CLONAL SELECTION AND EXPANSION

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The initial stage of B cell development in the bone marrow (known as antigen-independent stage) is carried out without the presence of any stimulating antigen or foreign body. The B lymphocytes so produced are generally known as incompetent B cells because they have not encountered any antigen or pathogen. Such B cells only circulate in the blood before being transported to the lymph nodes or spleen until a foreign body is encountered in the body. However, upon encountering an antigen, the B cells become activated and proliferate in order to differentiate into numerous plasma cells (for antibody production) and memory B cells for immunological memory should the antigen invade the body the second time in the future. The proliferation of B cells at this stage into more B lymphocytes for the production of antibody-producing plasma cells and memory B cells is generally known as clonal expansion/selection. The term clonal selection and clonal expansion shall be used synonymously in this section even though they both connote different definitions to some extent. In clonal expansion/selection, a particular B cell or T cell undergo cell division and differentiate into clones of B cells and T cells respectively with unique antigenic specificity as that of the original B cell or T cell that they emanated from.

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Clonal expansion is the enlargement in the number of competent B cells or T cells with the same antigenic specificity as the progenitor (parent) B cell or T cell. Such B or T cells arise from the same clone of B or T lymphocytes. The expansion of B and T cells in this fashion is controlled by the clonal selection theory. This later stage of B cell development is known as the antigendependent stage because the activation and differentiation of B cells require a prior exposure to antigens.B cells have very short lifespan (about 8 weeks) and they die-off if they fail to encounter an antigen during their short lifespan. B lymphocytes circulate as incompetent B cells and compete amongst themselves for space in the secondary lymphoid organs (e.g., spleen) where they remain for the invasion of foreign bodies or antigens.

The naïve or incompetent B cells that die-off because they did not encounter antigen for activation and proliferation die through a biological process known as apoptosis. The formation of specific antibodies each and every time an antigen invades the host is mainly directed or mediated by the prior interaction of the foreign body with antibody-secreting B cells. It is noteworthy that the B lymphocytes are saddled with surface receptors, example membrane-bound IgD (mIgD) or membrane-bound IgM (mIgM) that react specifically with the invading antigen. After this interaction between the antigen and the immunologically responsive B cells, the B cells proliferate into clones of B cells that produce numerous antibody-secreting plasma cells that secrete immunoglobulins that are specific for the antigens.

A clone is a cluster of cells that arise from a single progenitor cell. This mechanism through which antibody-secreting plasma cells emanate from a collection of activated or immunologically responsive B lymphocytes is known as clonal selection. Clonal selection is largely responsible for the secretion of numerous antibodies with specificity for unique antigenic determinant sites or epitopes of antigens. Clonal selection as earlier stated, is the immunological mechanism in which antigen-binding receptors of B cells and T cells stimulate the lymphocytes (i.e., B cells and T cells) to proliferate into a clone of lymphocytes that produce effector cells (e.g., antibodies, T helper cells and T cytotoxic cells) with the same antigenic specificity as their progenitor or parent cell. It is naïve or immunocompetent B cells that become activated through antigen-antibody reaction, and then differentiate or proliferate into numerous antibody-secreting plasma cells and memory B cells.

While the plasma cells go on to secrete antibodies, the memory cells remain in the general circulation to mount attack against the same pathogen should it appear the second time. The number of B or T cells produced during clonal selection/expansion is amplified; and the process ensures that sufficient amount of memory lymphocytes (B and T cells inclusive) with unique antigenic specificity are always available to assuage the activities of invading pathogens or antigens in the body. Aside the secreted antibodies, the immunologically responsive B cells also proliferate into memory B cells which remain dormant but viable in the blood circulation until a later time when similar antigen invades the host’s body again. The advent of memory B cells explains the reason for the rapid response of antibody production in secondary immune response.

Effector cells of the immune system are immunologically responsive cells that directly encounter antigens and facilitate their neutralization and possible elimination from the host. Examples of effector cells include plasma cells and T cells. Plasma cells are the effector cells of the humoural or antibody-mediated immunity mainly responsible for antibody secretion while the effector cells of the T cells are T helper cells (CD4+) and T cytotoxic cells (CD8+). Self reactive T lymphocytes (i.e., T cells that attack host cells instead of antigens) are eliminated from the thymus through the process of clonal deletion. In summary, the proliferation of B cells and T cells into effector cells is largely governed by the clonal selection theory. The clonal selection theory postulates that clones of effector B cells and T cells arise from a single parent cell that is stimulated through antigen-binding to reproduce similar lymphocytes with unique immunologic specificity and memory.

The clonal selection theory postulates that all the antibody molecules on a single B cell (i.e., antibodies that originated from a single progenitor or parent B cell) have the same antigenic specificity as their parent B cell. This also applies to the differentiation of naïve T cells into immunocompetent T cells with antigenic specificity as that of their parent T cell.The clonal selection theory is a biological theory that explains the unique specificity of antibody formation. This theory is generally based on the certainty that each lymphocyte is programmed to produce a particular type of immunoglobulin that is eventually selected by prior contact with an antigen or pathogen. All the B and T cells in the expanded parent clones are specific for the epitopes of the original pathogen or antigen that activated their production and selection/expansion into effector cells (i.e., memory B cells, memory T cells and immunocompetent B and T cells). The clonal expansion of T cells occurs after the T cells have encountered an antigen presented by any of the MHC molecules. The T cells (e.g., CD4+ helper T cells) secrete cytokines which go on to stimulate an antigen-activated B cell to proliferate and differentiate into antibody-secreting plasma cells that eventually produce specific antibodies that bind and facilitates the degradation and removal of the invading pathogen or antigen. This explains how the B cells and T cells cooperatively neutralize the activities of antigens in the body.

Further reading

William E.P (2003). Fundamental Immunology. 5th edition. Lippincott Williams and Wilkins Publishers, USA.

Stevens, Christine Dorresteyn (2010). Clinical immunology and serology. Third edition. F.A. Davis Company, Philadelphia.

Silverstein A.M (1999). The history of immunology. In Paul, WE (ed): Fundamental Immunology, 4th edition. Lippincott Williams and Wilkins, Philadelphia, USA.

Paul W.E (2014). Fundamental Immunology. Seventh edition. Lippincott Williams and Wilkins, USA.

Male D, Brostoff J, Roth D.B and Roitt I (2014). Immunology. Eight edition. Elsevier Saunders, USA.

Levinson W (2010). Review of Medical Microbiology and Immunology. Twelfth edition. The McGraw-Hill Companies, USA.

Berzofsky J.A and Berkower J.J (1999). Immunogenicity and antigen structure. In Fundamental Immunology, 4th edition., W.E. Paul, ed., Lippincott-Raven, Philadelphia. 

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