B cells and natural killer cells Flashcards
(25 cards)
Where do B cells arise from
Arise from a common lymphoid progenitor – like T cells
Where are B cells selected
In the bone marrow
What are other characteristics of B cells
B cells recirculate – tissues and lymphatics until they are challenged by an antigen
B cells do not need antigens to be presented to them by the MHC
For activation they interact with the soluble antigen or on the surface of obstacles
They are 1 of the classes that are professional antigen presenting cells
B cells present antigens on MHC-II to T cells
Where do B cells go after leaving the bone marrow
B cells will leave the blood vessels and into the interstitial space
Lymph nodes will be encountered where B cells can reside
B cells can also be in the spleen
How do B cells develop
Haematopoiesis occurs in the bone marrow of the long bones, pelvis and sternum
B cells develop and mature in the bone marrow through the pathway pro-B –> precursor B –> B cell
They undergo Ig gene arrangement to reach maturity
10% of B cells mature and exit the bone marrow but are naïve (they have not found an antigen)
They will die in the periphery after a few days if no antigens are encountered
What is central selection/tolerance
B cell development / selection of non-self-reactive B cels show similarities with the T cell thymic selection but occurs mainly in the bone marrow
There are 3 checkpoints in B cell development
CD79a and CD79b expression on late pro-B cells – are important for signal transduction during B cell maturation
Successful recombination of the H-chain locus
Same applies for the L-chain locus
If any of these 3 points do not occur apoptosis will occur
What are important milestones for B cells during maturation
Mature B cells express IgD > IgM (IgM following BCR activation)
B cell self-tolerance initiates when IgM expression begins
B cells do not need to recognise self (MHC) like T cells – however they must ignore (or tolerate) self (MHC)
Negative selection ensures that B cells ignore self
Any B cells that produce antibodies that interact with multivalent cell surface self (MHC) cross linking of BCRs (high avidity) causes the B cell to die (apoptosis)
a receptor rearrangement stage before death 2nd chance to
produce a non-self reactive BCR
What happens to BCRs that react with soluble self Ag at low valence
down regulate IgM
(IgD) alone –> anergic (non-reacti
How do B cells activate
BCR-Ag interaction activates LYN (a protein) - this phosphorylates Igβ (CD79b) and CD19 of the (CD19/CD21/CD81 complex)
A cascade of phosphorylation events occur – culminates in RAS / PI3 kinase activation
InsP3 generation and Ca2+ release
Ras (proliferation)
Differentiation InsP3 mediated Ca2+ spikes and oscillations mediate the activation of NF-(kappa)B and/or NFAT transcription factors
NF-(kappa)B = nuclear factor kappa-light-chain-enhancer of activated B cells
NFAT = nuclear factor of activated T cells – supports proliferation
What are the 2 mechanisms B cells can activate
T-dependent and T-independent
Types of B cells
B-2 cells are the most abundant (generally named “B cells”
B-1 cells
Follicular B cells
Marginal zone B cells
Regulatory B cells
Plasma B cells
How is the T-dependent mechanism mediated
TD response is mediated by B-2 B cells interacting with the TD antigens
TD antigen cross-links BCR – some BCR TD antigen complex is internalised, processed and presented on MHC-II
T helper cells engage with the B cells through complementary TCR and co-stimulation to B cell via CD40
How does the T-independent mechanism differ and how is it mediated
T-independent (TI) has 2 mechanisms
TI-1 is where the B cell binds to the antigen at BCR amd recieves a co-stimulation via the “toll-like receptor” (TLR) from a super antigen like LPS
TI-2 antigens are often bound to complement protein C3d – this crosslinks BCR (12-16 crosslinks required) with co-stimulation from CD21
What are the positives and negatives of the T-independent mechanism
This speeds up the humoral response from the B cells but misses out on cytokines which are secreted by the T helper cells
This prevents Ig class switching from happening
How is the T-dependent mechanism activated
B cells enter the lymph node through the high endothelial venules into the “T cell zone” - this is where the Ag challenged B cells interact with T helper cells
TD activated B cells migrate to germinal centre –> leads to clonal proliferation in dark zones
Clones with high Ag affinity are selected in basal light zones (differnetiate)
Plasma cells / memory precursors proliferate in apical light zone
What is the role of TH2 cytokines
They are central to B cell TD activation, proliferation and Ig class switching
IL-4, IL-5 or IL-6 plus CD40 ligation mediate clonal proliferation and differentiation to IgM secreting plasma cells
How does B cell isotype switching occur
Class switching requires cross-talk between CD40 and IL-4
CD40 activation is required for NF-(Kappa)B activation – nuclear localisation
IL-4 is required for STAT-6 activation
This binds upstream of S(epsilon) IgE constant chain gene segment
Promotes AID (activation induced deaminase) binding and subsequent genomic splicing
What can mature naive B cells express
Mature naïve B cells express both cell surface IgD and IgM
How do natural killer cells arise
They differentiate early from the T cell lineage
They do not express T or B cell markers (CD3, CD44, CD8, CD19)
NK cells are innate (not adaptive) in function and are believed to be more primitive
What is the general immunophenotype for NK cells
CD3-CD19-CD56+
What system do NK cells belong to
The innate immune system
What is expressed on the surface of an NK cell
They express CD94 / NKG2a at their cell surface
This complex interacts with MHC-I (HLA-E)
This interaction sends a suppressive signal to the NK cells
What happens when MHC-I (HLA-E) is lost from the cell surface
When cells become malignant HLA-E (MHC-I) is lost from the cell surface (missing self) –>CD94 /NKG2a mediated NK cell suppression is lost
NK becomes activated and releases cytolytic vesicles (degranulate) killing malignant cell
NK cells (CD56++) secrete IFN(gamma) and IL10 – therefore they have an immune regulatory role
NK cells (CD56+) are cytotoxic in function
What is ADCC
antibody-dependent cell cytotoxicity
