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Describe the process of lymphocyte development highlighting unique genetics that occur in the development of lymphocyte diversity.

The two types of lymphocytes which respond to immunity include T and B lymphocytes. Among all the leukocytes they are the second commonest and smallest.
Lymphopoiesis begins in the bone marrow because all the precursors are made in the bone marrow. It begins in the primary lymphoid organs also known as the central lymphoid organ.

T and B cells have different mechanisms of recognizing antigens. B and T cells constitute the adaptive immunity.

T cell development.

T cell constitutes of 2 alpha and 2 beta chains which form a heterodimer with both a constant and variable region. The invariant accessory chains associated with the alpha: beta chains CD3?, a CD3? and 2 CD3?.
T cells start their differentiation in the bone marrow the differentiate into maturity in the thymus hence the name T cell. The progenitor cells migrate to the thymus to be thymocytes and settle in the cortex where they develop and evolve to committed T cells. A few of the T cells make it to committed stage because of selection where some undergo apoptosis. They undergo programmed killing because some become self-antigen intolerance and others develop nonfunctional receptors. T cell development is dependent on genetic recombinance and extracellular signals. Immature T lymphocytes express neither CD4 nor CD8.

Mature T cells move to secondary lymphoid organs which include spleen, lymph nodes and the peyer’s patches via the blood. Alpha thymosin, beta 4 thymosin, thymopoietin and IL-7 facilitate development and maturity of T cells. Activated lymphocytes multiply, change into effector cells and memory cells.
T cells can be divided into 2 according to their coreceptors; helper T cells and cytotoxic T lymphocytes. Cytotoxic T lymphocytes are CD8+ while helper T cells are CD4+ and are dependent on the expression of pTCR for survival that have remodeled beta chains and surrogate alpha chains in the DN3 stage of development. Cytotoxic T lymphocytes kill intracellular antigen proteins which express class I MHC while helper T cells produce cytokines which recruits phagocytes including macrophages and B lymphocytes. T helper cells are further divided into type I and II according to the interleukins they express. For antigens to be recognized by the T cells they have to be presented in molecules bound to MHC which is highly polymorphic and has many variant genes. Class I MHC is coded by K, D and L genes while class II is coded by A and E.

B cell development.

Meanwhile, B cells undergo maturity in the bone marrow and are dependent on the nonlymphoid stromal cells by providing adhesive contacts with the developing B cells and growth factors that promote proliferation . B cells development and maturity is influenced by IL-7.
During normal B cell maturation, Ig heavy-chain are rearranged first, followed by the light chain rearrangement. Immature cells have IgM on their surfaces which is expressed once the light chains genes are assembled.

Final stages of development of immature B cells occur in peripheral lymphoid organs. Mature B cells express IgD in addition to the IgM on the cell surface after further differentiation at the periphery when they survive selection.
B cell development involves combinational rearrangement of the J, D and V segments in the H loci and the V and J genes in the L chain. Beginning of germinal cell reaction when the gene expression in B cell changes dynamically after being activated in the secondary lymphoid organs after being induced by an antigen.

The germinal cell reaction is identified by isotype switching, clonal expansion at the H locus of Ig, somatic hypermutation of V gene in the H locus and affinity maturation of BCR which is found on pre-B cells which have differentiated from pro-B cells(progenitor). Entry into the pre-B cell stage begins when H gene segments functionally rearranges. This is followed by 1 or 2 cell division of the pre-B cell and rearrangement of the genetic segment so that an immunoglobulin M is expressed on the surface (immature B cell). This immature B cell then migrates to the secondary lymphoid organs such as the spleen where they develop to naïve B cells. Each antibody has 2 similar antigen binding sites because of the disulfide bond between the 2 identical light chains and 2 identical heavy chains in the BCR. The isotypes of effector mechanisms include IgA, IgD, IgE, IgM, IgG. Antibodies participate in neutralization, opsonization and activation of complement activity when induced by a pathogen. B cells require expression of BCR for survival in the peripheral system.

. T and B lymphocytes have a wide range in the responses against presented antigens because of their antigen variable specificity.
In the secondary lymphoid organs, the lymphocytes interact with antigens, pathogens and other cells. They trap and concentrate foreign substances and secrete antibodies and mediators such as cytokines. Population of B and T cells vary in spleen due to destruction and elimination of pathogen in blood.

In the lymph nodes pathogens are filtered by lymphocytes. Peyer’s patches are lined with lymphocytes and dendritic cells that filter pathogens.

Specificity is determined in their early differentiation when the DNA sequences encoding the variable regions of Ig, in B cells, and TCRs, in T cells, undergo somatic rearrangement of the gene sequence. Genes act at different specific stages of differentiation to encode lineage specific transcription factors, GF, DNA recombinases, chemokines and terminal deoxy transferases which leads to diversity and rearrangement of antigen receptor genes.

Lymphocytes originate from a common lymphoid progenitor cell CD34+ which is a pluripotent stem cell of hemopoiesis. Immunoglobulin IgM is expressed on the surface of immature B cells. From the common progenitor they differentiate into pro B/T cells then when they express one chain of pre-antigen receptor, they differentiate in pre-B/T cells. The ones which fail to express pre-antigen receptor die.

Immature B/T cells express complete antigen receptors which either have strong antigen recognition or weak antigen recognition. These that interact strongly with self-antigens are removed from repertoire.
T cell progenitors develop in the bone marrow then migrate to the thymus. In the thymus the precursor rearranges its T-cell receptor genes. Positive and negative selection occurs in the thymus where the immature T cells that recognize self MHC receive signals for survival and are therefore removed from the repertoire. Negative selection occurs in the medullary region. Positive selection occurs in the cortex where cells that do not recognize self MHC are removed by neglect. Mature T cells migrate to the periphery of lymphoid organs where they encounter foreign antigens. Activated T cells migrate to the point of infection where they proliferate and eliminate infections.
Lymphocytes recognize the presence of lymphocytes using lymphocyte receptors; immunoglobulins from B cells and T-cell receptor on T cells. The unique antigen specificity is determined by the structure of the antigen binding site. This is due to the variation in the amino acid sequence. The antigen binding site is made from the variable regions of receptor protein chains.

An invariant constant region provides effector and signaling functions and is linked to the variable region. Gene rearrangement is the assembling gene segments, which a piece of encoded regions, into developing lymphocytes to form a complete sequence by somatic DNA recombination. Somatic recombination refers to the process of DNA rearrangement and deletion.

B cells undergo a further modification on the variable region in a process known as somatic hypermutation and this occurs only after being activated by antigens the enzyme called activation-induced cytidine deaminase is used.

High point of mutation occurs in the variable region to enhance the diversity of B cells in response to an antigen.
The shape of the v region determines the specificity of a particular antibody.
The rearrangement of the B cell variable occurs when the cell is in the progenitor stage in the bone marrow. Multiple forms of variable, diversity and joining genes can be rearranged and joined in different combinations to ensure diversity.
In humans, antibodies consist of both light and heavy chains which have the different types of genes rearranged. The D gene is only present in the heavy chains.  
Terminal deoxynucleotidyl transferase enzyme is also responsible for changing the variable produced by adding an extra chromosome to the 3 above regions.

REFERENCES
Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK27123/ on 12/11/2018
Retrieved from https://www.uptodate.com/contents/normal-b-and-t-lymphocyte-development on 9/11/2018
Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2504865/ on 10/11/2018