Lecture 12 - B cell mediated responses Flashcards
Primary focus: what is it, how long does it last
Primary focus - forms when t-cells and b-cells meet, (do lots of reading for this or rewatch lecture or both im SO confused lmfao…)
T cells and B cells proliferate in primary focus for several days
Some B cells differentiate into antibody-synthesising plasmablasts, others migrate to lymphoid follicle.
Plasmablasts = 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.
Some plasma cells stay in lymphoid organs (short lived) or migrate to bone marrow where continue to produce Ab.
Differentiation of B cell into plasma cell associated many morphological changes.
Reflect commitment to production of large amounts of Ab (20% of protein synthesised by cell).
Prominent perinuclear Golgi apparatus and extensive rough endoplasmic reticulum.
Plasma cells can no longer present antigen to T cells as they do not express MHCII.
T cells can still provide important signals for plasma cell differentiation and survival e.g. IL-6 and CD40L.
Plasma cells can have a range of lifespans, some a few weeks some extremely long-lived – explains persistence of Ab responses.
Germinal centre in lymph nodes
Reading
Primary focus leads to prompt secretion of specific Ab, mostly IgM isotype – immediate protection.
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 (Lecture 8, BIOL21242).
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
*
Peripheral B cell tolerance
Peripheral tolerance is a process that prevents autoreactive B cells from maturing in peripheral lymphoid tissues
prevents mature B lymphocytes to respond against self-antigens in peripheral tissues by anergy, deletion, and regulation.
What mechanisms are autoreactive b cells destroyed?
*Failure to bind and present antigen -> fail to receive survival signals
* Binding of soluble self antigen -> apoptosis
* Role of T follicular regulators`
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 - CD40-CD40L binding
Differentiation - IL-21 - BLIMP1 expression
Hypermutation - IL-21, IL-4 - AID and BCL-6 expression
Immunoglobulin class switching - IL-4, TGFbeta, IL-17, and IL-21 secreted - promotes class switching
Adhesion - SAP binds to SLAMF
Attraction - CXCL13 secreted - causes CXCL5 expression
Class switching: what is it caused by?
Class switching involves rearranged V region of the heavy chain being placed in front of a different C region, selection of particular C region is not random but directed by cytokines.
Antibody distribution
Pathogens can find their way to most sites of body – antibodies widely distributed to combat them.
Most classes of antibodies distributed by diffusion from site of synthesis but some require specialised transport mechanisms e.g. delivery to lumen of lung or gut.
Antibodies of different classes are adapted to function in different compartments of the body.
Any V region can become associated with any C region (through class switching) progeny of a single B cell can produce Abs that share same specificity but provide protective functions appropriate each body compartment.
IgM
First produced in humoral immune response, can be expressed without class switching.
Low affinity but form pentamers – higher overall avidity when binding to multivalent antgens e.g. bacterial capsular polysaccharides.
Due to large size pentamers usually found in blood stream (not in intercellular spaces in tissues).
Especially effective in activating complement system (Lecture 4).
Infection of blood stream has serious consequences important that it’s controlled quickly.
Some IgM produced secondary response but other antibodies come to dominate later in response.
Inhibited by:
IL-4
TNF-gamma
TGF-beta
IgA
Monomeric, diffuse easily out of blood into tissues. IgA can form dimers. Unlike pentameric IgM affinity of individual antigen-binding sites is critical.
IgA = poor opsonin and weak activator of complement.
IgA functions mainly as neutralising Ab, often dimeric IgA at sites where few phagocytes e.g. out in lumen of gut.
High affinity - can neutralise bacteria toxins
IL-5 augments production
Induced by:
* TGF-b
* IL-21
IgG
IgG principal class of antibody in blood. IgA principal class in secretions. IgG is the only antibody subclass that can substantially cross placenta.
IgG = efficient opsonin for engulfment of pathogens by phagocytes and good activator of complement.
High affinity - can neutralise bacteria toxins
IgG1
IgG2A
IgG2B
IgG3
IgE
IgE, low levels in blood or extracellular fluid but bound avidly by receptors on mast cells. Antigen binding activates mast cells leads to coughing, sneezing, vomiting – expel infectious agents.
Induced by IL-4
Inhibited by INF-gamma
IgG1
?
IL-4 and IL-21
IFN-γ
