B lymphocyte mediated immunity Flashcards
what are the 2 roles of BCRs
- initiate signalling cascade upon Ag binding
- deliver Ag to intracellular sites for antigen processing & presentation to T-helper cells
what are the 2 types of B cell activation
thymus-dependent: via T-helper cells
thymus-independent: via BCR clustering
thymus-dependent B cell activation
- needs the help of T cells
- presents protein antigens
- CD40:CD40L is the signal for survival
- T cell secretes IL-21 for proliferation and differentiation
thymus-independent B cell activation
- 2 types: TI-1 antigen (clustering of BCRs, TLR) TI-2 antigen (BCR + C3d and CR2)
- BCR clustering leads to signalling
- presents multivalent antigens (carbohydrates)
what is linked recognition
how B cells and T cells work together in B lymphocyte mediated immunity -to mount an immune response against the same pathogen
- present in B cell mediated immunity
what is the second signal required for B-cell activation by thymus-dependent antigens
- from helper TCR:MHC II
- NFkB pathway
what is the second signal required for B-cell activation by thymus-independent antigens
- TLR binds LPS
- myD88 and IKKy activate NFkB pathway
what is the first signal required for B-cell activation
- BCR binding antigens
- PI-3 kinase activates Ras/MAPK pathway to activate AP1 and NFAT TF’s
what is Mcl1
anti-apoptotic gene which is transcribed in the thymus-dependent pathway of B-cell activation
what are the different cytokines that T-helper cells provide to activate B cells and control their differentiation
IL-6
TGF-B
IFN-y
IL-4
how do T-helper cells provided help to B cells that recognize a linked epitope
- T cells are activated to antigens that may reside within the viral particle
- B cell that recognizes a surface epitope of a virus can process and present other antigen epitopes
how do antigen-binding B cells meet T cells at the border between T-cell area and B-cell follicle in SLO’s
(give step by step)
- before activation resting B cells express CXCR5 and reside in follicles, T cells express CCR7 and reside in T-cell zones
- activated B cells induce CCR7 and EBI and T cells induce CXCR5
- both cells migrate to follicular and inter-follicular regions
- B and T cells aggregate at the periphery of follicles
what is the fate of B and T cells after they aggregate in periphery of follicles
- some B cells migrate to form a primary focus and differentiate into plasmablasts
- some T cells induce Bcl-6 and become T-FH cells
what are the 2 possible differentiation steps that B cells which receive T cell help can undergo
- T-FH interaction, remain in follicle: form plasma blast (primary focus) + plasma cell
- no T-FH interaction, outside follicle: form germinal center
what is the difference between a primary and secondary focus?
primary = B cell with no TH interaction, early and rapid Ab production - short-lived
secondary = B cell with strong TH connection, sustain and long-term Ab production, long-lived
when inside lymphoid follicles, activated B cells form…
germinal centers: site for refining B-cell responses (affinity maturation + somatic hyper mutation, class switching)
when B cells form germinal centres inside lymphoid follicles, how do the plasma cells get to bone marrow?
- when B cell encounters antigen in the follicle it forms a primary focus
- some proliferating B cells migrate into the follicle to form a germinal centre
- plasma cells migrate to the medullary cords or leave via efferent lymphatics
- plasma cells migrate to the bone marrow
what are the different zones of germinal centers
- mantle zone
- Dark zone
- Light zone
The dark zone of a germinal center
- contains rapid proliferating B cells (centroblasts) that express CXCR4
- CXCR4 is attracted to CXCL12 produced in dark zone
- densely packed with proliferating cells
- somatic hypermutation of Ig genes happens here
The light zone of a germinal center
- contains T-FH cells
- contains slower proliferating B cells (centrocytes) that express CXCR5
- CXCR5 is attracted to CXCL13 by follicular DCs in light zone
- affinity maturation where B and T-FH test reactivity to new Ig happens here
- cells can return to dark zone for additional rounds of Ig mutation if needed
which area of the germinal centre does class switching happen in
the dark zone
centrocyte vs centroblast B-cell make-up
centrocyte: CXCR5, CD83, CD86
centroblast: CXCR5, CXCR4
where does the primary antibody become diversified
centroblasts (dark zone)
includes somatic hypermutation and class switch
what is the difference between affinity maturation and somatic hypermutation
- IgM is the first antibody made but does not have high affinity
- somatic hypermutation introduces mutations into the rearranged Ig V regions to produce a diverse pool of B cells
- affinity maturation ensures only B cells producing high-affinity antibodies survive and expand
basis of class (isotype) switching
- facilitated by cytokines secreted by T-helper cells
- occurs within the germinal centre AFTER antigen contact
- class switch in H chain constant region gene initiated by AID
what is AID
activation-induced cytidine deaminase
initiates Ig gene rearrangement for class switching
which antibodies are produced before class switching
IgM and IgD
which antibodies are produced after class switching
IgA, IgG and IgE
IgM isotype characteristics
- Default C region used for mature naive B cell Ig
- rapid first phase of B cell response to primary infection
- low affinity, high avidity
- large, primarily in blood
IgD isotype characteristics
- co-expressed with IgM during maturation
- no known function
IgG isotype characteristics
- class switching
- 4 subclasses
- monomeric
- small, diffuses into tissues
- found in blood and extracellular fluid
- the predominant antibody class
- transported across the placenta
- high affinity
IgE isotype characteristics
- class switching
- monomeric
- small, diffuses into epithelial tissues, but less abundant
- sensation of type 2 immune cells (mast cells)
- high affinity
IgA isotype characteristics
- class switching
- can exist as monomers or dimers
- smaller, diffuse into secretions at mucosal epithelial surfaces
- transferred through breast milk
- high affinity
which antibody classes can diffuse into extravascular sites
all IgG classes and the IgA monomer
which antibody class transports across the epithelium
IgA dimer
what are the 5 mechanisms of protection by antibodies
- neutralization
- opsonization
- antibody-dependent cell-mediated cytotoxicity by NK cells
- sensitization by mast cells
- compliment activation
protection by antibodies: neutralization
- antibody protects cells by blocking toxin or bacterial adhesion binding to cellular receptors
- best neutralizers = IgA and IgG
- doesn’t need additional activation of other immune cells
protection by antibodies: opsonization
- allows for phagocytosis of the pathogen
- best opsonins = IgM and IgG
- mediated by Fcu/y receptors on phagocytes (macrophages and neutrophils)
protection by antibodies: antibody-dependent cell-mediated cytotoxicity by NK cells
- NK cells (or CD8 T cells) destroy antibody-bound targets by ADCC
- best ADCC activation antibodies = IgG
- antibody binds antigens on the surface of target cells and the Fc receptors on NK cells bind these antibodies to kill cell by apoptosis
protection by antibodies: sensitization by mast cells
- best mast cell activating antibody = IgE
- antigen binding cross-links IgE molecules to activate mast cell and release granule contents
- also activates anti-parasitic functions
protection by antibodies: complement activation
- best complement activators = IgM and IgG
- C1q binds one IgM OR 2 IgG
- C1q:CRP’s complex then binds to antibodies binding microbes
what is somatic hypermutation
when Ig genes are mutated
what are the targets of each mechanisms of protection by antibodies
neutralization = extracellular pathogens, toxins
opsonization = extracellular bacteria, fungi
sensitization for NK cells = intracellular pathogens (viruses)
sensitization of mast cells = extracellular parasites
activate complement = extracellular bacteria, fungi
