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Immunology and Infection > Development and Activation of B cells > Flashcards

Development and Activation of B cells Flashcards

1
Q

what are the advantages of the adaptive immune system?

A
  1. diversity/specificity

2. memory

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2
Q

why is it important that the adaptive immune system has diversity/specificity?

A
  • immune system has a large repertoire of lymphocytes, which express uniquely different receptors
  • innate causes collateral damage but we only want to kill the infected
  • very specific and can target exactly
  • has a large variety of T and B cells which can recognise any pathogen
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3
Q

why is it important that the adaptive immune system has memory?

A
  • innate has no memory
  • memory allows a more rapid and effective response on a secondary encounter with an antigen
  • keeps a reserve of immune cells
  • second time the response is more aggressive and quick
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4
Q

what are the 5 principles of clonal selection?

A
  1. each lymphocyte has a single type of receptor with a unique specificity
  2. each lymphocyte bears multiple of the same receptor
  3. cells that have receptors for self-molecules are deleted from the repertoire
  4. interaction between an antigen and a receptor leads to activation of that lymphocyte
  5. the derived daughter cells are identical to the activated parent cell
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5
Q

how is clonal expansion initiated?

A
  • each receptor has a different shape
  • A B cell has the right receptor for a pathogen
  • will the one cell clonally expand
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6
Q

what do B cells produce?

A

antibodies

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7
Q

what are the roles of B cells?

A
  • neutralise toxins and viruses
  • help in the phagocytosis of pathogens
  • destruction of bacteria and virus
  • act as an antigen presenting cell to activate T cells
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8
Q

what are the 2 forms of immunoglobulins?

A
  1. as a membrane receptor that binds an antigen

2. as a secreted fluid phase molecule that directs a specific immune function

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9
Q

what immune functions can immunoglobulins direct?

A
  • complement fixation
  • opsonisation
  • neutralisation
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10
Q

what is the hinge region of the immunoglobulin?

A

gives flexibility, helps to bind

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11
Q

what is the variable region of the immunoglobulin?

A

amino sequence is variable from one B cell to another

- antigen binding happens at the top at the variable region

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12
Q

what are the 5 types of heavy chains?

A

IgM IgG IgD IgA IgE

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13
Q

what are the 2 types of light chains?

A

kappa (K) and lambda (y)

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14
Q

how is the immonglobulin isotype defined?

A

types of heavy and light chain recombine

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15
Q

what is the hinge region susceptible to?

A

cleavage by 2 enzymes:
papain
pepsin

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16
Q

what is the role of the enzyme papain?

A
  • cleaves at the hinge releasing the arms
  • Fab fragments
  • Fab fragments can bind antigen but lack any function
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17
Q

what is the role of the enzyme pepsin?

A
  • cleaves just underneath the hinge region
  • Fab2 fragment
  • could bind an antigen but no function
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18
Q

what did the Fab and Fc regions show?

A
  • showed that the top was for recognition

- the bottom, the Fc region, determines the immunoglobulin domain

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19
Q

what do B cells recognise?

A
  • recognise extracellular molecules/antigens
  • look for the shape of the molecules on the surface of the pathogen
  • match to the B cell receptor
  • lock and key recognition
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20
Q

what is the hyper variable region (HV)?

A
  • within the variable region
  • high levels of amino acid variability
  • amino acids in the HV regions determine the shape of the antigen binding site
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21
Q

what is the size of the adult immunoglobulin repertoire?

A

about 10^11 different immunoglobulins

- however, the human genome only encodes for ~30, 000 genes

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22
Q

what are HV regions the result of?

A
  • result of random rearrangement/combinations of defined gene segments
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23
Q

what are the heavy chain gene segments?

A

V, D and J

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24
Q

what are the light chain gene segments?

A

V and J

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25
Q

which heavy chain is rearranged first?

A
  • IgM heavy chain is rearranged first
  • followed by the light chian
  • IgM is the first BcR made
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26
Q

what does splicing result in?

A

brings the constant region next to the variable region resulting in a complete light chain

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27
Q

how does the heavy chain recombine?

A
  • D recombines with J first
  • then with V
    (ordered recombination)
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28
Q

what is combinatorial diversity?

A

can produce many different immunoglobulins

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29
Q

what is the 23-12 rule?

A
  • you have a recombination signal sequence (RSS)
  • 2 types: 23 base pair spacer and 12 base pair spacer
  • a 23 spacer can only recombine with a 12 spacer
  • means orientation will be in the correct way to get a functioning protein
  • gives diversity
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30
Q

why does recombination only occur in lymphocytes?

A

B and T cells have recombination activation genes 1 and 2 (RAG 1 and RAG 2)
- allow the recombination of RSS upstream of the gene segment

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31
Q

what is the role of RAG 1 and RAG 2?

A
  • RAG proteins bind to the RSS
  • brings them close together and forms a hair pin loop
  • has endonuclease complex which cuts at the RSS segments leaving free ends
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32
Q

what is the signal joing?

A

extrachromosomal circular piece that is lost from the genome when the cell divides
- DNA we dont want forms a circle and gets secreted away

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33
Q

what is the coding joint?

A

brings the gene segments together

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34
Q

what is the result of the ‘nick’ in the DNA strand left by the activtiy of endonuclease?

A
  • leaves free ends

- enables random addition/removal of nucleotides

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35
Q

what enzyme facilitates the addition and removal of nucleotides during recombination?

A
  • enzyme terminal deoxynucleotide transferase (TdT) adds N nucelotides to the D-T pairing of the heavy chain
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36
Q

what happens once nucleotides have been added to the free ends during recombination?

A

DNA is repaired with DNA ligase

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37
Q

how is there combinatorial diversity?

A

heavy and light chain pairing

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38
Q

how is there junctional diversity?

A

TdT

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39
Q

what is tolerance?

A
  • immune system has evolved strategies to protect us from itself
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40
Q

how does autoimmunity occur?

A
  • failure to tolerate the adaptive immune system

- need some quality control

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41
Q

where are B cells assessed for auto reactivity?

A
  • when they develop in the bone marrow and completed in the spleen
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42
Q

Describe the HSC stage in B cell development?

A
  • develop into common lymphoid progenitor
  • makes it responsive to a chemokine CXCL12
  • holds a potential B cell in the bone marrow
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43
Q

what is the CLP stage in B cell development?

A
  • transcription factors

- heavy chains recombine first

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44
Q

what is the pro B stage in B cell development?

A
  • recombines again

- you have the heavy chain in side the cell not on the surface

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45
Q

what is the quality control that happens at the PreB stage in B cell development?

A
  • does the heavy chain have the capability to bind a light chain
  • make a surrogate light chain
  • if the heavy chain can complex with the surrogate light chain it will progress
  • if not it will die
  • get the rearrangement of the light chain
46
Q

what is the quality control that happens at the immature B cell stage in B cell development?

A
  • the receptor is on the surface
  • expressed with the proteins in our body
  • presented to the B cell
47
Q

what happens if the B cell recognises its own molecule at the second quality control stage?

A
  • re-initiate rearrangement of the light chain V region segments to form a new shape in the antigen binding site
  • called receptor editing
  • die if the new receptor still has auto-reactivity for self-antigens
48
Q

what happens if the B cell doesn’t recognise its own molecule at the second quality control stage?

A
  • immature B cell leaves the bone marrow and moves to the spleen to complete development
  • transition into the type of B cell it will become
49
Q

what form of B cells secrete immunoglobulins?

A
  • B cells themselves do not secrete antibodies

- plasma cells that secrete antibodies

50
Q

what is the transmembrane receptor of the B cell?

A
  • transmembrane and a small cytoplasmic component
  • held on the surface of the B cell
  • membrane BcR
  • B cells express Ig heavy chain transcripts
51
Q

what does the Fc region define?

A
  • defines its function in the body
  • Fab gives antibody specificity
  • Fc gives it its function
52
Q

what happens if you swap the Fc region for one class of antibody to another?

A
  • can change the function
53
Q

how do antibodies facilitate eradication of microbes?

A
  • neutralisation of microbes and toxins
  • opsonoization and phagocytosis of microbes
  • antibody dependent cellular cytotoxicity
  • phagocytosis of microbes opsonized with complement fragments
  • inflammation
  • lysis of microbes
54
Q

how do antibodies facilitate the neutralisation of microbes and tozxins?

A
  • antibodies bind surface molecules needed for microbe to bind to the host cell
  • most microbes need to get inside to use the host cell
  • if you block this then they can’t infect the cell
55
Q

how do antibodies facilitate the opsonization of microbes?

A
  • antibodies bind microbe then bind to FCyR on phagocytes
  • can trigger phagocytes
  • common for dealing with bacteria
56
Q

what is antibody dependent cellular cytotoxicity?

A
  • antibodies binds microbes then binds FCyR on NK cells which then kill the microbe
57
Q

how do antibodies facilitate the phagocytosis of microbes?

A
  • antibodies bind microbe activate complement which targets microbe to phagocytosis
  • through C3b - phagocytes have C3b receptor and can form the immune complex
58
Q

how do antibodies facilitate inflammation?

A
  • antibodies bind microbe activate complement that recruit other immune cells
59
Q

how do antibodies facilitate lysis of microbes?

A
  • antibodies bind microbe and activate complement to kill the microbe
60
Q

what does the B cell recognise?

A
  • lock and key approach. can recognise
    1. continuous epitope (amino acids in one long line)
    2. discontinuous epitope (shape made when the molecule is folded)
61
Q

why is B cell recognition important to consider in experiments?

A
  • for instance if the proteins been denatured
  • if the antibody doesn’t recognize it this could be because it recognizes a discontinuous epitope
  • therefore the experiment would fail
62
Q

what molecules does the BcR have?

A
  • Iga and IgB molecules
63
Q

what happens when an antigen binds to the BcR?

A
  • causes a change in the cytoplasmic region which trigers the phosphorylation of co-receptors Iga and IgB and transmission of signals
64
Q

how can BcR signal be amplified through co-stimulatory molecules?

A
  • complex of CD19/CD81 and a complement receptor
  • works with BcR for activation
  • provides costimulatory amplification
65
Q

what is complement through BcR activation?

A
  • C3 can be cleaved into C3d

- combine with complement receptor 2 which amplifies signals into the cell

66
Q

what happens once an antigen has bound to the BcR?

A

gets internalised and turned into peptides

67
Q

why are CD4 T cells needed for activation?

A
  • vital for activation and differentiation of B cells into plasma cells
  • peptides are put on the surface of the B cell wil MHC II
  • activates the CD4 T cell which releases cytokines
  • causes B cells to proliferate, class switch and differentiate into plasma cells
68
Q

what is the role of CD4+ Tfh cells?

A

unique cells essential for activation, class switching and differentiation of activated B cells into plasma cells

69
Q

what cytokines are involved into CD4 Tfh?

A
  • IL-6 causes naive CD4 T cells to differentiate in Tfh
  • IL-6 - STAT3 - activates TF Bcl-6
  • produces the cytokine IL-21
70
Q

where does B cell activation occur?

A

in secondary lymphoid tissue

71
Q

how does B cell activation occur?

A
  • initiated at junction of the B cell follicle zone and T cell zone
  • B cells receiving activation signals enter specilaised germinal centres within B cell follicles
  • very few B cells enter the germinal centre
72
Q

what are germinal centres?

A
  • dynamic environments
  • clonal expansion of desired B cell (need massive numbers)
  • need to change the BcR shape slightly
  • need a reassessment of BcR
  • class swithcing
  • recieves signals to differentiate to plasma cells
  • generate memory B cells which lie in wait for re-infection
73
Q

how is the shape of BcR changed slightly?

A
  • refining of antigen-binding site (somatic hyper mutation)
  • first B cells triggered - not as high affinity
  • when it changes slightly you could change specificity for your own cells/tissues
74
Q

what happens if the BcR recognises your own peptides after re-assessment?

A
  • no second chance if it is autoreactive there is no further rearrangmeent
75
Q

what happens to short term plasma cells?

A

go into the bloodstream and secrete lots of antibodies and then dies

76
Q

what happens long term plasma cells?

A
  • small proprotion

- go to the bone marrow and secrete small amounts of antibodies

77
Q

what occurs in the dark zone?

A

expansion

78
Q

what occurs in the light zone?

A

selection of B cells, the honing and class switching

79
Q

what is the follicular dendritic cell?

A

central to the B cell response - they act as depots of the antigen the BcR is specific for

80
Q

what is the role of follicular DCs?

A
  • produce IL-6 to help maintain Tfh and IL-21 that acts on B cells to help differentiation and proliferation
  • continuously stimulating to BcR to see if its specific for the microbial antigen
81
Q

what is the role of IL-6 in B cell activation?

A
  • binds to CD4 T cells
82
Q

what is the role of IL-21?

A
  • causes upregulation of the chemokine receptor CXCR5
  • reacts specifically with the chemokine in the germinal centre
  • CD4 T cell activated will now move into the germinal centre
83
Q

what is somatic hyper mutation?

A
  • enables antigen binding site to become more specific with each encounter with the same antigen
84
Q

what does somatic hyper mutation enable?

A

mutations in the hypervariable region enable a tighter fit between the BcR and
antigen
- hones the antigen binding site further

85
Q

what happens to B cells that have undergone somatic hyper mutation?

A

have BcRs re-screened to determine if the mutations generated lead to an autoreactive BcR if so the B cell dies

86
Q

what is Activation Induced Deamnase (AID)?

A
  • important in initiating somatic hyper mutation

- de-animates cytosine to uracil

87
Q

what happens when you transcribe the BcR with RNA polymerase II?

A
  • end up with free ssDNA

- AID capable of binding the ssDNA

88
Q

how can uracil be processed?

A
  • replication (basically ignores it and causes transition mutations
  • basic residues to form and then edit (processed by uracil DNA glycosylase)
  • cause mutations to occur later on in the AT sections closer to the uracil
89
Q

what does the Fc region lead to?

A

lead to very different antibody structures and function, each class has their own function

90
Q

what are the different classes of antibodies

A
  • IgM
  • IgD
  • IgG
  • IgE
  • IgA
91
Q

how does the immune system decide which class of antibdoy?

A
  • what is the infection

- where is the infection

92
Q

why is AID active in the germinal centre?

A

to facilitate class switching

93
Q

what are the switch regions?

A
  • mature B cells express IgM and IgD first
  • when rearranging and transcribing you get ssDNA
  • AID binds to switch regions
  • AID makes it a better antibody and switches the antibdoy
94
Q

how does AID facilitate class swithcing?

A 
causes a hair pin loop and brings the switch region from IgM and the switch region form whatever class of antibdoy you want to produce close togehter
- joins them
 slashes out all the intervening sequencing
95
Q

what does the FcYRIIB do?

A
  • assess how much free IgG you have in your body
96
Q

how does eradication work when the antigen levels begin to drop?

A
  • start having too much free IgG specific for the pathogen that has not got saturation for its antigen binding site
  • signal for the B cell to start sucking up the IgG#- - binds to the receptor, negative transmission to de-phosphorylate everything thats switched on
  • effectively switches the B cell back off
97
Q

what happens if theres a mutation in FcYRIIB?

A
  • linked to autoimmune production of auto-antibodies to host cells
  • cant switch off activated B cells
  • have a strong response to own cells
98
Q

describe primary v secondary antibody response?

A
  • maturation of humoral immune response is characterised by Ig with increased affinity for its cognate antigen and switching of the Ig class
  • secondary - B memory cells - much quicker
99
Q

what is IgM?

A
  • first youll produce in an immune response
  • a low affinity antibody
  • key role in protection during an immune response
100
Q

what is the structure of IgM?

A
  • forms a penatmeric structure with 5 immunoglobulins held together by a protein called the J chain
101
Q

how does IgM make up for its low affinity?

A

has 10 antigen binding sites which generates a strong signal

102
Q

what is IgG?

A
  • high affinity antibody that has a key role in memory immune responses
  • most common immunoglobulin in serum
  • can cross the placenta (protect developing baby)
  • generated following class switching of IgM
103
Q

what is IgA?

A
  • small amounts in the blood
  • found in mucosa tissues, tears and breast mile
  • neutralises toxins - in food and in drink
104
Q

what is the structure IgA?

A

exists as a dimer two monomeric immunoglobulin units held together by a J chain

105
Q

what is IgE?

A
  • least common in serum
  • binds to sepcilaised Fc epsilon receptors on mast cells, basophils and eosinophils
  • strongly involved in allergic reactions and clearance of parasitic infections
106
Q

what is the structure of IgE?

A
  • a monomer

- has an extra constant domain C4

107
Q

how do you get allergic reactions?

A
  • influenced by genes
  • individuals that are pre-disposed to developing allergies are atopic
  • have higher circulating levels of IgE
  • many genes thought to play a role in susceptibility to allergies inherited
  • causes degranulation of mast cells and basophils that have epsilon receptors
108
Q

how does IgE affect asthma?

A

IgE activates mast cells to release inflammatory mediators

109
Q

what are the features of asthma?

A
  • bronchospasm, swelling and airflow obstruction
  • get inflammation, obstruction and hyper responsivenss
  • can be a genetic pre-disposition
110
Q

what are the to hypothesis of asthma?

A
  1. hygiene hypothesis: the cleaner we are the more susceptible to allergies we are
  2. infectious-asthma hypothesis: infections/microbiome is different

Immunology and Infection (13 decks)

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