lecture 6 Flashcards by abbie forsyth

What induces clonal deletion?

recognition of self Ag in bone marrow

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What happens when non-self Ag activate a B cell?

allows it survival and differentiation into plasma cell that produces same antibody as the BCR

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What happens once B cells have survived the bone marrow selection process?

B cells move into the blood and lymphatics

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What does antibody secretion by plasma cells result in?

Neutralisation - antibody prevents bacterial adherence
Opsonisation - antibody promotes phagocytosis
Complement activation - antibody activates complement, which enhances opsonisation and lyses some bacteria

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How are B cells activated?

Needs several signals
Naïve B cells express membrane Ig/BCR (IgM (+IgD)) and encounter non-self Ag in secondary lymphoid tissue
Binding of Ag to BCR provides signal 1 to B cell

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What is the molecular basis of Ag/BCR signal 1?

BCR associated polypeptides involved in signalling
Crosslinking BCR activates intracellular kinases

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What is ITAM? What is it’s function?

tyrosine-based activation motif
activated by phosphorylation when receptors are ligated and produces an intracellular signal - leading the cell to do something

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How can signal 1 be increased/enhanced?

If antigen has activated complement cascade - lots of C3b
Complement receptor 2 (CR2) on B cell surface (CD21) - CR2, CD19, CD81 form the BCR co-receptor complex which augments the signal

Binds antigens by B cell receptor and complement receptors on surface
Each b cell has same complement receptor
Means that they can recognise both antigens and other b cells

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If Ag that binds BCR is coated with C, what else can it bind to?

It can also bind CR2 on B cells to give an increased signal
Has complement attached so can engage complement receptor
BCR/CR2 signal sending is stronger that from just BCR

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How do B cells receive signal 2 differently depending on the type of Ag they bind?

Thymus-independent Ag - signal 2 is provided by the antigen itself or by extensive cross-linking of BCR
Thymus-dependent Ag - signal 2 is provided by CD4+ T cells

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What peptides do T cells only signal?

peptides displayed by mhc

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How do TI and TD antigens interact with B cells differently?

TD antigen only interacts with BCR
TI can interact with multiple receptors
Can take antigen up and process it to express its antigens on its mhc class 2 so b cell can activate t helper cell which binds peptide from that antigen producing signal 2

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What is the role of Thymus-independent (TI) Ags?

they lead to antibody production (only IgM) with no requirement for T cell involvement

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What are the two types of TI Ags?

1) TI-1 Ag
2) TI-2 Ag

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Why can TI Ags only lead to antibody production of IgM?

No class switching without t cells can only stay as IgM

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What is the role of TI-1 Ag?

As well as binding to BCR, TI-1 Ag also bids to other receptors on all B cells providing signal 2
In high concentrations, these Ag act as polyclonal activators (mitogens for B cells) - will activate many B cells irrespective of their different BCR
The two signals (1 from BCR, 2 from TLR) lead to B cell activation proliferation and antibody secretion

What is the role of TI-2 Ag?

They contain repeated epitopes, often polysaccharides important in some bacterial infections (coated)
Therefore they will cross-link many BCR molecules on same B cell surface
Take longer to induce B cell activation
Antibody responses to TI-2 typically don’t develop until >6 years in humans

How do TI-2 Ags class switch?

activated dendritic cells release a cytokine BAFF that augments production of antibody against TI-2 antigens and induces class switching

What is the role of Thymus dependent (TD) antigens?

Antibodies to TD Ag require presence of CD4+ T cells
Antibody responses seen to TD Ag are much better than to TI Ag

How do TD antigens work?

T cells are activated by MHC/peptide on APC and BCR binds the antigen producing signal 1
Then B cell internalises Ag, process and presents Ag to CD4+ T CELLS to receive signal 2 via CD40/CD40-L interaction
Cytokines secreted by T cell help B cell to class switch hence all class of antibodies can be produces to TD Ag

Why would you want to convert a TI Ag to a TD Ag?

to improve the efficiency of a vaccine against pathogens that have T1 antigens

How are TI Ags converted to TD Ags?

1) B cell binds bacterial polysaccharide epitope linked to tetanus toxoid protein
2) Antigen is internalised and processed
3) Peptides from protein component are presented to the T cell
4) Activated B cell produces antibody against polysaccharide antigen on the surface of the bacterium

Give three examples of a conjugate vaccine?

Haemophilus influenzae type B
MenC
pneumococcal conjugate vaccine

How do conjugate vaccines work?

They give a protective response which requires antibodies to capsular polysaccharide (which is a TI Ag)
Coupling this to a protein such as tetanus toxoid converts it to a TD Ag -
T-Dependent response to T-Dependent antigen

Why are B/CD4+ cell interactions important for a good antibody response?

B cells enter lymph node from blood If a B cell comes into contact with its specific Ag it can then be activated If Ag is TD, B cell presents peptide from Ag to CD4+ T helper cells at the boundary of the T/B areas within the lymph node forming B/T cell conjugates

What B/CD4+ interactions take place?

In the secondary lymphoid structures, B cell binds Ag via BCR and presents peptide (on MHC class II) from Ag to activated CD4+ T cell T cell then expresses CD40 ligand which secretes cytokines B cell receives signal 2 from T cell via CD40 ligand binding and via cytokine from T cells binding receptors -> B cell proliferation

What does the CD40 signal induce?

Activation induced deaminase (AID) which is required for class-switching and somatic hypermutation

How are B cells activated with TD Ag?

Conjugates of B lymphoblasts and T cells move to primary follicles (B cell areas) Form germinal centres (GC) within a B cell follicle in secondary lymphoid tissues B cells divide rapidly to become centroblasts and undergo somatic hypermutation of Ig genes and isotype switching to differentiate into non-dividing centrocytes Proliferates and hyper mutates in dark zone before moving into light zone to give more help

How do B/CD4+ cell interactions lead to GC formation?

Once in a GC, B cells: 1) either differentiate into plasma cells - secrete various isotypes, high affinity antibody, somatically mutated 2) form long-lived memory cells - recirculate 3) or die within lymphoid tissue - if BCR no longer binds antigen

What is sonic hypermutation?

Introduces point mutations into V regions of Ig Approx. one mutation/V region/ cell division - this is 10^6 x normal DNA mutation rate Using activation induced deaminase (AID) and DNA repair genes

What are follicular dendritic cells?

The are not bone-marrow derived dendritic cells and do not activate T cells Cells in primary follicles that capture intact AG for centrocytes to bind via BCR They do not arise from hematopoietic stem cells Macrophages at periphery of germinal centres

How do follicular dendritic cells capture antigens?

via FcR and CR as immune complexes

How do follicular dendritic cells oversee B cell affinity maturation?

Centrocytes that have undergone somatic hypermutation express mutated BCR on surface Centrocytes thus compete with each other for AG on FDC and for signals If mutated BCR binds with antigen on FDC better than unmutated then will present more efficiently and receive CD40 signal from T(FH) cells (failure = apoptosis or recycle to dark zone) Those centrocytes that have generated higher affinity BCR survive to differentiate into plasma cells

What are follicular T helper cells?

Specialised to provide help for B cells Found predominantly in the B cell follicles of the lymph node Secrete either Th1 or Th2 type cytokines Can be identified with specific markers that differ from other CD4 Th cells

What is the role of CD40, expressed by B cells?

CD40 signal via CD40-L expressed on follicular helper T cell - protects centrocytes from apoptosis Induces isotype switching - different cytokines induce different isotypes to be produced

What happens if there is a CD40-L deficiency?

hyper-IgM syndrome

How does isotype class switching occur?

BCR on B cell in GC will initially be IgM - co-expressed with IgD by differential mRNA splicing Activation-induced deaminase (AID) induces DNA breakage new constant region of antibody joined without affecting existing VDJ region

Which different Ag induce different isotypes?

Random generation of repertoire of BCR and TCR Many self-reactive specificities will be produced If no tolerance, autoreactivity would lead to serious pathology