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Ig Gene Rearrangements
Immunoglobulin genes are found on several different chromosomes:
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Chromosome 14
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Heavy chian gene
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Chromosome 2
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Kappa light chain gene
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Chromosome 22
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Lambda light chain gene
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Even on one chromosome the immunoglobulin genes are organized as discontinuous
DNA segments along the gene (germline configuration). The separated DNA
segments in both the heavy and light chain genes are the variable (V)
regions, the joining (J) regions and the constant (C) regions. The heavy
chain genes also include a diversity (D) region.
A series of sequential gene rearrangements, transcription, and translation
events take place, beginning at the time when a lymphoid stem cell commits
to becoming a B cell progenitor.
Rearrangement of the heavy (H) chain gene begins the process by which
lymphoid precursors develop into functioning B lymphocytes and produce
Ig.
The process begins on chromosome 14 where (1) a DH region must first
rearrange with a JH region and, if successful, then (2) rearrange with
a VH region to produce a VH/DH/JH segment*. During RNA transcription (3)
splicing joins the VH/DH/JH segment to one of the eight constant regions
which are, in order, Cm; Cd; Cg3; Cg1;
Ce2; Ca1; Cg2; Cg4;
Ce1, and Ca2. Cm
is closest to the JH region.
* The need for two successful rearrangements (steps1&2) to produce
a VH/DH/JH segment, requires in most (>80%) cases the rearrangement
of both heavy chain alleles, as the first attempt is often not successful.
At time of transcription, intervening sequences (introns) are
removed by RNA splicing. The addition of polyA and the splicing of secretory
or membranous sequences dictates production of secretory (cytoplasmic)
Ig or membranous (surface) Ig or both.
Following transcription, the messenger RNA is translated into
a completed heavy chain protein.
Initially B cells produce an immunoglobulin with a heavy chain of the
m Ig class as the m
gene is closest to the JH region.
Synthesis of a m heavy chain from the first
allele blocks rearrangement of the other chromosome (allelic exclusion).
If the cell fails to achieve a successful m
recombination, it is presumed to die. Furthermore, production of m is necessary for light chain rearrangement to
take place (next ).
The assembly of the kappa gene (short arm of chromosome 2) is
successful in about 60% of human B lymphocytes. Each of the Vk
segments is accompanied by a leader (L) sequence. The Vk segments encode the first 95 N-terminal amino
acids. Positions 96 -108 are encoded by one of five joining (Jk)
gene segments. The constant (Ck) portion of
the kappa light chain (amino acids 109 - 214) is encoded by a single constant
(Ck) region separated from the Jk
region by an intervening sequence or intron.
DNA rearrangement (1) places a single Vk segment directly adjacent to one of five Jk
segments. During transcription (2), introns are removed by RNA splicing.
Then messenger RNA is translated into a completed kappa light chain protein.
If a k rearrangement was successful, future l
rearrangement is blocked and the l genes remain
germline.
Should both the two kappa alleles fail to successfully rearrange
to form a Vk/Jk segment, an attempt
is made to assemble a light chain segment using lambda genes. Thus in
approximately 40% of cells a rearrangement process takes place on chromosome
22 where the lambda light chain gene is located.
The major difference between kappa and lambda genes is that rather than
a single Ck region as found with kappa, the
lambda gene contains six Cl regions each associated
with a particular Jk region.
Again, rearrangement of the DNA places a single Vl segment directly adjacent to one of six Jl
segments. During transcription, any intervening sequences are removed
by RNA splicing, following which the messenger RNA is translated into
a completed lambda light chain protein.
If k rearrangement fails and a successful l rearrangement takes place, the k genes are either aberrantly rearranged or deleted
entirely. As with failure of heavy chain recombination, if all k
and l attempts at recombination fail, the cell
is thought to die.
Light chain allelic exclusion allows a B lymphocyte to make only one
type of antibody.
Once a successful light chain, (kappa or lambda), is produced it is attached
to the heavy chain (usually m) for either secretion or membrane insertion.
At first B cells produce an immunoglobulin with a heavy chain of either
the m or in some instances m and d. Later a more
distally located constant region can be moved into proximity with the
already assembled VH/DH/JH segment. This heavy chain class switch
allows identical VH/DH/JH antigen specificity to be expressed with different
constant regions. Thus effect or function varies, but with the same antibody
specificity. See B cell maturation.
The B lymphocyte gene rearrangements are the means by which B cells respond
to untold numbers of antigens, producing millions of different B cell
clones. This diversity arises from the almost limitless recombinations
allowed by the variable, diversity, and joining genes; by junctional diversity,
and by variable gene somatic mutations (resulting in affinity maturation
in antibody responses).
The molecular genetics of B lymphocytes is linked to B cell growth, differentiation,
and response including immumoglobulin production. B cell growth and immunoglobulin
production is similar in plasma cell disorders, but is uncontrolled and
lacks antigenic stimuli.
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