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230 Cards in this Set

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  • Back
What mediates the humoral immunity?
serum Ig, which are proteins secreted by the B cells
What are the 5 major classes of Ig?
IgG, IgA, IgM, IgD, IgE
Briefly describe the Ig structure?
Consists of two identical light chains and two identical chains linked by disulfide bridges
What does the hummoral immunity result from?
activities of antibodies
What was the first branch of immunity studied?
humoral immunity
Historically what were the "humors"?
the fluids of the body
What are the three major purposes of the humoral immunity?
Neutralization, Opsonization, Complement activation
What does the humoral immunity protect?
the extracellular spaces of the body
How might the "humors" be transferred between individuals?
-transfusion
-from mother to fetus
How many antigens do each of the variable regions of the antibody recognize?
both recognize a single antigen
How many domains might a heavy chain consist of?
4-5
How many domains does a light chain have?
2
What are the types of light chains?
kappa and lambda
What are the differences in the functions between the light chains?
unknown
What are the two fragments of the Ig?
Fab & Fc
Fab
fragment antigen binding
Fc
no antigen-binding activity
What do the Fc and Fab fragments allow for in research?
they allow researchers to determine which portion of the molecule was involved in various functions
What portion might be involved in targeting tumor cells?
Fv portions
Which of the classes have no hinge region or disulfide bonds in their structure?
IgM & IgE
Which is the first of the five classes to be produced?
IgM
Which is produced second and in what order do the others follow?
IgG is second, followed by IgA, IgD and IgE
What determins the function of each class?
heavy-chain structure
W/o the hinge region do IgM and IgE have flexibility?
YES
Other than presence and absence of the hinge region what else varies between the classes in the structure?
location of carbohydrate groups
What does RNA processing determine?
which class is formed
What signals the B cell to undergo class-switching?
cytokines
Where are B cells with IgM on their surface found?
on secondary lymphoid organs
Which Ig can diffuse into the brain and cross the placenta to give an infant immunity to the pathogens which she has been in contact with?
IgG
Which of the Ig produces the pentameric structure?
IgM
How many antigen binding sites does the IgM have?
10
What limits binding to 5 or fewer large antigens on the pentameric structrure?
Steric hindrance
Why is it so hard for the IgM to cross the epithelial layer?
it is a large structure
Where is IgM usually found?
blood
What is IgM very effecient in?
complement activation
What is the main Ig in breast milk?
IgA
Where is the IgA found?
secretions: tears, saliva, mucus, sweat, gastric fluid, breast milk
What form is IgA usually found in?
dimeric
How many binding sites does the dimer have?
4
What does the IgA protect us from?
infections of the respiratory and GI tract
Is the IgA class complement activating?
no
What is the function of IgA?
anti-viral activity
How are IgA:antigen complexes in the mucus eliminated?
cliliated epithelial cells
How does the IgA cross the epethelial layer?
by binding the poly-Ig receptor
Which immunity is IgA very important in?
Innate
Describe the process of the IgA crossing the epethelial layer?
-binding of IgA to receptor on basolateral face of epithelial cell
-edocytosis
-transport to apical face of epithelial cell
-release of IgA dimer at apical face of epithelial cell
What protects the IgA dimer from proteolytic cleavage in the gut of an infant?
the secretory component
How does IgA protect an infant through breast milk?
passive immunity; binds to microbes in GI tract & prevents attachment to babies gut
When does a baby begin generating its own Ab?
6 months
What are some problems that breast milk helps prevent?
diahrrhea, ear infections, lower respiratory illness, childhood lymphomas, SIDS, UTI, juvenile diabetes, meningitis, botulism
What do the V regions of Ig have that increases the diversity of antigen binding?
three hypervariable regions
Where are the three hypervariable regions found?
within the antigen binding sites
What is another name for the HV regions?
CDR (complementarity-determing regions)
What is the remainder of the V region (besides the HV region)?
framework region (FR)
What does the combination of V- regions of the heavy and light chains result in?
antigen-specificity
What increases the number of different Ig molecules?
different combinations of heavy chains and light chains
What is the name for the variability of heavy and light chain ?
combinatorial diversity
What does the pairing of the V- region of the heavy chain and the V- region of the light chain domains?
the hypervariable loops of the polypeptide combine to create a single antigen binding site
Describe the generation of diversity in Ig?
DNA (somatic recombination); RNA (transcription & splicing); Protein (peptide chain
What is somatic recombination?
recombination that occurs among DNA segments in somatic cells
How is genetic information transmitted?
as multiple segments
How are gene segments assembled into complete genes?
somatic recombination
How many combinations occur per clone of the lyphocyte?
one
In what order does selection take place?
it is random
How productive is the random process of selection?
it is 55-75% errors, LOTS OF ERRRORS
Where are the three Ig loci found?
On three different chromosomes (light HV kappa, light HV lambda, heavy HV)
What does the heavy chain have that corresponds to the Ig classes?
multiple "C" regions
What is the order of heavy chain gene rearragement?
D-J, V-DJ, VDJ joins C segment
Where does heavy chain gene rearrangement occur?
pro B cell
What is the order of light chain gene rearrangement?
V-J, VJ joins C segment
Where does light chain gene rearrangement take place?
pro B cell
Where does class switching take place?
peripheral organs
What do VDJ regions contain that direct recombination?
recombination signal sequences (RSS) at the junctions
How many base pairs does the RSS contain?
12 or 23 base pairs
What does the 12/23 rule correlate to?
one and two turns of the DNA helix
What does the 12/23 rule state?
that a 12bp can only join to a 23bp
What does the 12/23 rule prevent?
two V segments on one strand of a chromosome from binding to each other
What are the enzymes that catalyze recombination?
RAG-1 & RAG-2 (recombinatoin activating genes)
Are the RAG-1 and RAG-2 enzymes important to the recombination?
yes, very
When are the RAG proteins expressed?
only when lymphocytes are assembling their antigen receptors
If someone were RAG deficient what would be the outcome?
they would be extremely immuno-compromised in that they could not produce Igs or TCRs
How do RAG proteins function, as far as numbers go?
synergistically (very large amounts)
Where does the RAG-1:RAG-2 function as a dimer?
in the VDJ recombinase
What do the RAG proteins do exactly in the recombination sequence?
they interact with one another to bring the segments closer together, then they cleave the DNA
What does TdT (terminal deoxynucleotidyl transferase) do?
increases diversity and function to add N-nucleotides and junctions
What do P-nucleotides result from?
"hairpins"; when the RAG complex binds to and cleaves RSS it yields a hairpin, RAG mediated cleavage of hairpin generates palindomic P-nucleotides
What do P- and N- nucleotides result in?
increased diversity
What do exonuclease cleave?
unpaired strands
What happens with N-nucleotides?
they are added at random by the TdT enzyme, up to 15 may be added
What do out of frame rearrangements result in?
disruption of the triplet reading frame for translation of the protein and premature stop codons
How many VJ and VDJ rearrangements are productive?
only one in three of each , therefore fewer than 1/9 of pre-B cells mature and leave the bone marrow
What is the result of pre-B cells leaving the bone marrow?
you have an Ig that has to be edited to be sure that it is not self-reactive
Briefly outline the stages of a B cell?
development and selection in the bone marrow and later in the periphery activation and proliferation & differentiation
Describe the development stage of a B cell?
B-Cell precursor rearranges its Ig genes; generation of BCR in the bone marrow
Describe the selection stge of a B cell?
Immature B cell bound to cell-surface antigen is removed from the repertoire, negative selection in the bone marrow
Describe the activation stage of a B cell?
Mature B cell bound to foreign antigen is activated, B cells migrate to the peripheral lymphoid organs
Describe the Proliferation and differentiation stages of the B cell?
activated B cells give rise to plasma cells and memory cells; antibody secretion and memory cells in the bone marrow and lymphoid tissue
What does B cell maturation depend upon?
Ig rearrangement
What happens in the pro-B cell?
Heavy chain D-J rearrangement, then V-DJ if the first rearrangement is not productive rearrangement continues on the other chromosome
What happens in the pre-B cell?
expresses a completed heavy chain; light chain rearrangement begins
What happens in the immature B cell?
expresses a productive IgM molecule (BCR) on the cell surface; antigen specificity is confirmed b/c successful completion of the genes that code for proteins to make one antibody molecule has occured, immature B cells cannot interact w/ any antigen at this point or it will induce apoptosis
What happens in the mature B cell?
B cells that are expressing both IgM and IgD antibody molecules on their cell surface can now be released from the bone marrow and interact with antigen in the periphery
What are the other molecules necessary for the stages of development of the B cell in addition to the production of BCR?
accessory molecules
When are the accessory molucules present?
in the pro-B (signaling protein chains Ig-alpha/Ig-beta are expressed), & in the pre-B cell (surrogate light chain comprise of V pre-B and lambda5, associates w/ the successfully rearranged muheavy chain)
What are the four main processes responsible for generation of Ig diversity?
combinatorial diversity of heavy and light chains, combinatorial diversity of gene segments utilized, juctional diversity introduced at joints of gene segments, somatic hypermutation in mature B cells
What is the main result of somatic hypermutation?
antibody affinity for antigen
Where does somatic hypermutation occur?
the germinal centers of the secondary lymphoid orgnans
What do somatic hypermuatations influence?
affinity of antigen binding, mainly occur in the CDRs
Are somatic hypermutations usually base substitutions or deletions?
base substitutions
What does allelic exclusion insure?
specificity for only one antigen
Is allelic exclusion strategic or random?
random
What is allelic exclusion?
expression of only one of the two alleles of a genes in a diploid cell
What would happen if both alleles were rearranged and expressed?
the cell would have more than one antigen specificity
What happens when the rearragement has occured?
the recombination "machinery" is turned off?
What happens when B cells do not productively rearrange?
H and L genes undergo programmed cell death
What happens when immature B cells that bind self antigens?
they undergo apoptosis or become anergic
How might a self-reactive B cell be rescued from cell death?
by replacing the self-reactive receptor with a new receptor
What is the process that replaces self-reactive receptors?
receptor editing
What are the two types of B cell activation?
TD & TI
How many light chain possibilities are there in humans?
approx. 320
How many heavy chains possibilities are there?
8262
How many combinations are there to make one Ig molecule?
8262 x 320 = combinations of heavy & light chains
What is junctional diversity?
addition or subtraction of nucleotides at the recombination site
What might result in imprecise DNA recombination?
junctional diversity, mutations that may occur in the V genes or H or L chains, receptor editing when all DNA segments are not removed following the first VJ or DJ rearragement a second rearrangement may occur, somatic hypermutation
When the Naive B cell enters the peripheral lymphoid organ what happens if it does not encounter its antigen?
cell death
How many Naive B cells undergo cell death b/c they do not encounter their antigen?
approx. 90%
What activates the Naive B cell?
T helper cells + Antigen
What alters the effector function of the B cell but does not change the cell's antigenic specificity?
Class Switching
What two factors does class switching depend on?
antigen stimulation (CD40) and cytokines from T cells
Which chain does the class switching and determines the function of the Ig?
heavy
Does class switching require RAG enzymes?
no
How productive is the class switching process and why?
100%, b/c switch regions are located in introns and cannot cause framehsift mutations
When does class switching occur?
after Ag stimulation
Is class switching organized or random in process?
organized, directed by cytokines from T helper cells
In which stages is mIg expressed on the B cell and in which ones is it not expressed?
expressed: immature and mature

not expressed: pro-B, pre-B or plasma
How can the BCR internalize Ag?
via receptor-mediated endocytosis
BCRs are closely associated with signal transduction molecules, what are these?
molecules that communicate messages from the outer membrane to the nucleus of the cell
What happens following binding of Ag to BCR?
Ig-alpha and Ig-beta transmit the activation signal via phosphorylation ITAMS (immunoreceptor tyrosine-based activation motifs)
On the B cell what presents the Ag to the T cells?
MHC Class II
What is critical for antibody class-switching and w/ what does it interact?
CD40 ; CD154
T cells only recognize antigen when presented by...?
MHC class 2
How does the structure of the secondary lymphoid organs increase the liklihood of antigen stimulation?
it increases the liklihood of B and T cells coming in contact w/ one another
Chemoattractant cytokines
chemokines
Secondary lymphoid organs are specialized for what?
trapping cells that have found their Ag
What is it in the secondary lymph organs that traps Ag B cells?
dendritic cells
What realeases chemokines?
dendritic cells
What goes on in the germinal center of the lymph nodes?
high B cell proliferation, somatic hypermutation, affinity maturation, class switching, follicular DCs trap Ag-binding B cells, release chemokines
What are the chances of B and T cells coming in to contact with each other without the help of lymph tissues?
very low more than one in a million
Interaction of the b cell with a helper T cell activates the B cell to establish what?
primary focus of clonal expansion which will last for several days after which the many of the cells in the primary focus undergo apoptosis, some differentiate into plasma cells
Plasma cells are terminally differentiated B cells that secrete large amounts of Ig, what does this mean?
They can not become anything else, they will carry out purpose and die
Does the resting B cell or the Plasma cell have high concentrations of surface Ig?
Resting
Which has high concentrations of MHC class II resting B cells or Plasma cells?
resting B cells
Which has a high-rate of Ig secretion resting B cells or plasma cells?
plasma cells
What is the role of the resting B cell?
bind Ag by their surface molecules & present to T cells via the MHC class II, the T cells signal the B cell to proliferate, class-switch, and undergo somatic hypermutation
What is the role of the plasma cell?
to secrete large amounts of Ab, no longer class-switch or undergo further somatic hypermutation
Characteristics of the primary response:
initiated by naive B cell, takes 5-10 days, predominately IgM secreted, smaller amount of Ab produced, lower antigen affinity
characteristics of the secondary response:
initiated by memory B cell, 1-3 days, other classes such as IgG are largely produced, larger amounts of jAb are produced, greater Ag affinity
humoral immunity
refers to immune responses that involve Ab; can be transferred to another individual by using antibody-containing serum
heavy chain
the larger of the two types of chains that make up a normal Ig or Ab
passive immunization
immunization of an individual by the transfer of Ab synthesized in another individual
light chain
the smaller chain of the Ig molecule; occurs in two forms kappa and lambda
IgM
the class of Ig characterized by mu H chains; IgM is the first to appear on the surface of B cells and the first to be secreted following B cell stimulation w/ antigen
IgG
the class of Ig characterized by the gamma H chains; the most abundant class of Ig found in plasma
IgA
the class of Ig characterized by alpha H chains; antibodies are mainly secrected by mucosal lymphoid tissues
IgD
the class of Ig charactererized by delta H chains; a cell surface Ig co-expressed on naive B cells together w/ IgM; may function as a coreceptor that binds to IgD receptors expressed on T cells
IgE
the class of Ig characterized by te epsilon H chains; involved in allergic reactions
Poly-Ig receptor
binds to IgA at one surface of an epithelial cell, transports it through the cell and releases it at the opposite lumenal surface; the IgA can then participate in protecting the mucosal system
secretory component
cleaved component of the poly-Ig receptor that attaches to dimer IgA and protects it from proteolytic cleavage as it is transported through an epithelial cell
J chain
a polypeptide involved in the polymerization of Ig molecules IgM and IgA
Fc receptor
a receptor on a cell surface w/ specific binding affinity for the Fc portion of an Ab molecule found on many types of cells
FcRn receptor
allows IgG to pass through placenta to fetus
ADCC
a phenomnon in which target cells coated with Ab are destroyed by NK cells that bear receptors for the Fc region of the coating Ab the receptors allos the NK cells to bind to the Ab-coated target
What are the activities of Ab that contribute to hummoral immunity?
neutralization, opsonization, complement activation
How do the constant regions of the various classes of Ig differ?
IgM & IgE have any extra constant region and are missing the hinge region/disulfide bonds, also the carbohydrate groups vary between classes
Where are the various Ig classes found throughout the body?
IgG--plasma & brain & heart
IgA--breast milk, mucosal surfaces
IgE--epithelial surfaces
IgD--surface of B cells, function as BCR (like IgM)
IgM--found on surface of secondary lymphoid organs, & in the heart
Which Ig classes are complement activating?
IgM
How does IgA cross the epithelium?
by binding to the poly-Ig receptor:
-binds to receptor on basolateral face of epithelial cell
-endocytosis
-transports to apical face of epithelial cell
-release of IgA dimer at apical face of epithelial cell
When does an infant geneate its own Ab and how is it protected until then?
at 6 months infants can make its own Ab, until then it relies on the IgG that it received while in the womb (which protects it from the antigens the mother has been in contact w/) and IgA it receives through breast milk
What is the function of the FcRn receptor in protection of the fetus/newborn?
it allows IgG to pass through the placenta and facilitates absorptoin of maternal IgG from colostrum
What is the role of IgE in allergic response?
IgE binds to Fcreceptors on mast cells; when IgE Ab are crosslinked by Ag this triggers degranulation by mast cells.....ALLERGIC RXN.
What is mast cell degranulation?
allergic reaction
How do Fc receptors enhance phagocytosis by macrophages?
they allow the macrophages to be activated once the Ab are bound by the Fcreceptors; aggregation of Ig on bacterial surface allows cross-linking of Fcreceptors
How do NK cells function in ADCC?
the Fcreceptors on its surface cross-link with Ab bound to the surface of a target cell signaling the NK cell to kill the target cell, the target cell dies by apoptosis
hypervariable regions (CDR)
portions of the l and h Ig chains that are highly variable in amino acid sequence from one Ig molecule to another and that together constitute the antigen-binding site of an antibody molecule. Also in portions of the T cell receptor that constitute the antigen-binding site
germ line
refers to genes in germ cells as opposed to somatic cells; in immunology, refers to genes in their unrearranged state rather than those rearranged for production of Ig or T cell receptor molecules
somatic recombination
recombinatoin that occurs among DNA segment in somatic cells
surrogate light chan
nonrearranging chains expressed in conjunction w/ the mu chin in the pre-B cell; form part of the pre-B cell receptor
recombination signal sequence
direct recombination
12/23 rule
states that a 12bp sequence can only join to a 23bp sequence
RAG enzymes
recombination activating genes, catalyze recombination
TdT enzyme
terminal deoxynucleotidyl transferase, increase diversity and function to add N-nucleotides at junctions
P-nucleotides
result from palindromic sequences added by DNA repair enzymes
N-nucleotides
added at random by the TdT enzyme, up to 15 nucleotides may be added
non-productive rearrangement
out of frame rearrangements disrupt the triplet reading frame for translation of the protein and often result in premature stop codons
How does an individual make so many different antigen specific B cells from just 30-40,000 genes?
rearranging
pro-B cell
earliest stage of B cell differentiation in which H chain rearranges
pre-B cell
expresses rearranged H chain and light chain performs rearranging
immature B cell
IgM-positive, IgD-negative cell in the B cell lineage; easily tolerized by exposure to antigen
mature B cell
B cells w/ IgM and IgD on their surface
somatic hypermutation
change in the variable region sequence of an antibody produced by a B cell following antigenic stimulation, resulting in increased Ab affinity for Ag
anergy
a state of Ag-specific non-responsiveness in which a B cell is presnet but functionally unable to respond to antigen
clonally ignorant B cell
a state whereby autoreactive lymphocytes are neither anergized, deleted, nor receptor edited, instead they co-exist w/ antigen and remain in an unactivated state b/c of their weak affinity for the autoantigen or a low concentration of autoantigen
TD activation
signal 1 comes from binding of Ag to the BCR

Ag is taken into Bcell for processing and presentation by MHCII to T cell

Signal 2 is the binding of CD40 (on Bcell) and CD40L (on T cell) and/or cytokines secreted by T cell

TD antigens illicit the strongest humoral response
TI activation
tends to be non-protein Ag

activation not well understood

Signal 1 occurs via cross-linking several BCRs at one time

Signal 2 comes from binding of other component on the Ag
What are the four life stages of a B cell and where do they occur in the body?
B-cell precursor (rearrages Ig genes) (Bone Marrow)

Immature B-cell (negative selection) (Bone Marrow)

Mature B cells (migrate to peripheral lymphoid organs) periphery

Activated B cells (secretion of memory cells in bone marrow and lymphoid tissues) periphery
What are the four processes responsible for generation of Ab diversity?
-combinatorial diversity of heavy and light chains
-combinatorial diversity of gene segment utilized
-junctional diversity introduced at joints of gene segments
-somatic hypermutation in mature B cells
What are the sources of variation in the 3 CDRs?
junctional flexibility, p-nucleotides, n-nucleotides, somatic hypermuatation
class switching
alters the effector function of the B cell but does not change the cell's Ag specificity
switch region
region of B cell H chain DNA at which recombination occurs in an Ag-stimulated cell; allows isotype switch
BCR
the cell surface receptor of b cells for a specific Ag composed of a transmembrane Ig molecule associated w/the invariant Igalpha and Igbeta chains in a noncovalent complex
accessory molecules
Ig alpha and Ig beta

molecules other than the Ag receptor and major histocompatibility complex that participate in cognitive activation and effector functions of T lymphocytes
germinal centers
secondary lymphoid structures that are sites of intense B cell proliferation, selection, maturation, and death during Ab responses. They form around follicular dendritic cell networks after migration of B cells into lymphoid follicles
follicular dendritic cells
cells w/in lymphoid follicles that are crucial in selecting Ag-binding B cells during Ab responses. They have Fc receptors that are not internalized by receptor-mediated endocytosis, thus holding Ag-Ab complexes for long periods
plasma cell
the Ab producing end stage of B cell differentiation
primary response
the immune response resulting from first encounter w/ Ag; generally small, w/ a long induction phase or a lage period; generates immunological memory. in primary B cell response mainly IgM Ab is made
secondary response
initiated by memory B cell; larger amounts of ab are produced, greater Ag affinity
Memory B cell
generated by secondary response due to earlier primary response
affinity maturation
the sustained increase in affinity of Ab for an Ag with time following immunization. The genes encoding the Ab variable regions undergo somatic hypermuatation w/the selection of B lymphocytes whose receptors express high affinity for the Ag
apoptosis
a form of programmed cell death caused by activation of endogenous molecules leading to fragmentation of DNA
necrosis
swelling of the cell and diffusing of the DNA irritating nearby tissue
What stages of B cell development are in the bone marrow and what stages occur in the peripheral lymph organs?
development of B cells and immature B cell negative selection : bone marrow

mature B cell and activation: peripheral lymph organs
What two factors are responsible for class-switching?
Ag stimulation & cytokines from T cells
Compare and Contrast class-switching and somatic recombination?
class switching / som. recomb.

organized / random
always productive / high failure
no RAG / RAG
after Ag / pre Ag
What is the role of MHC II in B cell activation?
it presents Ag to T cells
What is the role of T helper cell in B cell activation?
activates the B cell
What events occur in the germinal centers?
high B cell proliferation
somatic hypermuatation
follicular DCs trap Ag-binding B cells
How do peripheral lymph organs aid in the encounter of Ag specific B cell with the appropriate T cell?
they increase the odds that the Ag specific B cell and T cell will find each other/Ag binding B cells are selectively "trapped" in the T cell zones of the lymphoid organs, interaction w/ a helper T cell activates the B cell to establish a primary focus of clonal expansion which will last for several days
What are the characteristics of plasma cells?
they have low surface Ig, low surface MHC II, high rate of Ig secretion, low growth, low somatic hypermutation, and low isotype switching
Characteristics of primary response?
initiated by naive B cell, takes 5-10 days, predominatly Ig M secreted, smaller amount of Ab produced, low Ag affinity
Characteristics of secondary response?
Initiated by memory B cell, 1-3 days, classes such as IgG largely produced, larger amounts of Ab are produced, greater Ag affinity