From studies and predictions such as Dreyer and Bennett's, it shows that the light chains and heavy chains are encoded by separate multigene families on different chromosomes. They are referred to as gene segments and are separated by non-coding regions. The rearrangement and organization of these gene segments during the maturation of B cells produce functional proteins. The entire process of rearrangement and organization of these gene segments is the vital source where our body immune system gets its capabilities to recognize and respond to variety of antigens.

1. Dr. Dinesh C. Sharma,
Associate Professor and Head-Zoology
K.M. Government Girls P.G. College, Badalpur, GB Nagar, India

2. • An antibody (Ab), also known as an immunoglobulin (Ig), is a
large, Y-shaped protein produced mainly by plasma cells (B-
lymphocyte) that is used by the immune system to
neutralize pathogens (bacteria, viruses etc.).
• The antibody recognizes a unique molecule of the pathogen,
called an antigen, via the fragment antigen-binding (Fab)
variable region. Each tip of the "Y" of an antibody contains
a paratope (analogous to a lock) that is specific for one
particular epitope (analogous to a key) on an antigen, allowing
these two structures to bind together with precision.
• Using this binding mechanism, an antibody can tag a microbe or
an infected cell for attack by other parts of the immune system,
or can neutralize its target directly (for example, by inhibiting a
part of a microbe that is essential for its invasion and survival).
Depending on the antigen, the binding may impede the biological
process causing the disease or may activate macrophages to
destroy the foreign substance.
• The ability of an antibody to communicate with the other
components of the immune system is mediated via its Fc
region (located at the base of the "Y"), which contains a
conserved glycosylation site involved in these interactions. The
production of antibodies is the main function of the humoral
immune system.

3. 1. Fab region
2. Fc region
3. Heavy chain
4. Light chain with one variable (VL)
and one constant (CL) domain
5. Fc region with paratope
6. Hinge regions
Paratope
• A paratope, also called an antigen-binding site, is a
part of an antibody which recognizes and binds to
an antigen.
• It is a small region (of 5 to 10 amino acids) of the
antibody's fragment antigen-binding (Fab region),
and contains parts of the antibody's heavy and light
chains.
• Each arm of the Y shape of an antibody monomer is
tipped with a paratope, which is a set of
6 complementarity-determining regions (CDR
loops)- 3 of each light and heavy chain extending
from the fold of antiparallel beta sheets.
• The part of the antigen to which the paratope binds
is called an epitope. This can be mimicked by
a mimotope.
• The engraved inner portions of idiotype (encircled
region no.5 in the diagram) is the paratope where
the epitope of the antigen binds.

4. • During the development of B cells, the immunoglobulin gene undergoes
sequences of rearrangements that lead to formation of the antibody
repertoire.
• For example, in the lymphoid cell, a partial rearrangement of the heavy-chain
gene occurs which is followed by complete rearrangement of heavy-chain
gene. Here at this stage, Pre-B cell, mμ heavy chain and surrogate light chain
are formed. The final rearrangement of the light chain gene generates
immature B cell and mIgM.The process explained here occurs only in the
absence of the antigen.
• The mature B cell formed as RNA processing changes leaves the bone marrow
and is stimulated by the antigen then differentiated into IgM -secreted plasma
cells. Also at first, the mature B cell expresses membrane-bound IgD and IgM.
These two classes could switch to secretory IgD and IgM during the
processing of mRNAs.
• Finally, further class switching follows as the cell keep dividing and
differentiating. For instance, IgM switches to IgG which switches to IgA that
eventually switches to IgE
B-Cell Development

5. The multigene organization of immunoglobulin genes
From studies and predictions such as Dreyer and
Bennett's, it shows that the light chains and heavy
chains are encoded by separate multigene families on
different chromosomes. They are referred to as gene
segments and are separated by non-coding regions. The
rearrangement and organization of these gene segments
during the maturation of B cells produce functional
proteins. The entire process of rearrangement and
organization of these gene segments is the vital source
where our body immune system gets its capabilities to
recognize and respond to variety of antigens.

6. The light chain gene has three gene segments. These
include: the light chain variable region (V), joining region
(J), and constant region (C) gene segments. The variable
region of light is therefore encoded by the
rearrangement of VJ segments. The light chain can be
either kappa,κ or lambda,λ. This process takes place at
the level of mRNAs processing. Random rearrangements
and recombinations of the gene segments at DNA level
to form one kappa or lambda light chain occurs in an
orderly fashion. As a result, "a functional variable region
gene of a light chain contains two coding segments that
are separated by a non-coding DNA sequence in
unrearranged germ-line DNA" (Barbara et al., 2007).
Light chain multigene family

7. Heavy chain contains similar gene segments such as
VH, JH and CH, but also has another gene segment
called D (diversity). Unlike the light chain multigene
family, VDJ gene segments code for the variable
region of the heavy chain. The rearrangement and
reorganization of gene segments in this multigene
family is more complex . The rearranging and joining
of segments produced different end products because
these are carried out by different RNA processes. The
same reason is why the IgM and IgG are generates at
the time.
Heavy-chain multigene family

8. Variable-Region Rearrangements- The variable region rearrangements happen in an orderly
sequence in the bone marrow. Usually, the assortment of these gene segments occurs at B cell maturation.
Light chain DNA
The kappa and lambda light chains undergo rearrangements of
the V and J gene segments. In this process, a functional
Vlambda can combine with four functional Jλ –Cλ combinations.
On the other hands, Vk gene segments can join with either one
of the Jk functional gene segments. The overall rearrangements
result in a gene segment order from 5 prime to 3 prime end.
These are a short leader (L) exon, a noncoding sequence
(intron), a joined VJ segment, a second intron, and the constant
region. There is a promoter upstream from each leader gene
segment. The leader exon is important in the transcription of
light chain by the RNA polymerase. To remain with coding
sequence only, the introns are removed during RNA- processing
and repairing. In summary,

9. Heavy chain DNA
The rearrangements of heavy-chains are different
from the light chains because DNA undergoes
rearrangements of V-D-J gene segments in the
heavy chains. These reorganizations of gene
segments produce gene sequence from 5 prime to
3 prime ends such as a short leader exon, an
intron, a joined VDJ segment, a second intron and
several gene segments. The final product of the
rearrangement is transcribed when RNA
polymerase

10. Mechanism of variable region rearrangements
It is understood that rearrangement occurs between specific
sites on the DNA called recombination signal sequences (RSSs).
The signal sequences are composed of a conserved palindromic
heptamer and a conserved AT- rich nonamer. These signal
sequences are separated by non-conserved spacers of 12 or 23
base pairs called one-turn and two-turn respectively. They are
within the lambda chain, k-chain and The processes of
rearrangement in these regions are catalyzed by two
recombination-activating genes: RAG-1 and RAG-2 and other
enzymes and proteins. The segments joined due to signals
generated RSSs that flank each V, D, and J segments. Only genes
flank by 12 -bp that join to the genes flank by 23-bp spacer during
the rearrangements and combinations to maintain VL-JL and VH-
DH-JH joining.

11. Generation of antibody diversity
Antibody diversity is produced by genetic
rearrangement after shuffling and rejoining one of
each of the various gene segments for the heavy and
light chains. Due to mixing and random recombination
of the gene segments errors can occur at the sites
where gene segments join with each other. These
errors are one of the sources of the antibody diversity
that is commonly observed in both the light and heavy
chains. Moreover, when B cells continue to proliferate,
mutations accumulate at the variable regions through
a process called somatic hypermutation. The high
concentrations of these mutations at the variable
region also produce high antibody diversity.

12. Class-switching
When the B cells get activated, class switching can occur. The
class switching involves switch regions that made up of multiple
copies of short repeatts(GAGCT and TGGGG). These switches
occur at the level of rearrangements of the DNA because there
is a looping event that chops off the constant regions for IgM
and IgD and form the IgG mRNAs. Any continuous looping
occurrence will produce IgE or IgA mRNAs. In
addition, cytokines are factors that have great effects on class
switching of different classes of antibodies. Their interaction
with B cells provides the appropriates signals needed for B cells
differentiation and eventual class switching occurrence. For
example, interleukin-4 induces the rearrangements of heavy
chain immunoglobulin genes. That is IL- 4 induces the switching
of Cμ to Cγ to Cκ

13. Cytokines are a broad and loose category of small proteins
that are important in cell signaling. Cytokines are peptides,
and cannot cross the lipid bilayer of cells to enter the
cytoplasm. Cytokines have been shown to be involved in
autocrine, paracrine and endocrine signaling as immuno-
modulating agents. Their definite distinction from hormones is
still part of ongoing research. Cytokines include chemokines,
interferons, interleukins, lymphokines, and tumour necrosis
factors, but generally not hormones or growth factors.
Cytokines are produced by a broad range of cells, including
immune cells like macrophages, B lymphocytes, T lymphocytes
and mast cells, as well as endothelial cells, fibroblasts, and
various stromal cells; a given cytokine may be produced by
more than one type of cell.

14. https://en.wikipedia.org/wiki/Organization_and_expression_of_immunoglobulin_genes