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49 Cards in this Set

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What does it take for a B cell to differentiate in an Ab-secreting cell?
2 signals:
- binding of the Ag to the BCR
- either CD40/CD40L + cytokines OR recognition of a bacterial constituents via receptors other than the BCR
What are the 2 different types of 2nd signal the B cell can receive?
It varies depending on the nature of Ag:
- proetein Ag -> Helper T cell -> thymus-dependent Ag
- bacterial polysacc -> no T cell needed -> Thymus-independent Ag
What is linked recognition?
- B cell must interact with a T cell that responds to the same antigen
- epitope recognized by T cell must be linked to that recognized by B cell (but does not need to be identical)
What is particular about the linked recognition of more complex antigens?
B and T cells may not even recognize the same protein
How do T helper cells activate B cells?
- recognize antigenic peptide presented by MHC II on B cell surface
- Helper T synthesizes effector molecules (CD40 ligand and cytokines: IL-4 proliferation and IL-5,6 differentiation)
What does B cell needs in order to proliferate and differentiate?
- BCR ligation
- CD40 ligation
- cytokines receptor ligation
- other signals delivered from direct T-cell contact
What is the effector function of Abs determined by?
heavy-chain constant (C) domain (mu, gamma1, gamma2b, gamma2b, epsilon and alpha)
What is isotype switching?
- when a given heavy-chain V domain becomes associated to the C region of any isotype
- it is directed by CD40L and cytokines
What disease can occur in individuals with mutation to CD40L?
X-linked hyper IgM syndrome (high IgM levels and traces of other isotypes since mutation doesn't allow isotype switching)
What is the role of certain cytokines in regulating Ig iosotype expression?
different cytokines preferentially induce switching to partiuclar isotypes
By which mechanism do the cytokines induce switching?
- by stimulating transcription at low rates of mRNA from 5' end of switch regions (near heavy-chain C gene)
- "switch" transcripts are not translated
- translation makes "switch" regions accessible to enzyme AID, APE1 and UNG
What are the roles of AID, APE1 and UNG?
introduce single-strand nicks in the DNA
What repairs nicks in DNA during isotype switching?
DNA-PK and other repair enzymes initiate double-strand break repair, join the switch regions and remove intervening sequences
How is isotype switching different from V(D)J recombination?
- all isotype switch recomb is productive
- does not require RAG enzymes
- it happens only when mature B cell encounter foreign Ag and not during cell development
- switching is not random but directed by external signals (CD40 and cytokines)
What is the frequency of naive lymphocytes for any given Ag?
1/10^4 to 1/10^6
The chance that a B cell encounters a T cell that recognizes the same Ag?
1/10^8 to 1/10^12
Where do B and T cells segregate in periph lymphoid tissue?
B cell: follicles
T cells: paracortical areas, periarteriolar lymphoid sheath, T cell area (GALTS)
How does an Ag-specific B cell manage to encounter a T cell with an appropriate specificity?
- B cells enter the T zones as they migrate to the follicles
- B cells that have bound Ag thru their BCR are stopped in the T-cell zone (increased adhesion molecules and chemokine receptors such as CCR7)
- this maximizes their chance of encountering a T cell that can activate them
What happens to some B cell and their cognate T cell?
they migrate at the junction of the T cell area and the red pulp where they divide to form a primary focus
When does the primary focus appear?
5 days after infection
What is a plasma blast?
a cell that is actively dividing and that will later secrete Abs, some proliferating B cells become plasmablast
What do plasmablasts differentiate into?
short-lived plasma cells that secrete Abs for a few days or die (immediate protection)
What do other B cell blasts do?
along with T cells, they migrate to a nearby follicle where they start to proliferate further and form what is called a germinal center
What do activated B cells do when they enter the follicle?
divide intensively (once every 6 hr) - centroblasts, they form a dark zone in the germinal center
What do centroblasts give rise to?
centrocytes (re-express Ig on their surface) which migrate towards follicular dendritic cells - form light zone of germinal center
What happens to the B cells that were in the follicle before development of germinal center?
they are pushed to the outside to form the mantle zone
What is affinity maturation?
the gradual increase in affinity of Abs for the Ag
What two processes result in affinity maturation?
- somatic hypermutation in the Ig V region genes
- selection of B cells in which somatic hypermutation has produced Ig with hugh affinity for Ag
Where does somatic hypermutation occur?
in dividing centroblast, it is a random process and it occurs at a high rate (1 bp/ 10^3/ cell division)
What are the results of somatic hypermutation?
mutant Ig are expressed on the surface of centrocytes:
- no longer recognize Ag OR
- bind Ag with a lower affinity than the Ig expressed by precursor B cells
- bind antigen with a higher affinity than the Ig expressed by precursor
How do the centrocytes get selected?
in 2 stages:
- centro must bind and take up Ag and then interact with Ag-specific T cells
- surviving B cells undergo repeated cycles of mutation and selection
How is the Ag stored in the GC?
it can be in the form of Ag:Ab complement or complex bound to Fc and complement receptors on surface of FDC
What happens of GC B cells that survive?
- they first differentiate into plasmablasts
- some plasmablasts then differentiate into plasma cells or memory B cells
What protein regulates differentiation into plasma cells?
BLIMP-1 (transcriptional repressor that switches off genes)
What are the differences between plasmablasts and plasma cells?
- plasmablast: high surface Ig, have surface MHC II and high rate of Ig secretion
- plasma cell: low surface Ig, no surface MHC II, and high rate of Ig secretion. Also, it can no longer grow, undergo somatic hypermutation and isotype switching
What happens to plasma cells?
- a subset will live in the bone marrow for a long period of time
- others will migrate to the red pulp of the spleen
What memory B cells?
they express surface Ig but do not secrete Ab at a high rate (have same changes as their precursor)
What are thymus-independent Ags?
bacterial polysacc, polymeric proteins and lipopolysacc that can stimulate naive B cells without T cell help
- there are 2 classes of TI Ags: TI-1 and TI-2
How does TI-1 operate at high conc?
at high concentration, TI-1 Ags induce proliferation and differentiation of B cells in absence of specific Ag binding to surface Ig
How are B cells generated?
by polyclonal activation, TI-1 Ags are called polyclonal B-cell mitogens
How does TI-1 operate at low conc?
only B cells whose Ig receptors bind to TI-1 molecules are activated
How are the B cells generated?
TI-1 Ag-specific antibody response
What are TI-2 Ags?
consist of bacterial cell-wall and capsular polysacc (highly repetitive structures)
What do TI-Ags activate?
- only mature B cells
- B-1 cells and marginal zone B cells respond well to TI-2 Ags
What is the advantage of their repetitive strcuture?
TI-2 Ags alone can signal B cells to produce IgM Abs
What is BAFF?
a TNK family cytokine, it can augment production of Ab by B cells and induce class switching
Why are cell wall polysacc hard to attack?
they resist to ingestion by phagoctyes -> don't present bacterial peptides -> don't stimulate T cell response
What do Abs do against bacterial cell wall?
- opsonize by macrophages
- present bacterial peptides with MHC molecules
- stimulate T cell response
Which Ag does not show any Ab response in infants?
TI-2 Ags