Glossary of Chpt 3 2
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- characteristics of a good immunogen
- -structurally diverse/heterogenous
-unrelated to the host
-How the Ag is presented - stay local
- Host response to Ag
- -Genotype - determines CDR, how it will respond to the Ag, how susceptible to the pathogen it is.
-Dose response curve
(Quantity, Frequency, Repeated)
- how many multigene families are HC or LC derived from?
- lambda - from one multigene family
kappa - from one family
heavy chain - from one family
- what does a multigene family consist of?
- multiple V, D (in hc), J, and C gene segments
- What gene segments contribute to
- V, D, and J contribute to variable.
- what gene segments contribute to constant regions of immunoglobins?
- only C
- What encodes an Ab immunoglobulin?
- one V, one D, one J, and one C
- Where does genetic rearrangement occur when making the genes for antibodies?
- in the primary lymphoid organs - thymus and bone marrow
- What two main components constitute the mechanism of gene rearrangment?
- -RSS - Recombination Signal Sequences - the initiation of mechanism
-Enzymatic joining of segments - the process of mechanism
- What are RSS?
- Recombination Signaling sequences
-They are sequences flanking gene segments. They signal to the enzymes where to recombine/join the segments.
- Process of Gene Recombination
- 1. Recognition of RSS by Recombinase Enzymes. Synapsis - bring Signal Sequences (ss) and their coding sequences (cs) into close proximity.
2. Rag-1 and Rag-2 cleave one DNA strand at juncture of ss and cs.
3. Cut other dna strand with free 3' OH; produces hairpin structure on cs; ss is flush 5'.
4. Cut hairpin for room for P-region nucleotides. trim with endonuclease.
5. N-addition on Heavy Chains w/ TDT.
6. Repair/ligation of coding joint and signal joint via DSBR enzymes.
- nonproductive rearrangement:
- imprecise joining of V-D-J segments for variable sequence of antibody is out of phase; triplet reading frame is not conserved for codons, so multiple stop codons are present.
- productive rearrangement
- gene segments are in phase during v-d-j rearrangement and joining, so reading frame is read-able and translatable into protein.
- allelic exclusion - what is it, purpose?
- -we get Alleles from both parents for gene rearrangement for antibodies. (genes with segments for lambda from ea. parent, genes w/ segments for kappa from ea. parent, etc.)
When one is successful, the other is turned off so we don't get both.
- what if we didn't have allelic exclusion?
- B cells would express two different antibody molecules.
- how is allelic exclusion carried out?
- once protein antibody is expressed and translated, the mechanism of gene rearrangement is shut off. a negative feedback mechanism.
- How is antibody diversity generated?
- -Multiple germ-line gene segments (VDJ)
-Random Combinatorial Joining of those segments
-Junctional flexibility (where jcts are)
-Combinatorial association of H/L chains
- junctional flexibility
- the fact that when segments are combining during gene recombination, even though RSS's join PRECISELY to generate the Signal sequence, Coding sequences join IMPRECISELY (junction is between varied pairs of amino acids)
- palindromic (mirror) addition of nucleotides complementary to the coding sequence after it is cleaved to make the hairpin loop by RAG 1/2. after the endonuclease randomly cleaves the hairpin, repair enzymes do p-addition.
- what is the order of gene segment joining in HEAVY CHAIN rearrangement
- D joins to J, then V joins to D-J
- terminal deoxynucleotidyl transferase - catalyzes nucleotide addition (n-addition) to joints during D-J and V-DJ joining in gene rearrangement.
- Where is N-addition localized in antibodies?
- AT CDR-3!! Complementarity determining region - generates more diversity in antigen-binding region
- combinatorial association of H/L chains
- final way to generate diversity.
VDJ w. C
VJ w. C
- How do we get the different classes of Ig? (IgM, IgD, etc)
- class switching in constant reg. genes.
-Switch region upstream of C segments
-Cytokines are switch factors affecting the expressed class
-Circular excision product is produced, containing swtich regions and skipped classes.
- negative and positive selection
- neg. selection = selection of Tcells that have a high affinity for self - they are apoptosed.
pos. selection = selection of tcells that have an intermediate/nominal affinity for self.
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