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B cell Maturation and Antibody Synthesis I
October 31 Lecture
38
Immunology
Graduate
11/06/2011

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Term
Epitope
Definition
general term about antigens referring to specific site on antigen for which the antibody is binding (aka the antigenic determinant )
-somewhere between 5-6AA’s make up one (and then you can make an antibody against it that will bind to it) ;
-based on sequence as well as physical structure of protein that gives rise to itself
Term
2 types of epitopes
Definition
1) linear
2) conformational
Term
Linear epitope
Definition
linear sequence of amino acids ; dependent on this linear array ; regarding specific site on antigen for which the antibody is binding (antigenic determinant)
a. (heating would not change the expression bc it is a linear sequence and this sequence is maintained)
Term
conformational epitope
Definition
this is a specific site on an antigen for which the antibody is binding (antigenic determinant) exquisitely dependent on folding of the protein (based on sequence as well as physical structure of protein giving rise to these determinants ) ; ex. Globular protein
a. (heat would end up changing the epitopes and would denature this protein because it would no longer be globular, and instead the epitopes would be lost)
Term
how many epitopes are on high MW proteins?
Definition
lots
Term
how many epitopes are on low MW proteins?
Definition
FEW

not as many as there are on high MW proteins
Term
what types of epitopes can b cells see?
Definition
they can see both linear and conformational epitopes, see something native, maybe even the whole protein
Term
what types of epitopes can t cells see?
Definition
they can only see linear epitopes to become activated
Term
what happens once t cells and b cells recognize their respective epitopes?
Definition
they can then communicate with one another
Term
is an antigen instructive?
Definition
NO, it is not instructive

receptors are expressed completely randomly
Term
explain why antigens are not instructive
Definition
-b cells mature in bone marrow, and produce components of immunoglobin, and when t cells leave thymus they have random gene rearrangement process too devoid of the antigen
-antigen does not instruct these receptors
-If antigen enters body, then it might lead to changes that can lead to affinity maturation (this is a case where antigen can play a role in diversification of antibodies but if the b cell never had a receptor to begin with, it never would have responded to undergo affinity maturation.
Term
Idiotope
Definition
refers to specific type of epitope (general term for which elements of antibody will bind).
-Is the specific epitope that is formed when the antibody heavy chains and light chains are assembled to form a specific antigen. (specific example is one that is associated with heavy chains and light chains); this means that you need to think of antibodies as antigens
Term
B cells have idiotypes based on the range of ________ that they express on their variable domains; this defines the specificity or clonality of that b cell for its unique antigen; thus this helps us make antibodies against our own antibodies so we can regulate our own immune response in the body
Definition
idiotopes
Term
Pro-B cells mature into what?
Definition
Pre-B cells
Term
Pro-B cells mature into Pre-B cells
There are 2 stages:
Definition
1) Immature stage makes IgM
2) Mature stage makes both IgM and IgD
Term
cytoplasmic mu
Definition
when there’s production of heavy chain without the light chain in the pre-b stage
Term
what happens if you have heavy chain and no light chain?
Definition
it wont work

(if you don’t have heavy chain and light chain then you don’t have functional antibody because either chain on their own is not an antibody).
Term
Surrogate light chain
Definition
notifies cell that it can then take heavy chains at membrane surface and it asks to then become a light chain ( then cell can undergo light chain rearrangement, and it makes both heavy and light chain and then immunoglobin)
Term
Pro-B cell- D-J rearrangement
Definition
early stages of heavy chain production
Term
As b cell begins to mature in bone marrow, in order to become functional b lymphocyte it must make membrane _________
Definition
immunoglobin
Term
is rearrangement of gene segments planned or random?
Definition
random
Term
sterile transcript
Definition
when DNA is spliced, if it is not recombined in frame, then it will become this
Term
apoptosis
Definition
a b cell is not considered a b cell until in undergoes rearrangement. If it doesn't undergo rearrangement, then it does this.
Term
what is downstream of J segments?
Definition
exons that encode for all the different isotypes
Term
There are a series of gene segments in 3 families for heavy chain:
1)
2)
3)
Definition
1)V gene segments which are upstream of D gene segments (or diversity gene segments)
2)D gene segments which are upstream of J gene segments
3)J gene segments
Term
D-J rearrangement
Definition
a D segment will rearrange with a J gene segment
-just involves a few nucleotides that encodes for amino acids) it will be transcribed and then translated into a domain (encode for around 110 amino acids each and then variable domain encodes for around 90 to 95 AA’s ,
-D will encode about 3-5, and J is around 5-10);
-through rearrangement you can then create an enormous repertoire of options for AA sequences so we can make huge array of antibodies correlating with antigens that enter our body)
Term
in DJ rearrangement, what are the steps?
Definition
a.)Each b cell has a unique idiotype, that b cell uses in a clonal nature to response to antigen ; each b cell is clonal in nature and has a highly specific receptor for antigen generated through these kinds of recombination steps
b.Example: D3 rearranges with JH4
c.Forms a DNA circle (episome) that gets removed by VDJ-recombinase (made up of many enzymatic activities) -for b cells and for t cells when they produce t cell receptor (thus everything between the two segments being rearranged gets spliced out)
Term
what mediates gene rearrangement of DJ rearrangement?
Definition
VDJ recombinase


this takes out the spliced gene segments that will not be encoded for
Term
what are the steps after DJ rearrangement?
Definition
1) recombine one of V gene segments with the rearranged DJ segment. You must define the V gene segment. (ex. D3 rearranges with VH2) thus VH1 is fine, but VH2 will recombine and everything downstream of JH4 is fine.) all the information will be found in the heavy chain of immunoglobin molecule. Certain elements are brought into association to initiate transcription to make primary transcript
2.) Then primary transcript must be processed by post transcriptional modification
3.) RNA splicing
4.) All the gene segments stay upstream of the 4 mu domains
Term
what are the 4 simple steps of gene rearrangement for heavy chain?
Definition
1) D-J
2) V-DJ
3) RNA processing to make mRNA
4) Make protein
If process occurs faithfully, you will only have one of each gene segment for an antibody
Term
leader element (L)
Definition
each variable region possesses this
Term
cytoplasmic mu.... is it variable or highly conserved?
Definition
highly conserved!

it is NOT rearranged
Term
t cells from thymus

(are they successful in rearrangement?)
Definition
Greater than 90% of t cells from thymus will die because they didn’t rearrange right or other reasons
Term
class switch recombination...
is is antigen-dependent or antigen-independent?
Definition
antigen-dependent
Term
VDJ rearrangement...
is is antigen-dependent or antigen-independent?
Definition
antigen-independent
Term
is light chain rearrangement more complex than heavy chain rearrangement?
Definition
NO!

Light chain rearrangement is even easier bc you don’t have DJ segments for light chain. So for light chain, you have series of v gene segments upstream of J gene segments and then there is 1 light chain constant domain (fixed so not part of our rearrangement)
Term
example of variable light chain rearrangement
Definition
Ex. V Kappa 1 rearranges with V kappa 4 so it forms circular episome ( but this process only occurs after heavy chain rearrangement) without heavy chain, light chain rearrangement is meaningless. (must only be after cytoplasmic mu is present in the cell)
Everything between the 2 segments becomes circular dna lost in cell division. Then forms primary mRNA transcript and gets processed. Now you have V kappa 1 J kappa 4 and constant kappa. Then gets translated. Variable and constant domains are made and now you have a light chain
Term
If you have a heavy chain and then a light chain made already then you have a _________
Definition
b cell!


Then the b cell can leave the marrow and then see the periphery (spleen , tonsils, appendix, etc) where there are aggregates of lymphatics (secondary lymphatics)
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