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Heavy Chain Rearrangement

Heavy Chain Rearrangement. The B cell receptor is made up of two kinds of proteins, the heavy chain ( Hc ) and the light chain ( Lc )., Each of these proteins is encoded by genes that are assembled from gene segments.

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Heavy Chain Rearrangement

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  1. Heavy Chain Rearrangement • The B cell receptor is made up of two kinds of proteins, the heavy chain (Hc) and the light chain (Lc)., Each of these proteins is encoded by genes that are assembled from gene segments. • Each B cell has 2 chromosome 14s (Mom + Dad)…but a B cell makes only one kind of Ab. So the segments on one chromosome have to be “silenced”.

  2. This works like a card game with 2 players. It is “winner takes all”..each player tries to rearrange its card (gene segments) until it finds a arrangement that works. The first player to do this wins. • The players in the card game first choose one each of the possible D and J segments, and these are joined deleting the DNA sequences in between.

  3. Then one of the many V segments is chosen, and this “card” is joined to the DJ segment, again by deleting the DNA in between. • Next to the rearranged J segment is a strong of gene segments (CM, CD, etc) that code for the various constant regions. • By default, the constant regions for IgM and IgD are used to make the BCR, simply because they are first in line.

  4. Next, the rearranged gene segments are tested. (if the gene segments are not lined up right, the protein translation machinery will encounter a stop codon and terminate protein assembly. • If the segment passes the test, that chromosome is used to construct the winning Hc protein. This heavy chain protein is then transported to the cell surface, where it signals to the losing chromosome that the game is over.

  5. If the heavy chain rearrangement is productive, the baby B cell proliferates for a bit, and then the light chain players step up to the table. The rules of the game are similar to those of the heavy chain game, but there is a second test…the completed heavy chain and light chain proteins must fit together properly to make a complete antibody. If this does not occur, the B cell commits suicide.

  6. To produce antibody the B cell has to be activated. “Naïve” or “virgin” B cells have never encountered their antigen. • Activation of a naïve B cell requires 2 signals: the first is the clustering of the B cell’s receptors and their associated signaling molecules. A second signal is required (co-stimulatory signal) (Note: in T cell-dependent activation, this second signal is supplied by a helper T-cell). • In response to certain antigens, naïve B cells can also be activated with little or no T cell help (T-cell independent)

  7. Once B cells have been activated, and have prolifereated to build up their numbers, they are ready for maturation. Maturation occurs in 3 steps: • class switching (where a B cell can change the class of antibody it produces) • somatic hypermutation (rearranged genes for the BCR can undergo mutation and selection that can increase the affinity of the BCR for the antigen • career decision (B cell decides whether to become a plasma or memory cell)

  8. Virgin B cells first produce IgM (default). As the B cell matures, it has the opportunity to change the class of Ab to either IgG, IgE or IgA. • The gene segments that code for the constant region for IgM are next to the constant regions for IgG, IgE or IgA, switching is easy: • Cut off the IgM constant region DNA and paste on one of the other constant regions.

  9. Somatic Hypermutation • Normal overall mutation rate of DNA is extremely low (~ 1 mutated base /100 million bases). However, the chromosome area where B cell are encoded is highly restricted, which means that an extremely high rate of mutation can occur (~1 mutated base per 1000 cases). • This high rate of mutation is called somatic hypermutation. It occurs after the V,D, and J segments have been selected, and usually after class switching.

  10. Somatic hypermutation changes the part of the rearranged Ab gene that encodes the antigen binding region of the Ab. Depending on the mutation, there are three possible outcomes. • The affinity of the Ab for the Ag may remain unchanged, my increase or may decrease • For maturing B-cells to continue to proliferate, they must be continually re-stimulated by binding to their Ag. Therefore, because those B cells whose BCRs have mutated to a higher affinity are stimulated more easily, they proliferate more frequently.

  11. Because they proliferate more frequently, the result is that you end up with many more B cells whose BCRs have high affinity for their Ag.

  12. BUT, hypermutation in TCRs is not beneficial (remember you want them to recognize self---but not over react>>autoimmune problems)

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