Specificity and antigen receptor rearrangement (Diversity)
The complex and diverse immune system is genetically regulated by
somatic generation of variations on the basis of a limited number of
germ-line genes. Each germline cell in the body contains genes for
immunoglobulin and also a T cell receptor. The genes are divided into
sections designated V (variable), D (diversity), J (joining) and C
(constant).The V, D and J regions contain different versions of the same
genes. Gene rearrangement occurs during the lymphocyte development. A
single gene from each section is selected while the other genes are
eliminated. The new V, D, J sequence is spliced onto the heavy chain
gene. Since these joins are random, this process generates considerable
diversity. This diversity is even greater in the case of the heavy chain
genes in which the variable heavy (VH) genes combine
with a D gene which comprises a hypervariable region which in turn
recombines with one of a cluster of J gene. Further variation occurs by
the association of different light chains with the heavy chains, and
possibly by changes of the arranged immunoglobulin genes by somatic
mutations in the course of B cell ontogeny, and the arrangement of the α
and β chains of the T cell receptor. It should be noted that this
rearrangement is random and does not require the presence of antigen.
Antigen-driven proliferation occurs in the secondary lymphoid organs
where the lymphocyte and its progeny are specific for a single epitope
on an antigen. Throughout life a person is exposed to a wide variety of
antigens and consequently produce antibodies with a corresponding wide
range of specificities. Of some 1020 immunoglobulin
molecules in the circulation there are an estimated
105 -108different specificities
[21, 22].
The lymph node ensures thorough mixing of antigen,
immunocompetent cells and immunoglobulins The constant slow flow of
lymph from the tissues back to the blood ensures that antigenic sampling
by the immune system can be easily carried out. The sampling occurs in
the lymph node sinuses, which are lined by histiocytes capable of
trapping antigen, particularly when coated with antibody. Simultaneously
blood carrying lymphocytes arrives at the node. The peripheral blood
contains 2 x 109 lymphocytes/ml, 70% of which are T
cells. The cells continuously recirculate from the blood to the lymph
node, to the thoracic duct and back to the blood. Antigen carried in the
lymph is highly likely to meet its specific lymphocyte, because the two
flows meet in the lymph node. The post-capillary venules in the lymph
node are lined by cuboidal epithelial cells and are the site of
lymphocyte emigration from the cardiovascular to the lymphatic system.
The mixing of lymphocytes with antigen leads to a second phase of
proliferation and differentiation. Proliferation and differentiation of
the B cells occurs in the germinal centre. Firstly, plasma cells are
produced that migrate to the medulla, where they secrete large amounts
of specific immunoglobulin. Secondly, memory B cells are produced ready
to confront the antigen on subsequent exposure. The secondary immune
response is characterized by the rapid production of IgG, because the
clone of specific B cells has multiplied and the immunoglobulin genes
have already switched from IgM to IgG transcription. T cells migrating
through the node will proliferate and differentiate as well, but around
the blood vessels of the paracortex. The specific T cells produced,
unstimulated lymphocytes, immunoglobulin that leaves the lymph node at
the medulla, return via the thoracic duct to the bloodstream and
ultimately arrive at the tissue from which the lymph was draining. In
most cases, antigens are stopped at the lymph node and prevented from
further progress through the body. In some overwhelming infections,
however, organisms will elude the first line of defence, enter the
bloodstream and then the lymphoid tissue of the spleen becomes very
important [23, 24].
The spleen is essentially an enlarged lymph node with a very
similar arrangement. The splenic lymphoid tissue (the white pulp)
consists of aggregates of T cells and B cells arranged around the
arterioles. The spleen has two main roles: mounting immunological
reactions to blood-borne antigens in the systemic circulation and the
removal of abnormal red blood cells.
Mucosa-associated lymphoid tissue , which is present beneath the
mucosa , from the tonsils to the anus, is responsible for generating
immune response to gut contents. Similar lymphoid aggregates can also be
found in the respiratory tract. There are B and T cell areas similar to
those found in the lymph node, but the B cells have a tendency to
infiltrate the epithelium possibly as a way of sampling the antigens in
the lumen as particularly seen with the secretory IgA antibodies from
Peyer’s patches (Gut associated lymphoid tissues (GALT)) in the terminal
ileum [1].