Rearrangement

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Rearrangement

• The normal process by which antibodies and T cell
  receptors are made

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So What Is a Rearrangement?

• Rearrangement is a term used to describe a
  recombination of DNA within a single chromosome.

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Rearrangement

• Remember that every immunoglobulin molecule and
  every TCR contains both a variable region and a
  constant region and that the variable region is
  the part of the molecule that interacts with the
  antigen.

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TCR T cell receptor
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Immunoglobulin Antibody B cell receptor (BCR)
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What is meant by the term rearrangement in
relation to DNA?

• Antigen independent maturation of B and T cells
  to immunocompetent B and T cells that express
  receptors for antigen recognition involves a
  rearrangement of the cells germline DNA.
• Germline DNA DNA that is an exact sequence
  replicate of the genome present at fertilization
  of egg by sperm. It has not been rearranged.
• Most cells in the body maintain copies of
  germline DNA.

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Rearrangement continued

• The genes that code for the different chains of
  the B and T cell receptors include a large number
  of exons.
• The exons that code for the variable regions of
  the immunoglobulin molecules and TCRs are called
  the variable (V) segments, diversity (D)
  segments, and junctional (J) segments, and those
  that code for the constant regions are called the
  C segments.

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Shematic of germline genes for TCR alpha and beta
and immunoglobulin heavy and kappa light
chains Note how large a number n is!
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Rearrangement continued

• For the immunoglobulin heavy chain, there are
  100-200 different V regions, 30 different D
  regions, 6 different J regions, and 9 different C
  regions.
• For the TCR beta chain, there are 75-100
  different V regions, 2 different D regions, 13
  different J regions, and 2 different C regions.
• Note these numbers are more current than those
  on the preceding schematic.

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Change V1 to Vn in the right hand column.
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Rearrangement continued

• The first step in the rearrangement process
  involves the the apposition of one D segment of
  the gene with one J segment by deletion of all
  intervening sequences, both coding and non-coding
  (a DJ rearrangement).
• In a similar process a V segment becomes apposed
  to the DJ rearrangement to form a VDJ
  rearrangement.

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Rearrangement continued

• After rearrangement of the DNA, transcription
  occurs.
• Subsequent splicing of the primary transcript
  with deletion of noncoding sequences results in
  apposition of VDJ to C coding regions to form a
  mature VDJC mRNA which can be translated into an
  immunoglobulin heavy chain or TCR.

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Gene Rearrangements to make an
antibodyRemember this rearrangement is
happening in the gene not during RNA processing.
Can you list multiple inaccuracies in this
animation?
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Rearrangement continued

• Once the productive rearrangement occurs on one
  chromosome, an active protein chain is
  synthesized and it provides a trigger to prevent
  rearrangement of the other allele (allelic
  exclusion).
• Thus each B or T cell expresses only one
  immunoglobulin or TCR, respectively.

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Rearrangement continued

• This complex process of rearrangement allows for
  tremendous diversity of both the cell-mediated
  and humoral arms of the immune system, and the
  ability to respond to a wide array of antigens.

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Review How do translocation and rearrangement
differ?

• Translocation is the recombination of DNA between
  two different chromosomes. Rearrangement is the
  recombination of DNA within a single chromosome
  (and within a single gene).
• Translocations are abnormal. Rearrangements of
  genes for immunoglobulins and TCRs are normal.