Immunoglobulin Genes

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How many multigene families are there for Heavy Chains and Light Chains?: One for each type of chain.
-one heavy chain multigene family
-one light chain multigene family

Each family contains many gene segments.
There are many gene segments on the Kappa-chain (light) multigene family; -How many V segments? -How many J segments? -How many C segments?: 85

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Only one of each segment type contributes to the light chain protein.
What are the three types of multigene families?: -Lambda
-Kappa
-Heavy chain
What gene segment types contribute to variable regions on antibodies?: VJ and VDJ
What gene segments contribute to non-variable (Fc) regions of antibodies?: C
describe the gene segment rearrangement process in general, and where does it occur?: random gene rearrangement that occurs in the primary lymphoid organs = thymus and bone marrow.
What are the 2 main components of the mechanism that allows/directs gene rearrangement?: 1. RSS - Recombinational Signal Sequences

2. Enzymatic gene segment joining
What are RSSs? How many types are there?: Recombinational Signal Sequences.

They show where recombination (making joints) should occur.

2 types: One-turn RSS and two-turn RSS;
What is the significance of the two different types of RSSs?: One-turns recognize 2-turns. They recognize each other;

The D segments only have 1-turn on either side of the segment, The V and J segments only have 2-turn.

Therefore, V can only join D, and VD can only join J. (no VJD)
What enzymes participate in enzymatic joining of gene segments?: Rag-1 and Rag-2

Endonuclease

Terminl deoxynucleotidyl transferase (TDT)

DSBR
What are RAG 1/2? What do they do?: Recombination activating genes.

-Bring together RSS's
-Cut DNA to form HAIRPIN
What does Endonuclease do? Why?: Cuts the hairpin formed by RAG1/2.

To form a place to do P- and N-additions.
What is P-addition?: Addition of nucleotides to the cleaved hairpin (by endonuclease). Forms a
PALINDROME.
What is N-addition? What does it?: Addition of Nucleotides to cut hairpin.

Terminal deoxynucleotidyl transferase
TDT
What repairs the dna after Gene segment joining and hairpin/addition?: DSBR - doubl. strand break repair enzymes; repair/join coding sequences.
2 results of random gene rearrangement/joining:: -formation of coding joint
-formation of signal joint.
What is the "coding joint" a code for?: the variable regions (VJ and VDJ) of the immunoglobulin DNA.
If you don't have Rag enzymes or DSBR, what is the result?: SCID - severe combinatorial immune deficiency
What is Evidence for gene rearrangement?: presence of circular dna in the thymus
what is "junctional flexibility"?: imprecise joining of the coding sequence.
Meaning, codons are 3-aa sequences; if a V and J segment join and make a STOP codon, it is NONPRODUCTIVE.
2 products of junctional flexibility: what is the consequence?: In-phase or Out-of-phase joining.

In-phase can be translated.

Out of phase contains a premature stop codon and will not be translated into protein.
What is unique about Rag 1/2 and TdT expression?: only occurs in lymphoid cell lines; that's the only place where this REARRANGEMENT occurs; not in other chromatic DNA.
Why do T and B cell genes rearrange?: to create a diverse reportoire of cells that can recognize all different Ags.
What do animals with defective gene rearrangement lack?: MATURE B/T cells; leads to SCID, the lack of ANY specific immune response;
What mechanism produces either Membranous or Secretory Ig?: Differential RNA processing.
Which cells have Membranous Ab? Which cells have Secretory Ab?: Membranous: Native/memory B cells

Secretory: Plasma cells - the effectors
What is Allelic exclusion? When does it happen? What is the significance?: the inhibition of one copy of the Ig genes (from one parent) so that only one set is expressed. Occurs once one set is properly rearranged.

Significance: if you had two sets expressed, you would have two antibody clones for the same antigen.
What is Somatic Hypermutation? WHERE does it happen? When does it happen? Why?: -Random gene mutations on the VJ or VDJ gene segments.
-In activated B cells, in the germinal center.
-After activation by Antigen.
-to generate different affinities in the antibodies, to select the best population.
7 things that generate ANTIBODY diversity:: 1. Fact that there are multiple gene segments in each multigene family.
2. Random combinations of those segments.
3. Junctional flexibility
4. P-addition
5. N-addition
6. Somatic Hypermutation
7. Combinatorial association of LC and HC
What follows somatic hypermutation? why?: Affinity maturation

to select the B cells with better affinity that was generated by the random mutations of somatic hypermutation.
What maturational level are the B cells that undergo -Variable region rearrangement -Constant region rearrangement: Variable: immature, in the primary lymphoid organs.

Constant: Mature, in the peripheral lymphoid tissues, after Ag activation. Then they differentiate into effector/memory cells.
What is the mechanism of class switching? When/where? What happens?: DNA looping; after Ag stimulation, in the peripheral lymphoid tissues.

DNA loops and VDJ joins with one of the Constant heavy segments.
What does class switching explain?: How one specific mother antibody clone can have different effects (different Fc regions).
What Switch Factor tells the Bcell which class to switch to?: Cytokines.
What does Differential RNA processing allow?: Expression of both IgM and IgD on one naive B cell - the two differ in which membrane is bound, but b
What is Differential RNA processing?: Cleavage of the RNA transcript (ripe and ready for expression) before or after segments that encode secretory or membrane-bound genes for the C region.
Why can IgM and IgD be expressed in one naive B-cell simultaneously?: There's no switch site between their C gene segments; the RNA transcipt is not cleaved during RNA processing, so they both get transcribed and translated.

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