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].