepatmer and coding sequence creating a free -OH group at the end of the coding segment which joins to the phosphodiester bond on the opp strand of DNA, joining up and creating a DNA hairpin at the coding region

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50
Q

What is the break on the heptamer sequence called?

A

flush double-strand break

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51
Q

How are the blunt ends of the heptamer squence joined?

A

precisly bt a complex of DNA ligase IV and XRCC4

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52
Q

What binds to the 2 coding hairpin ends?

A

Ku

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53
Q

What subunit does Ku recruit?

A

DNA-PKcs

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54
Q

What protein is then recruited to the Ku:DNA-Pkcs complex?

A

artermis

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55
Q

What does DNA-PKcs do to the artermis subunit?

A

phosphorylates it

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56
Q

What is the function of artermis?

A

once phosphorylatedm opens the DNA hairpins by making a single-strand nick in the DNA

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57
Q

What is the significant about the nicking by artemis?

A

can occur at various points along hte hairpin- leads to sequnce variability in the final joint

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58
Q

What is the function of terminal doxynucleotidyl transferase?

A

adds nucleotides randomly to the single strand ends whilst DNA repair enzymes remove nueleotides from the sequence

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59
Q

What joins the processed ends of the coding region together?

A

DNA ligase IV

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60
Q

What is combinatorial diversity?

A

differnet combinations of gene segments; many differen combinations of heavy and light chain V regions taht pair to form the whole antigen-binding site

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61
Q

What is junctional diversity?

A

addition and subtraction of nucleotides by the recombination process

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62
Q

Why are some V gene segments seen more commonly in antibodies than others?

A

related to their rpoximity with intergenic control regions which activate recombination

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63
Q

What happens to immature B cells that express a receptor that binds to self-antigens?

A

will be marked for receptor editing

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64
Q

What happens if there is receptor editing?

A

there is further rearragngement and replacement of hte IgL-chain genes until non-self receptors are produced or the cell dies

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65
Q

Which chain is the equivalent of the light chain in TCRs?

A

alpha

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66
Q

What is affinity maturation?

A

the process by which B cells produce antibodies with increased affinity for antigen

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67
Q

Where does affinity maturation take place?

A

germinal centres of secondary lymphoid organs

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68
Q

What are the 2 processes involved in affinity maturation?

A

somatic hypermutation; clonal selection

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69
Q

What is clonal selection?

A

B cells that have undergone soamtic hypermutation compete for antigen and the B cell progeny with the highest affinity for antigen are selected for survival

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70
Q

What type of B cell is formed after specific antigen recognition and costimulation?

A

centroblast

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71
Q

What enzyme is inovlved in somatic hypermuation?

A

activation-induced cytidine deaminase

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72
Q

Which cells express activation-induced cytidine deaminase?

A

GC-activated B cells

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73
Q

What is hte function of light chain C regions?

A

structural attachment

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74
Q

What is the process by which naive B cells generate both membrane bound and secreted Ig?

A

alternative mRNA splicing

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75
Q

How are the subtypes of IgG named?

A

by decreasing order of their abundance in serum

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76
Q

Why is IgM not really found in tissues?

A

pentamer- high molecular weight

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77
Q

What are the functions of the Fc region?

A

Fc-receptor binding; complement activation; regulation of secretion

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78
Q

What antibodies bind to the FCy receptors?

A

IgG1 and

IgG3

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79
Q

What cells express Fcy?

A

macrophages and neutrophils

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80
Q

What is the cloest C gene to the Vh region?

A

m

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81
Q

What happens to mice lacking Cd exons?

A

delay in the process of afinity maturation

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82
Q

What must occur after RNA splicing to produce a mature IgM or igD antibody>

A

polyadenylation

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83
Q

What regulates the coexpression of IgD and IgM?

A

RNA processing

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84
Q

What is teh structureo f all membrane bound immunoglobulins?

A

monomers with 2 heavy chains and 2 light chains

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85
Q

What occurs in the dark zone of germinal centres?

A

B cells proliferate extensively and undergo SHM

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86
Q

What occursi n the light zone of germinal centres?

A

B cells are selected on their affinity for the antigen

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87
Q

What is not expressed on follicular dendritic cells that is expressed on other DCs?

A

MHC-II

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88
Q

What is the function of follicular dendritic cells?

A

trap and retain unprocessed antigen in the form of immune complexes, holding antigen for long periods of time

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89
Q

What receptors do follicular DCs use to trap and retain immune complexes?

A

CD32, CD23, CR1, CR2 and CR3

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90
Q

What is the function of follicular dendritic cells?

A

selection of high affinity of B cell clones and generation/maintenance of immunologic memory

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91
Q

What is somatic hypermutation also known as?

A

cyclic re-entry model

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92
Q

What are the 2 functions that the BCR plays?

A

initiates a signalling casacde upon binding antigens; delivers antigen to intracellular sites for antigen processing

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93
Q

What pathway does CD40 signalling in B cell activation activate?

A

non-canonical NFkB pathway

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94
Q

What is the function of the non-canonical NFkB pathway?

A

enhance B-cell survival by inducing the expression of anti-apoptotic moelcules e.g Bcl-2

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95
Q

What is the function of IL-21 released by Tfh cells?

A

activates STAT3 and enhances cellular proliferation and differentiation into plasma cells nad memory cells

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96
Q

How is IL-4 production by Tfh cells different tothe production by Th2 cells?

A

does not rely upon transcription factors GATA-3 and STAT6

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97
Q

What are antigens called which can induce antibody production in the absence of helper T cells?

A

thymus-independent antigens

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98
Q

What proteins make up the B-cell co-receptor complex?

A

CD21, CD19 and CD81

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99
Q

What complement fragments does CD21 bind?

A

C3d and C3dg

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100
Q

What happens when CD21 is bound?

A

brought near to the activated Bcr

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101
Q

What happens to CD19 when CD21 moves near to the BCR?

A

it is phosphorylated by teh activated BCR

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102
Q

What protein does the phosphorylation of CD19 recruit?

A

PI 3-kinase

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103
Q

What is the function of PI 3-kinase?

A

enhances proliferation, differentiation and antibody production

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104
Q

What is linked recognition?

A

T cells involved are activated by the same antigen recognised by the B cells

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105
Q

What are haptens?

A

small chemical groups that cannot elicit antibody response on their own

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106
Q

What is one of the functions of linked tolerance?

A

preserve self-tolerance as autoreactive antibodies will occur only if sel-reactive Tfh and B cells are present at the same time

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107
Q

What do naive B and T cells express that they use to exit from peripheral lymphoid tissues?

A

sphingosine 1-phosphate receptor (S1PR1)

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108
Q

What zone do naive B cells reside in in peripheral lymphoid tissues?

A

primary lymphoid follicles

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109
Q

How are the zones that B and T cells reside in established in peripheral lymphoid tissues?

A

different patterns of chemokine receptor expression and chemokine production

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110
Q

What chemokine receptor do naive T cells express?

A

CCR7

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111
Q

What ligands do stromal cells and dendritic cells in T-cell areas express?

A

CCL19 and CCL21

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112
Q

What chemokine receptor do naive B cells express?

A

CXCR5

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113
Q

What chemokine is expressed in the primary lymphoid follcile?

A

CXCL13

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114
Q

What cytokine do naive B cells encounter in the follicle that acts as a survival factor?

A

BAFF of the TNF family and APRIL

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115
Q

What cells secrete BAFF?

A

FDCs; stromal cells; dendritic cells

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116
Q

Why are opsonised antigens bearing C3b or C3dg accumulated in B cell follicles?

A

trapped by complement receptors CR1 and CR2 expressed on the surface of FDCs

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117
Q

What is the origin of FDcs?

A

nonhaematopoietic

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118
Q

What else can happen to opsonised particulate antigens in the peripheral lymphoid orgnas?

A

taken up by specialised macrophages in the subcapsular sinus of lymph nodes and the marginal sinus of the spleen

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119
Q

What is the function of marginal zone B cells?

A

shuttle between the marginal sinus of the spleen and the follicle, carrying antigen trapped in the marginal zone by macrophages for deposition on FDCs

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120
Q

What is another function of macrophages in the subcapsular sinus of lymph nodes?

A

restrict the dissemination of infection

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121
Q

Where do B cells go once it has encountered a specific antigen?

A

follicular and interfollicular areas

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122
Q

What chemokine receptor facilitates B cell movement to follicular and interfollicular regions?

A

EBI2

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123
Q

What chemokine receptor is expressed on B cells that causes migration of B cells along the interface netween the B cell follicle and T cell zone

A

CCr7

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124
Q

What is the ligand of CCr7?

A

CCL21

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125
Q

What do T cells express which causes movement to the border of the B cell follicle?

A

CXCR5

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126
Q

What is the function of both B and T cells moving to the borde between their regions?

A

increases the chance of recognising linked antigens

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127
Q

What adhesion molecules are involved in prolonging and stabilising cell-cell contact between Tfh and B cells?

A

SLAM; CD84; Ly108

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128
Q

What adaptor protein is required for mediating hte adhesion bewteen the adhesion receptors on Tfh and B cells?

A

SAP

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129
Q

What is found on activated B cells which helps Tfh cells complete differentation?

A

ICOSL

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130
Q

What transcription factors does ICOS signalling induce?

A

Bcl-6 and c-Maf

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131
Q

What is function of Bcl-6 and c-Maf?

A

needed for SAP production adn sustained contact between B and Tfh cells

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132
Q

What does decreased expression of CCR7 and increased expression of EBI2 cause in the activated B cell?

A

to move away from the boudnary with the T cell zone- in lymph nodes (interfollicular regions and subcapsular sinus); in spleen (splenic bridging channels )

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133
Q

Where are the splenic bridging channels?

A

region between the T cell rea and the red pulp

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134
Q

What is the primary focus?

A

aggregate of differentiating B cells

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135
Q

Where is the primary focus in the lymph nodes?

A

medullary cords

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136
Q

Where is the primary focus in the spleen?

A

extrafollicular foci in the splenic red pulp

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137
Q

What may some of hte proliferating B cells in the primary focus differentiate into?

A

antibody-synthesising plasmablasts

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138
Q

What happens to the B cells which do not move into the primary focus?

A

move into lymphoid follicle where they may eventually differentiate into plasma cells

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139
Q

What are plasmablasts?

A

cells that have begun to secrete antibody but are still dividing and express many of the characteristics of activated B cels that allow their interaction with T cells

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140
Q

What signals are important for plasma cell differentiation and survivla?

A

IL6 and CD40L

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141
Q

What do the B cells that have not formed the primary focus do?

A

into the parimary lymphoid follicle with their associated Tfh cell to form a germinal centre

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142
Q

What are follciles with germinal centres called?

A

secondary lymphoid follicles

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143
Q

Downregulation of what protein favours germinal centre formation?

A

EBI2

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144
Q

What is the germinal centre?

A

area of active cell division that forms within a surrounding region of resting B cells in the praimry follicle

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145
Q

What is the mantle zone?

A

the germinal center displaces the resting B cells towards the preiphery of the follicle-mantle zone

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146
Q

What isotype of antibody do plasmablasts secrete?

A

IgM

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147
Q

What are the rapidly proliferating B ells foudn in the dark zone called?

A

centroblasts

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148
Q

which chemokine receptors do centroblasts express?

A

CXCR4 and CXCR5

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149
Q

What ligand do stromal cells in the dark zone produce to train centroblasts in this region?

A

CXCL12

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150
Q

What is CXCL12 a ligand for?

A

CXCR4

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151
Q

What are centrocytes?

A

B cells which have reduced their rate of cell division; entered the growth phase, reduced CXCR4 expression and produce higher levels of surface Ig

152
Q

What do the abundant FDCs in the light zone express?

A

CXCL13 which is a ligand for CXCR5

153
Q

What is cyclic re-entry?

A

the process by which B cells can lose and gain expression of CXCR4 and move from the light zone to the dark zone and back again

154
Q

What separates the follicles in lymphoid tissues?

A

T cell zones

155
Q

Where does somatic hypermutation take place?

A

in the dark zone of the germinal centres

156
Q

What are tingible body macrophages?

A

macrophages that engulf apoptotic B cells characterising by dark-staining nuclear debris in their cytoplasm

157
Q

How does somatic hypermutation occur?

A

B cell mutate their V regions in the dark zone, then move to light zone, if can capture antibody from FDCs and present on their MHc II molecules will receive survival signals, then reenter dark zone and get more mutations- if not then die

158
Q

What gene is induced to prevent apoptosis in successfully binding antigen B cells?

A

Bcl-xL; CD40 interaction

159
Q

What type of mutation happens in SHM?

A

usually single-base substitutions with occasional insertions and deletions

160
Q

What action by AID intiates SHM?

A

deaminates cytidine to uridine residues in the Ig V regions

161
Q

What action by AID initiates class switch recombination?

A

cytidine residues in the switch regions are deaminated to uradine

162
Q

What needs to happen for AID to work?

A

AID target genes need to be unwound and not double-stranded (when they are being transcribed)

163
Q

What is the problem with the creation of uridine by AID?

A

not a normal dna nucleotide; but is in mismatch with the guanosine nucleoside

164
Q

What does the presence of uridine in the DNA trigger?

A

DNA repair mechanisms- mismatch repair; base-excision repair

165
Q

What detects the presence of uridine in the mismatch repair pathway?

A

MSH2 and MSH6

166
Q

What happens after MSH2 and MSH6 have detected uridine?

A

recruit nucleases that remove the nucleotide as well as adjacent nucelotides followed by a patch repair by DNA polymerase which is error-prone

167
Q

Which bases does mismatch reapir introduce mutations into?

A

nearby A:T base pairs

168
Q

What enzyme is invovled in the inital steps in the base-excision repair pathway?

A

uracil-DNA glyosylase

169
Q

What is the function of uracil DNA glycosylase?

A

removes the uracil base from the uridine to create an abasic site in the dna

170
Q

What enzyme is involved in replaces the abasic site in damaged DNA?

A

an error-prone translesion DNA polymerase: REV1

171
Q

What does REV1 do?

A

replaces the abasic site with a random nucleotide creating mutations in the C:G base pair

172
Q

What other enzyme is involved in mismatch repair?

A

polyn (an error prone polymerase)

173
Q

What guides classic switch recombination?

A

stretches of repetitive DNA known as switch regions

174
Q

Where do switch regions lie?

A

in the intron between the Jh gene segments and the C genes (except d)

175
Q

What is the order of the heavy chain exons in human DNA?

A

u; d; y3; y1; a1; y2; y4; e ; a2

176
Q

What is polymerase stalling?

A

movement of RNA polymerase throug hteh highly repetitive regions of the switch regions is occasionally halted

177
Q

What may cause polymerase stalling?

A

bubble-like structures called R-loops that form when the transcribed RNA displaces the non=-template strand of DNA double helix due to having many G residues in tandem on one strand

178
Q

What is necessary for AID to generate double strand breaks?

A

RNA exosome and Spt5

179
Q

What guides AID to the right switch region?

A

the intron containing the switch region is transcribed then spliced out and processed to form a G-quadruplex which binds to AID and the switch region to which it was transcribed

180
Q

How does double-strand breaks in DNA cause class switching?

A

the double-strand break reapir mechanisms joins the 2 switch regions (m and other class) together and excision of the regions in between

181
Q

what are P-nucleotides?

A

palindromic sequences added to the ends of the gene segments

182
Q

What enzyme is involved in added N-nucleotides?

A

Tdt

183
Q

What type of Ig chain are N-nucleotides more common in?

A

heavy chain

184
Q

Where do the antigen-independent phases of a B cell life take place?

A

bone marrow

185
Q

Where do the antigen-dependent phases of a B cells life take place?

A

in seconday lymphoid tissues- lymph nodes/spleem

186
Q

What molecules does membrane Ig associate wtih to form a fully functional BCR?

A

CD79a and CD79b

187
Q

What motif is found on CD79a and CD79b?

A

ITAM

188
Q

How many tyrosine residues are found on each ITAM?

A

2

189
Q

What is the BCR signalosome?

A

assembly of intracellular signalling molecules which allow the coordinated regulation of cellular events

190
Q

What must an antigen do to stimulate a BCr?

A

cross-link

191
Q

How does a protein kinase work?

A

removing a phosphate group from ATP and covalently attaching it to an amino acid that has a free hydroxyl group

192
Q

On what 3 amino acids do protein kinases phosphorylate proteins on?

A

tyrosine; serine and threonine

193
Q

How can tyrosine kinase-associated receptors assemble multiportein signalling complexes?

A

using proteins called scaffolds and adaptors

194
Q

What is the function of scaffolds and adaptors?

A

recruiting other proteins into a signalling complex so that interactions among these proteins can takep lace

195
Q

What domains are found within Src family proteins?

A

SH3 and SH2

196
Q

What does the SH2 domain recognise?

A

pYXXZ (pY-phosphorylated tyrosine; X-aa; Z-specific aa that it also recognises)

197
Q

What does the SH3 domain recognise?

A

proline rich regions

198
Q

What does PH recognise?

A

phosphorylated lipids

199
Q

What is the function of PH domains?

A

recruiting proteins to different membranes thus targeting them to appropriate cellular compartments

200
Q

What are lipid rafts?

A

special domains of the plasma membraen that are optimized fro the initation of cell signals

201
Q

What is ofen seen with lipid raft daomins?

A

differenital lipid composition and are enriched with signalling moelcules

202
Q

What is the function of lipid rafts?

A

triggering and regulating B cell activation through the recruitment of key mediators and adaptors associated with BCR signalling

203
Q

What is step on in B cell activation?

A

antigen binding crosslinks two isolated BCRs into the lipid raft micro daomins where Lyn (a Src) phosphorylates ITAMs within the Iga/b sheath

204
Q

What happens in step 2 of B cell activation?

A

recruitment and binding of the SH2 domains of Syk to phosphorylated ITAMs takes away Syk auto-inhibitory onstraint

205
Q

How is Syk kinase activity triggered by binding of SH2 domains of syk to phsophrylated ITAMs

A

allows phosphorylation of Tyr residues in Syk activation loop by itself or Lyn

206
Q

Why does Syk show high affinity binding to phosphorylated ITAMs?

A

has 2 SH2 domains

207
Q

What happens once Syk is activated?

A

co-ordinated assembly of hte signalosome is triggered

208
Q

What is the signalosome composed of?

A

variety of intracellular signalling molecules e.h phospholipase Cy2; phophoinositide 3-kinase; Vav; Bruton’s tyrosine kinase and B cell linker (adaptor 0

209
Q

What is the function of guanine-nucleotide exchange factors?

A

cause GTPAse to release GDP and to bind the more abundant GTP

210
Q

What is version of Syk in T cells (i.e what tyrosine kinase is recruited to phosphorylated ITAM in T cells)?

A

ZAP-70

211
Q

What is a difference between ZAP-70 and Syk?

A

ZAP-70 requires additional phosphorylation by Lck for activation whereas Syk is activated by binding

212
Q

What other name is CD21 known as ?

A

complement receptor 2

213
Q

What does binding of C3dg to CR2 (CD21) cuase?

A

cross links the BCR with the coreceptor complex (CD21: CD19: CD81) and phosphorylation of CD19 and augmentation of signallling thourght he BCR

214
Q

What chain does Syk bind to on the ITAM- conatining signalling chains?

A

Igb

215
Q

What happens once Syk is activated?

A

phosphorylated scaffold protein SLP-65 (BLNK)

216
Q

What is the version of SLP-65 in T cells?

A

LAT and SLP-76

217
Q

What is the function of SLP-65?

A

provides multiple sites for tyrosine phosphorylation and recruiting a variety of SH2-containing proteins

218
Q

What links SLP-76 to LAT?

A

Gads ( an adaptor protein)

219
Q

What is the function of PI 3-kinase?

A

phosphorylated PIP2 in the plasma membrane to PIP3

220
Q

What are the 4 downstream pathway induced by the phosphorylation by ZAP-70 of LAT and SLP-76?

A

activation of phospholipase Cy; activation og serine/threonine kinase Akt; recruitemnt of adaptor protein ADAP; activation og Vav

221
Q

what is the general function of PLC-y?

A

affects transcipriont

222
Q

What is the general function of the activation og Akt?

A

affects metabolism

223
Q

what is the function of the recruitment of ADAP?

A

upregulates cell adhesion

224
Q

What si the function of Vav?

A

intiates actin polymeriation

225
Q

What part of the BCR coreceptor compelx recruits PI 3-kinase?

A

CD19

226
Q

What does PLCy bind to in the plasma membrane?

A

PIP3 by its PH domain; PIP3 has been formed by the phosphorylation og PIP2 by PI 3-kinase

227
Q

What happens once PLCy binds to piP3?

A

binds phosphorylated LAT and SLP-76

228
Q

What does PLC-y activation require in T cells?

A

phosphorylation by Itk-

229
Q

What is Itk?

A

member of the Tec family of cytoplasmic tyrosine kianses

230
Q

What does PLC-y activation in B cells require?

A

Brutons tyrosine kinase

231
Q

What is the function of activated PLCy?

A

catalyses the breakdown of membrane lipi PIP2 into DAG and IP3

232
Q

What is DAG?

A

a membraen lipid

233
Q

What is IP3?

A

a diffsuble second messenger

234
Q

What does IP3 do once generated?

A

diffuses into the cytosol and binds to IP3 receptors on the ER

235
Q

What does binding of IP3 to the IP3 receptors on the ER cause?

A

opens receptors and releases calcium from the ER

236
Q

What are the 3 downstream branches of PLC-y activation?

A

stimulation of calcium entry; activation of Ras; activation of protein kinase C

237
Q

What is the result of calcium entry in the cytosol as a result of PLC-y?

A

activation of NFAT

238
Q

Which proteins does DAG recruit?

A

PKC; RasGRP

239
Q

What is needed for NFAT to enter the nucleus?

A

dephosphorylated

240
Q

What protein does the cytoplasmic Ca cause a conformational change in?

A

calmodulin

241
Q

What protein phosphatase does calmodulin activte?

A

calcineurin

242
Q

What does Vav do?

A

activates small GTPases which activates WASp-actin polymerization and integgrin aggregation and conversion of LFA-1 to high affinity

243
Q

What transcription actor does PKC activate?

A

NFkB

244
Q

What happens when calcium is depleted from the ER?

A

STIM1 aggregation

245
Q

What does aggregated STIM1 do?

A

binds and opens ORAI1 channels in the plasma membrane causing entry of extracellular calcium

246
Q

What is the decrease and calcium in the ER triggering extracellular calcium influx called?

A

store-operated calcium entry model (SOCE model)

247
Q

What type of transcirption factor is NFAT?

A

calcium dependent- require continous increase in calcium to remain in the nucleus

248
Q

What are the 3 members of the NFAT family?

A

NFATc1; NFATc2; NFATc3

249
Q

What is required to link PKCb to NFkB?

A

a NFkB signalling complex

250
Q

What is the NFkb signalling copmlex composed of?

A

CARMA1; BCL10 and MALT1

251
Q

What is the function of the NFkB signalling copmlex?

A

fine tunes NFkB signalling to maintain normal B cell proliferation/survival and idfferntiation

252
Q

How is IKKb activated (which then activates NFkB?

A

TAK1 which binds to the NFkB signalling complex then acts on IKK copmlex to activate it

253
Q

What is Ras?

A

a momeric G protein with very low GTPase activity on its own

254
Q

What protein activates Ras?

A

RasGRP3

255
Q

What does activated Ras cause?

A

a three-kinase relay which ends in the activation og MAPK

256
Q

What does MAPK mean?

A

mitogen-activated protein kinase

257
Q

What are the 3 kinases invovled in Ras signalling?

A

Raf–MEK1–Erk

258
Q

What transciption factor does Ras pathway activate?

A

AP1

259
Q

What is the function of Akt?

A

promotes cell survival and enhanced metabolic activity via mTOR

260
Q

What does Akt bind to?

A

PIP3 generated by PLCy

261
Q

What phosphorylated Akt?

A

PDK1

262
Q

What is a transcription factor?

A

protein involved in the regulation of gene expression by binding to regulatory regions upstream of genes

263
Q

What are the 2 functional regions of promoters?

A

DNA-binding domain and transcription activation domain

264
Q

What does the DNA-binding domain consist of?

A

amino acids that recognise specific DNA bases near the start site of transciprtion

265
Q

What is the function of the transcipriont activation domain?

A

interacts with the components of hte transcriptional apparatus (RNA polymerase) and affects the efficiency of gene transcription

266
Q

What do the NFkB family share?

A

a structurally conserved Rel homology domain

267
Q

What is the Rel homology domain?

A

300 amino acids at the N-terminus

268
Q

what is the function of the Rel homology domain?

A

mediates nuclear locatlisation; DNA binding; dimerization with other NFkB subunits and interaction with NFkB inhibitors- IkBs

269
Q

What are the negative modulators of the BCR?

A

FcyRIIb (CD32); CD22 and CD72

270
Q

What is the function of CD81?

A

regulatory- required for localization of CD21:CD19 into lipid rafts

271
Q

What is expressed on FcyRIIb which accounts for its regulatory function?

A

ITIMs

272
Q

What is the function of ITIMs?

A

recruit tyrosine phosphatases or inosital phosphatases which negatively regulate Src family PTKs

273
Q

What other regulatory reeptor functions like FcyRIIB?

A

CD72

274
Q

What is the function of CD27?

A

B cell co-receptor for T cell activation indicued ligands that promotes differntiation of B cells into plasma cells

275
Q

What is the function of TACI; BCMA and BAFF-R?

A

receptors for B cell activation factor (BAFF)- important for survival and differntiation signals

276
Q

What are antigens taht can activate B cells without T help called?

A

thymus independent antigens

277
Q

What are type I thymus-independent antigens?

A

bacterial cells wall components eg LPS

278
Q

What are type 2 thymus independent antigens?

A

large carbohydrate molecules with multiple repeating subunits

279
Q

How do II-1 activate B cells?

A

via TLRs

280
Q

How does TI-2 activate B cells?

A

crosslinking a number of BCR

281
Q

What type of B cell can TI-1s activate?

A

both immature and mature B cells

282
Q

What type of B cell can TI-2s activate?

A

only mature B cells

283
Q

What is seen in the response to T-independent antigens?

A

largely IgM Abs of low affinity which do show signif class switching, affinity maturation or memory cell formation

284
Q

What is polyclonal activation?

A

proliferation and differentiation of most B cells regardless of their antigen specificity

285
Q

What type of thymus independent antigens can stimulate polyclonal activation?

A

TI-1

286
Q

What other name are TI-1s given?

A

B-cell mitogens

287
Q

What is a mitogen?

A

substance that induces clels to undergo mitosis

288
Q

What is the lymph node divided into?

A

medulla and outer cortex

289
Q

What is the outer cortex of a lymph node subdivided into?

A

paracortex and follicles

290
Q

What is foudn in the paracortex of lymph nodes?

A

T cells

291
Q

What is found in the follicles of lymph nodes?

A

B cells

292
Q

What is the extrafollicular pathway of B cell differentiation?

A

form B cell follicles that localise in medullary cords

293
Q

What are the features of B cells of the extrafollicular pathway?

A

undergo low levels of class switching and somatic mutationgenerating short lived plasma cells that produce low affinity Abs

294
Q

What is the function of the extrafollicular pathway?

A

most immediate source of Ab-specific Abs to provide rapid protection before GC response is established

295
Q

What interaction is germinal centre reaction dependent on?

A

CD40/CD40L

296
Q

What is hte main chemokine in the dark zone of Gcs?

A

CXCL12

297
Q

What is the main chemokine in the light zone of GCs?

A

CXCL13

298
Q

Why do Tfhs express CXCR5?

A

access B cell follicles

299
Q

What IRF does NFkB activate?

A

IRF4

300
Q

What does IRF4 do in GC initiation?

A

induction of BCL6

301
Q

What does IRF do in GC exit?

A

downregulates BCL6 and promotes BLIMMP1–plasma cells

302
Q

What gene segments does the TCRa locus contain?

A

V and J gene segments

303
Q

What gene segments does the TCRb locus contain?

A

V, D and J segments

304
Q

Where does T cell recpetor gene rearrangement take place?

A

thymus

305
Q

What are the DNA circles resulting from gene TCR rearrangement called?

A

TCR excision circles (TRECs)

306
Q

What are TRECs used as markers for?

A

marker for T cells that have recently emigrated from the thymus

307
Q

How many C regions are there for the TCR?

A

1 Ca gene and 2 Cb genes

308
Q

What si the difference between the 2 Cb genes?

A

very closely homologous and no known functional distinction

309
Q

What is different about the RSS regions in the TCR and BCR genes?

A

surroudning the D gene in B cells, both have 12-bp spacing, which forces the D to go in between the V and J as they cannot join due to both having 23-bp spacing haowever, in T cells, the D gene has both 12-bp and 23-bp spacing and the J region has 12-bp and the Vsegment has 23- meaning that V and J could join however this doesn’t happen- other regulation which isn’t fully understood

310
Q

Which gene segments contribute to the CDR3 region in the TCR?

A

D and J segments

311
Q

What do the CDR1 and CDR2 regions of the TCR mainly bind to?

A

the relatively less variable MHC component of hte ligand

312
Q

What is the difference in the number of J segments between the TCRa chain and the Ig light chain?

A

has 61 vs 5 in the BCR

313
Q

Where are the cluster of genes encoding teh delta chain found?

A

entirely within the TCRa locus between the Va and Ja gene segments

314
Q

What compoensates for the fewer V gene segments in the Vd and Vy loci than in the TCRa or TCRb loci?

A

increased junctional variability

315
Q

Where do the amino acids encoding the junctional region lie in the TCR?

A

at the TCR binding site

316
Q

Why can T cells not express both ab heterodimer and yd heterodimer?

A

TCRa recombination deletes the TCRd chain locus

317
Q

What protein involved in recombination can be deleted and not prevent antigen receptor formation?

A

TdT

318
Q

What is the function of Tdt?

A

adds N-nucleotides and creates a massive amount of diversity seen in CDR3

319
Q

What are the 4 processes that contribute to the vast diversity of antibodies and BCRs ?

A

combinatorial diversity (different VDJ segment joining; junctional diversity-Artemis, exonucleases and TdT; different heavy and light chain pairings; somatic hypermutation

320
Q

What is the function of RAG-1 and RAG-2?

A

recognises RSS and creates single-stranded break

321
Q

What is the function of artemis?

A

nuclease activity to open the DNA hairpin and generate P-nucleotides

322
Q

What is the function of DNA-PKcs?

A

forms a complex with Ku to hold DNA together and phsophorylate Artemis

323
Q

What is the gene defect in ataxia telangiectasia?

A

ATM mutations

324
Q

What is the mutation in irradiation sensitive SCID?

A

artemis mutations

325
Q

What is the mutation in omenn ysndrome?

A

RAG 1 and RAG2 mutations resultiing in decreased recombinase activity

326
Q

What do IgA and IgM have as part of hte multimeric complex?

A

J chain

327
Q

What is alternaitve splciing in determining the balance of expression of IgM and IgD regulated by?

A

snRNP ZFP318

328
Q

What factor regulate membrane-bound vs secreted forms of antibodies?

A

CstF-64 and ELL2

329
Q

What isotypes can bind to Fcy receptors?

A

IgG1 and IgG3

330
Q

What receptor do IgA and IgG bind to which activity transports them to different body tissues and recycles them at the glomerulus?

A

FcRn

331
Q

what number of amino acids in a peptide can TAP1/2 transport?

A

8-16

332
Q

What residues does TAP1/2 like at the carboxy terminus?

A

hydrophoboid

333
Q

What residues does TAP not like in the first 3 amino-terminal residues?

A

proline

334
Q

What transcription factor do CD8 DCs require for their devleopment?

A

BATF3

335
Q

what can uniquiely identify CD8 DCs?

A

XCR1

336
Q

What is the function of TRiC?

A

protects peptides produced in the cytosol from complete degradation

337
Q

What other name is the invariant chain MHCII called?

A

CD74

338
Q

Defects in what protein results in decreased cytosolic peptide presentation on MHC-II?

A

IRGM3

339
Q

Give examples of receptors for growth factorsthat are receptor tyrosine kinases?

A

Kit and FLT3

340
Q

What type of receptor is the TGF-b receptor?

A

recpetor serine/threonine kinase

341
Q

What 3 pathways are required for the transcirption of IL-2?

A

AP-1; NFAT and NFkB

342
Q

Hoiw do GEFs enhance Ras activity?

A

catalyse the exchnage of GDP for GTP

343
Q

How do GAPs decrease Ras activity?

A

enhance GTPase activity of Ras- hydrolysis of GTp to GDP

344
Q

Whatpathway and function is Ras involved in?

A

MAPK pathway and AP1 activation

345
Q

What is the function of Cdc42 (Rho family)

A

WASp- actin polymerization and cytoskeleton reorganisation

346
Q

Waht is the function of Rap1?

A

LFA-1 aggregation and cellular adhesion

347
Q

What is the function of Rheb?

A

mTOR- cellular metabolism

348
Q

What is the effect of K63 polyubiquitination?

A

downstream cellular signalling

349
Q

What is the effect of K48 polyubiquitination?

A

degradation by the proteasome

350
Q

What is the effect of mono and di ubiquitination of surface receptors?

A

recognition by ubiquitin-binding proteins taht tagret receptor for degradation in lysosomes

351
Q

What gene is defective in XLA?

A

Btk

352
Q

What gene is defective in Wiscott-Aldrich syndrome?

A

WASp

353
Q

What genes in the T cell activation pathways can be defective in SCID?

A

ORAI1; carma1; Zap-70; Itk; Lck

354
Q

What disease is linked to a defect in NEMO?

A

V-linked hyohidrotic ectodermal dysplasia and immunodeficiency

355
Q

What is the equivalent of CD3 compelx in B cell?

A

Iga:Igb

356
Q

What is the equivalent of the CD21:CD19:CD81 compelx in T cells?

A

CD4 or CD8

357
Q

What is the equivalent of CD28 in B cells?

A

CD40

358
Q

What is the equivalent of Fyn, Blk, Lyn in T cells ?

A

Lck

359
Q

What is the quivalent of ZAP-70 in B cells?

A

Syk

360
Q

What is the equivalent of LAT:Gads:SLP-76 in B cells?

A

SLP-65 (BLNK)

361
Q

What enzyme helps PLCy in B cells instead of Itk?

A

brutons tyrosine kinase

362
Q

what is hte function of CD22 on B cells?

A

binds sialic acid containing glycoproteins found on mammalian cells- inhibitory receptors

363
Q

What happens to macrphages and DCs upon PRR stimulation?

A

expression of CD80 and CD86

364
Q

How is each downstream module of the TCR intiated?

A

by recruitment to LAT;Gads;SLP-76 complex or to the PIP3 generated by PI 3-kinase

365
Q

What are the 3 branches of PLCy signalling?

A

stimulation of calcium entry- activation of NFAT; activation of Ras and activation of protein kinase C

366
Q

What is the importance of NFAT in T cell activation illustrated by?

A

inhibitors of calcineurin e.g cyclosporin A which prevent dephosphorylation –effective immunsuppressant

367
Q

What happens to mice lacking protein kinase C-0?

A

mature T cells have a defect in the activation of NFkB and AP-1

368
Q

What is required for transcription of IL-2?

A

NFkB and NFAT and AP-1

369
Q

How does protein kinase C activate NFkB?

A

when recruited to DAG it phorphorylated CARMA1 which creates a scaffold and recruits TRAF6. TAK1 is recruited via TAb1/2 to the scaffold and phosphorylates IkB, releasing NFkB

370
Q

Why does a T cell need to change its cellular metabolism when activated?

A

to accomodate the energetic and macromolecular demands of rapidly dividing cells

371
Q

What are the functions of Akt which binds to PIP3?

A

inhibits cell death (phosphorylated BAD which inhibits Bcl-2); stimulate cell metabolism by increasing activity of glycolytic enzymes and upregulating nutrient recpetors; stimualtes mTOR

372
Q

What happens when mTOR is activated?

A

increased lipid production; ribosome biosynthesis; mRNA synthesis and protein translation

373
Q

What happens to ADAP-deficient T cells?

A

impaired proliferation and cytokine production after TCR sitmulation

374
Q

What is the function of ADAP signalling?

A

through Rap1 it promotes LFA-1 aggregation and high affinity conversion

375
Q

What are the 4 modules of signalling following TCR activation?

A

transcription factor activation (PLCy);cellular metabolism changes-Akt; LFA-1 aggregation and change via ADAP; actin polyermisation and cytoskeletal reorganisation via Vav

376
Q

What is the difference between PI3K recruitment in T cell and B cells?

A

T cells PI3K is recruited to to LAT:Gads:SLP-76 whereas in B cells PI3K is recruited to CD19

Basic Immunology- Module 1 (31 decks)

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