Lecture 12 - B cell mediated responses Flashcards
B cell survival: what maintains their survival in germinal centres?
B cells are inherently prone to dying, so maintaining their population is mostly reliant on survival signals:
* Antigen from APCs (dendritic cells)
* T cell interactions (Tfh cells)
Primary focus: what is it, what do they produce, how long do cells stay in it, what may they progress into, and how do they differentiate?
Primary focus - forms when T/B-cells encounter antigens and create a Focus that allows for T/B-cell development
Prompt secretion of specific Ab, mostly IgM isotype – immediate protection
T cells and B cells proliferate in primary focus for several days
Germinal centres - B-cells in the Primary Focus may move and form Geminal centres which allow for further proliferation, maturation, and development
- Some B cells differentiate into antibody-synthesising plasmablasts, while others migrate to the lymphoid follicle
- After a few days plasmablasts die or terminally differentiate into plasma cells.
- Some plasma cells stay in lymphoid organs (short-lived) or migrate to bone marrow, where they continue to produce Ab.
Plasmablasts: what are they and what do they do?
Cells that secrete Ab but have features of activated B cells that allow interaction with T cells e.g. MHCII
After a few days, plasmablasts die or terminally differentiate into plasma cells that either stay in lymphoid organs (short-lived) or migrate to the bone marrow where they continue to produce Ab
Plasma cell differentiation: what are the associated morphological changes, how long do they survive, and do they interact with T-cells at this point?
- Reflect a commitment to the production of large amounts of Ab (20% of protein synthesised by cell) - prominent perinuclear Golgi apparatus and extensive rER
- Plasma cells can no longer present antigens to T cells as they do not express MHCII
Plasma cells can have a range of lifespans, some a few weeks some extremely long-lived – which explains the persistence of Ab responses
Not directly, but T cells can still provide important signals for plasma cell differentiation and survival e.g. IL-6 and CD40L
Germinal centres: what are they formed from, what are they, and what do they do?
Activated B-cells move from near to the T-cell-rich zone and form germinal centres
Areas of intense B-cell proliferation that cause B-cells to undergo intense proliferation and somatic hypermutation
B cells undergo several important modifications in germinal centre that produce more effective Ab response:
* Somatic hypermutation, alters V regions of immunoglobulin genes and enables affinity maturation – survival of B cells with high affinity for antigen
* Class switching allows the selected B cells to express variety of effector functions for Abs of different classes
* B cells differentiate into memory B cells or plasma cells (these produce high affinity class-switch Ab during latter part of primary immune response)
B cells in germinal centres: how long do they survive and what affects their survival?
Prone to dying very quickly
Need survival signals:
* Antigen – supplied by FDCs
* Tfh cell interactions
Peripheral B cell tolerance: what is it and what is it caused by?
Peripheral tolerance is a process that prevents autoreactive B cells from maturing in peripheral lymphoid tissues
B-cell activation requires T-cell help through activation to the same antigen and so since T-cells that react to self-antigen aren’t able to become activated, they can’t activate B-cells
What mechanisms are autoreactive b cells destroyed?
- Failure to bind and present antigen -> fail to receive survival signals
- Binding of soluble self-antigen -> apoptosis
- T follicular regulators - suppress B-cell activation
Tfh: in what kind of ways do they affect B cells and how do they cause these effects?
Survival - BAFF, IL-4, costimmulation with CD40 - leads to BCL-2, BCL-XL, and MCL-1 expression
Proliferation - induced by CD40-CD40L binding
Differentiation - IL-21 secretion, causing B-cell BLIMP1 expression
Hypermutation - IL-21, IL-4 secretion causing B-cell TF expression - AID and BCL-6
Immunoglobulin class switching - IL-4, TGFbeta, IL-17, and IL-21 secreted and promote class switching
Adhesion - SAP binds to SLAMF
Attraction - CXCL13 secreted which causes CXCL5 expression
Class switching: what is it caused by and how random is it?
Class switching involves the rearranged V region of the heavy chain being placed in front of a different C region
The selection of a particular C region is not random but directed by cytokines but heavy V chains are random
Antibody distribution: why is a wide distribution required, what is their standard movement, and are there any exceptions?
Pathogens can find their way to most sites of the body – antibodies widely distributed to combat them
Diffusion
IgA - mucosal surfaces, IgA secreted as a dimer, binds to polymeric immunoglobulin receptor (pIgR) on overlying epithelial cells, and transcytosis occurs where it is released into the mucus layer by proteolytic cleavage of the extracellular domain of pIgR (aka secretory component) which remains associated with IgA as it is secreted and helps glue it in the mucus layer
Antibodies: how are they different between the classes and do they still have the same specificity?
Antibodies of different classes are adapted to function in different compartments of the body
Progeny of a single B cell can produce Abs that share the same specificity but provide protective functions appropriate to each body compartment
IgM: when is it formed, what is its affinity for specific antigens, where is it mostly found, what reaction is it best at causing, and what cytokines is it affected by?
First Ab formed - can be expressed without class switching
Typically low affinity but higher overall avidity - good at binding multivalent antigens
Usually found in the bloodstream (large-size pentamer) to control infections in the bloodstream (they may have serious consequences normally)
Complement
Inhibited by:
IL-4
TNF-gamma
TGF-beta
IgA: what is it, what does it do, what is its affinity for specific antigens, where is it mostly found, what reaction is it best at causing, and what cytokines is it affected by?
Monomeric Ab - principal class in secretions
Diffuse easily out of blood into tissues and can form dimers
High affinity - can neutralise bacteria toxins
IgA - poor opsonin and weak activator of complement, functions mainly as a neutralising Ab, often acting as dimeric IgA at sites where there are few phagocytes
Induced by:
* TGF-b
* IL-21
* IL-5 augments production
IgG: what is it, where is it found, what is its affinity for specific antigens, what reaction is it best at causing, what types are there, and what cytokines are they affected by?
Principal class of antibody in blood - the only antibody subclass that can substantially cross the placenta, monomeric Ab, can diffuse easily out of blood into tissues
High affinity - can neutralise bacteria toxins
IgG - strong neutralising Ab, efficient opsonin for engulfment of pathogens by phagocytes and good activator of complement
- IgG1 - IL-4 (ind), IL-21 (ind), IFNγ (inh)
- IgG2a - IL-4 (inh), IFNγ (ind)
- IgG2b - TGF-β (ind)
- IgG3 - IL-4 (inh), TGFβ (inh), IFNγ (ind)
IgE: what is it, what is its affinity for specific antigens, where is it mostly found, what reaction is it best at causing, and what cytokines is it affected by?
Monomeric Ab - can diffuse easily out of blood into tissues
High affinity
Low levels in the blood or extracellular fluid but bound avidly by receptors on mast cells
Activates mast cells and leads to coughing, sneezing, and vomiting – aiming to expel infectious agents
Induced by IL-4
Inhibited by INF-gamma
