B CELLS AND HUMORAL Flashcards
(112 cards)
1
Q
Are B and T cells morphologically similar under a microscope?
A
- YES! can’t tell them apart
2
Q
What is the name of an effector B cell?
A
- Plasma cells –> produces antibodies
3
Q
When can the adaptive immune response be WELL detected?
A
- Not until day 6
4
Q
What is a feature of plasma cell under the microscope?
A
- very HIGHLY developed ER
5
Q
What is the lymphocyte clones with unique specificity INDEPENDENT of?
A
- Foreign antigen
- i.e. there will already be an antigen specific clone floating in peripheral lymphoid organs–> just have to find it
6
Q
Is the immune response dependent on a foreign antigen?
A
- YES!
- Will actively find antigen specific clone
7
Q
What types of antigens can a BCR recognsie?
A
- ALL different types of antigens (3D conformation) –> e.g. lipids, metals, carbs, proteins ,DNA
8
Q
Which part of the BCR is the binding site?
A
- N terminus variable domains
9
Q
What do the constant region of the heavy chains determine in B cells? -
A
- The antibody isotype
10
Q
Humoral immunity is important for which type of microbes?-
A
- Exracellular microbes
11
Q
What type of antibody is active against Helminths?
A
- IgE
12
Q
What occurs in B cell deficiency?
A
- Person is susceptible to puss (pyogenic) forming bacteria (neutrophils)
13
Q
Which type of response occurs in asthma?
A
- IgE response (sm. muscle contraction)
14
Q
What are the two types of ANTIBODY responses?
A
- T cell dependent (high affinity Igs) and T cell independent (weak–> mainly IgM Igs and it is transient)
15
Q
What is the function of T cell dependent antibodies ?
A
- Can target polysaccharide capsule that bacteria use to evade phagocytosis (via IgM) thus will phagocytose
16
Q
What feature is given to ANTIGENS that promote independent Ig repsonses?
A
- They are polyvalent –> can cross link and BCR can give rise to strong signal e.g polysaccharides and nucleic acids
17
Q
Do B or T cells express PRRs?
A
- B cells express them! NOT T CELLS !!
- Because B cells can recognise the whole 3D conformation whereas T cells only recognise digested peptides
18
Q
Can PAMPs costimulate B cells in T cell independent Ig respone?
A
- YES!
- In this case SINGAL 1= BCR
and SIGNAL 2= PRR
19
Q
Why don’t B cells illicit T cell help for polysaccharides and nucleic acids?
A
- Because T cells recognise ANTIGEN (the peptide) and not the whole structure of the nucleic acids or polysaccharides (bc. no peptides in them)
20
Q
What occurs in a T cell dependent response?
A
- Isotype switching e.g. IgM –> IgG (on day 7)
21
Q
Which day does the primary immune response peak?
A
- Day 14 (approx.)
22
Q
What is affinity maturation?
A
- Quality of Ig (affinity to cognate antigen )
- Antibody affinity in second response generally higher than first response
23
Q
What occurs in the first week and then after that of a T cell dependent Ig response ?
A
- First week: IgM produced
- After first week: Isotype switching IgM–> IgG, IgA
- Memory forms to allow for faster and larger immune response
24
Q
Is the affinity of Ig produced in secondary Ig response higher or lower than first?
A
- HIGHER (via affinity maturation)
- Affinity of Ig produced and BCR increases with TIME and exposure to antigen (primary and secondary immune responses)
25
Why do TCRs not change affinity like BCR?
- Because T cells aren't as free to 'mutate'--> has to bind to MHC + peptide
26
Is B cell signalling homologous to T cell signalling?
- YES!
| - Is homologous BUT identity of molecules is different
27
What does BOTH B and T cell signalling involve? -
- RECEPTOR TYROSINE KINASES --> phosphorylating ITAMs (cytoplasmic regions) --> P'd Adaptor and scaffold proteins--> membrane proximal complex--> enzymes and second messengers--> TFs --> new proteins and genes
28
Is the BCR cytoplasmic domain short or long?
- VERY SHORT
| - so can't transduce signals alone
29
Which two signalling chains help the BCR transduce the recognition signal?
- Igalpha and Igbeta (ITAM motifs in cytoplasmic domain)
30
What is the equivalent molecule of Igalpha and Igbeta in T cells?
CD3
31
What happens to the Igalpha and Igbeta in the signalling pathway?
- Get phosphorylated via tyrosine kinase (Fyn, Lyn, Blk)
| - Create docking sites for signalling
32
Which 3 SRC family kinases can phosphorylate ITAMs of Igalpha and Igbeta? -
- Fyn, Lyn , Blk
33
What is the T cell equivalent of Fyn, Lyn, and Blk?
- Lck
34
What is the functional equivalent of Stk in T cells?
- ZAP70
35
What is the B cell coreceptor complex comprised of?
- CD21, CD19, CD81 (tetrospandin molecule)
36
How is complement involved in B cell signalling (signal 2) ?
- If C3D (complement) on antigen --> CD21 sends signal (via CD19) --> to LOWER threshold of signalling needed for B cell activation
(T cell equivalent is CD80/86-CD28)
37
What is upregulated in an activated B cell?
- B7 and MHC II for interaction with helper T cells
- Cytokine receptors
- Expression of CCR7 (migrate out of B cell follicle into T cell zone)
- Generation of plasma cells
- Expression of survival proteins
38
What is the germinal center reaction?
- B cells proliferate and differentiate (spleen and lymph node)
- T cell dependent Ig responses occur
- FDCs (Follicular Dendritic Cells) + TFH (T Follicular Helper cells) are involved
39
Do follicular dendritic cells present antigen ?
- NO
| - They are parenchymal cells
40
Do you find germinal centre reactions for T cell independent antibody responses? -
- NO! Only for T cell dependent
41
What is the function of FDCs?
- Antigen depot
- Have intact antigen stuck to their surface (Fc and complement receptors) --> Intact antigen available for B cell to recognise and phagocytose
42
Where do antigen specific B cells acquire antigen from?
- FDCs- displayed antigen via BCR
43
What do TFH cells do?
- T helper cell
- in B cell follicles
- Driving isotype swtiching and affinity maturation
44
Which T cells do B cells present antigen to? -
- TFH cells
1. B cells get antigen from BCR (FDC source) --> endocytose digest and process antigen
2. Peptide fragments presented on MHC II TO TFH cell
45
What response are TFH cells critical for?
- T cell dependent Ig responses
46
How does T cell help drive B cell proliferation and differentiation?
- B cells have CD40 and T cells have CD40 L
- Cytokines released by Th cell
- These drive cell proliferation and isotype switching
47
What are the 2 principal products of the germinal centre reaction ? ** (important)
1. Plasma cells (secreting Ig)
| 2. Memory B cells
48
What are the two zones of the germinal centre reaction and what do they represent?
- DARK ZONE --> B cell proliferation
| - LIGHT ZONE--> Interactions with Thelper and FDCs happens
49
Which two processes occur in the germinal centres? -
Isotype switching --> light zone
| Affinity maturation --> dark zone
50
What occurs in somatic hypermutation (affinity maturation) and where does it occur?
- occurs in germinal centre reaction (dark zone)
- AICD (Activation Induced Cytidine Deaminase) enzyme causes somatic point mutations in IgV genes (random process)
- Some will be HIGHER AFFINITY and SELECTED FOR in germline reaction
- Some will be LOWER AFFINITY
51
Where do high affinity B cells go after selection in the light zone?
- Go to dark zone to proliferate and differentiate into plasma cells
52
Do B cells or T cells drive isotype swithcing ?
- T Cells!
- CD40L is MANDATORY for this
- Cytokines determine which Ig isotype is secreted
53
Which Ig isotype is does the cytokine IFN-gamma drive?
- IgG1 and IgG3 subclasses of IgG
54
Which Ig type does Il-4 (made by Th2) drive?
- IgE
55
Which Ig type does TGF-Beta drive?
- IgA
56
What is the mechanism of isotype swithcing?
- CD40L + cytokine signalling --> AICD changes nucleotides
| - Switch regions cleaved then joined to other regions
57
What occurs in Ig feedback?
- B cells express FcgammaRIIB Tc receptor --> excess antibody (late immune response)
- FCgammaRIIB recognises complexes --> transduces signals --> INHIBITION OF ACTIVATION
58
What occurs in neutralisation?
- High affinity Ig will neutralise important molecule on pathogen (e.g. glycoprotein that virus uses)
59
What occurs in phagocytosis and opsonisation in terms of the effector functions of Ig ?
- Occurs via complement and Fc recpetors
- Opsonisation--> inflammation
- Igs through interaction with complement can recruit phagocytes to site of infection
60
What is lysis and cytotoxicity in terms of the effector functions of Ig?
- Complement dependent mechanisms of lysis and Fc dependent
61
Which 3 ways can Antibody fight infectious disease?
1. neutralisation (only high affinity IgG and IgA)
2. Opsonisation (IgG and IgA. IgM via complement)
3. Lysis ( via complement -MAC- IgG, IgM)
(ADCC--> IgG, IgA, IgE)
62
What does ADCC stand for?
- Antibody dependent cytotoxicity
63
What are Fc receptors?
- Receptors that bind to non-antigen binding region of Ig (constant domains of Ig heavy chains) --> Fc region
64
Which two systems are involved in B cell effector mechanisms?
- Fc receptors and complement
| - Like giving the antibody teeth ('deadly' to pathogen)
65
In general, when do Fc receptors and complement react with the constant region?
- Once Ig has BOUND antigen
- Ig changes conformation--> can now interact with Fc receptors and complement (exceptions to rule but don't need to know)
66
Where are most Fc receptors found ?
- On immune cells
- Some are inhibitory (on B cells) BUT most are ACTIVATING --> FcR binds Ig -antigen--> cell activated --> phagocytosis, degranulation, oxidative burst, cytokine production
67
Why does the Ig need to be complexed with antigen before binding to Fc receptor to activate?
- Bc. Fc receptor has low affinity for JUST antibody
68
Which Fc receptor has extremely high affinity for its antibody?
- FCER1 has HIGH AFFINITY FOR IgE (binds it monomerically)-- without antigen -exception
69
Is ADCC important for IgE?
YES!
| - For Helminths
70
Is there a lot of IgE in serum ?
- NO!
- because it is stuck on the cell surface of eosinophils, basophils, and mast cellsl--> very HIGH binding affinity
- not soluble
71
Which order do the complement proteins get activated in?
- C1--> C4--> C2--> C3--> C5-C9
72
What are complement proteins?
- Soluble proteins in serum
73
what are the 3 outcomes of triggering the complement pathway?
- Inflammation
- Opsonisation
- Cell lysis
74
Which complement pathway is the adaptive immune response?
- Classical pathway (bc.Igs are involved)
75
What ROUGHLY occurs in the classical complement activation?
- Ig binds to antigen on cell surface
- C1q RECOGNISES IgG or IgM bound to Ig
- C1r + C15 CLEAVE C4--> C2--> C3 convertase --> C3convertase --C3b--> C5 convertase
- then C 5 cleaved and later events occur
76
What occurs in inflammation to trigger complement?
- C3 + C5 proteolysis release soluble fragments C3a and C5a --> attract leukocytes to infection
- Leukocytes have receptors for C3a and C5a (chemoattractant gradients)
77
What occurs in opsonisation and phagocytosis to trigger complement?
- C3b on surface of cell/microbe
| - phagocytes have receptors for C3b--> microbe opsonised by C3b--> recognised by complement receptor and phagocytosed
78
What occurs in lysis to trigger complement?
- MAC--> pore in membrane --> osmotic lysis of microbe
79
What does DAF do?
- Binds to C3 convertases and dissociates them
| - Used to regulate the complement pathway
80
What are the 3 major regulatory molecules in complement activation?-
- CD46
- DAF (Decay Accelerating Factor)
- CD59
81
Which protein can inhibit complement in serum?
- C1 INH prevents proteases from becoming proteolytically active
82
5' end of heavy Ig heavy chain is known as what?
VDJ segments
83
What is the 3' end of the heavy Ig chain gene known as?
- Constant region- genes encoding different constant regions of heavy chain
84
During germinal center reaction what occurs (roughly)?
- Isotype swithcing occurs (AID cuts out switch regions and re-joins to change isotype)
85
What determines whether an Ig isotype can interact with Fc receptors and/or complement?
- Constant region on the Ig
| - Fc and complement will ONLY react with constant region ONCE Ig has bound antigen
86
Which Ig are there multiple subclasses for?
- IgG
87
What does IgD do?
- Acts as a RECEPTOR for naive B cells
- Not secreted
- Function not sure
88
What are IgM chacteristics?
- Receptor of naive B cells
- Needed for first adaptive immune response
- pumped out by plasma cells BEFORE affinity maturation
- LOW affinity so not good at neutralising
- HIGH avidity (pentamer so good at activating complement)
89
Does IgM activate complement well?
- YES!
- Better than IgG
- C1q--> Binds to Fc region of IgM and IgG when bound to antigen
90
What are some properties of IgG1?
- 4 subclasses
- MAJOR SERA Ig
- ACTIVATES complement (but not as good as IgM)
- GOOD OPSONISING Ig (because of Fc receptors)
- Good at neutralising (bacterial toxins, viral receptors)
- GOOD at ADCC (Antibody dependent Cellular cytotoxicity)--> via Fcgamma receptor of NK cells
- CAN CROSS PLACENTA
91
When is IgG formed in the immune response?
- AFTER germinal centre reaction--> T cell help during GCR drives affinity maturation--> quality of Ig goes up later in immune response
92
What are some properties of IgE and what is it found on?
- Fights HELMINTHS
- Allergy response
- Found on surface of mast cells, eosinophils, basophils with FcER complexed on
93
Why is there not much IgE in the sera?
- Because it binds to FcER1 with HIGH AFFINTIY
94
Can IgE activate complement?
- NO!
95
What are the effector functions of IgE dependent on?
- FcER1
96
Is IgE a neutralising antibody?
- NO bc. not found in sera
97
How does IgE drive Mast cell activation?
- covered with Fc receptors for IgE
| - Must cell undergoes signal transduction --> degranulates --> produces histamine, pro-inflammatory cytokines
98
What mediates the weep and sweep response and what responses do they cause?
- Tries to physically expel the worms (IgE crosslinking mast cells via FcER1)
- Pro inflamm cytokines
- Vasoamines WITH IL-4 and IL-13 (Th2) involved
- cause increase in smooth muscle contraciton
- increase in intestinal permeabiliy
- increase in mucous secretion by goblet cells in epithelium (wheezing in asthma attack), increased sensitivity of target cells to mast cell
99
How does IgE mediate ADCC against helminths?
- Eosinophils express FCER1 --> IgE with helminth crosslinking binds --> they become activated --> eosinophils degranulate --> toxic to larval stages of worms
100
What are the two types of IgA?
- Serum IgA (Proinflammatory)
| - Secretory IgA (antiinflammatory)
101
What are some properties of Serum IgA?
- 15% in serum
- Pro inflammatory
- IgA binds to the IgA receptor (Fcalpha R1-CD89) found on Marophages, Eosinophils, DCs, Platelets, Kuffper cells
- Activating phagocytosis, oxidative burst, ADCC, Proinflammatory cytokines (TNF, IL-1, IL-6)
102
What are the proinflammatory cytokines?
- TNF-alhpa
- IL-1
- IL-6
103
What are some properties of secretory IgA?
- IgA2 gene
- forms dimers in mucosal secretions
- Secretory IgA trransported across epithelia to intestinal lumen via TRANCYTOSIS
- Then IgA is in lamina propria (connective tissue where there is lymphoid tissue)
- IgA secreting plasma cell secretes dimeric IgA
- Binds to poly-Ig-receptor on basolateral membrane of cell --> endocytosis--> trancytosis--> lumen of intestine (piece of poly-Ig receptor remains stuck to the IgA dimer--secretory component)
104
When is IgA made in the immune response?
- Made AFTER the germinal centre reaction
| - Affinity maturation occured (high affintiy)
105
What 3 things can IgA do if bacteria produce toxins?
1. IgA can cross BACK into lamina propria and neutralise toxins (stop from damaging endothelial surface) -transported back into the lumen to neutralise
2. On gut surface, can bind and nuetralise toxins and pathogens
3. Internalised in endosomes
106
Why is secretory IgA non inflammatory and which diseases can it go wrong in?
- Bc. it must keep COMMENSAL bacteria alive!
- Also make sure that they don't go into another compartment
- this goes wrong with ulcerative colitis, Chrons etc.
107
What property must the Ig have for neutralisation to occur?
- Ig must be high affinity --> can block by penetration of microbe by binding to it (only if microbe binds to a virus specific receptor)
- e.g. diptheria, cholera, whooping cough
- Ig blocks binding of toxin to cellular receptor (thus no necrosis)
108
How important are Igs in cancer therapy?
- Igs bind to CTLA-4 and PD-1 (which are normally inhibitory molecules of T cells)
- igs binding turns OFF the inhibiotry signals
- thus turns T cells on to make them a better killer of e.g Melanoma
109
Why doesn't IgE opsonise? -
- IgE Fc receptor NOT expressed on phagocytes
- Designed to kill larger helminths
- phagocytes have receptors for C3b
110
What are two effector subsets of Igs that come from Lysis and cytotoxicity?
- Complement lysis
| - Fc dependent ADCC
111
What occurs in complement lysis?
- MAC (C5b, C6,C7,C8,C9_ pokes holes in the pathogen membrane (osmotic shock)
112
What occurs in Fc dependent ADCC?
- Antibody Dependent Cellular Cytotoxicity
- Ig--> Fc receptors and immune cells --> degranulation--> toxic to pathogen
e. g. IgG antigen binding to low affintiy Fc receptor (CD16)
- CD16 on NK cell causes killing of Ig coated cell
