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