Mechanism of Antibody Formation, Biology tutorial

Introduction:

Antibodies are present in biologic fluids throughout body and also on the surface of the few cell types. B cells are the only cells which synthesizes antibody molecule. They are found in cytoplasmic membrane compartments like endoplasmic reticulum and golgi complex and on surface of B cells and are expressed as integral membrane proteins. There are also secreted forms of antibody found on plasma, mucosal secretions and in interstitial fluid of tissues in the small amount.

Theories of Antibody Formation:

Two theories have been suggested to illustrate how antibodies are produced. They are selective and instructive theories. The first theory called as instructive theory by Linus Pauling suggested that all antibodies had only one polypeptide structure which on induction by combining with the antigen folded in diverse ways. This proposal was rejected as it was observed that all antibodies still retain their specificity even after denaturation and renaturation in presence of the antigen and furthermore antigen specific antibodies were detected on lymphocyte surfaces previous to exposure to antigen. Model of clonal selection theory takes place in two phases, the first phase involves generation of diverse immunoglobulins without being challenged by the antigen and subsequent incorporation in cell surface.

Production of Antibodies:

When body is exposed to the antigen on immunisation, stimulation of antibody production follows but continued exposure to that same antigen would make sure production of high affinity antibodies. B cells are activated to generate IgM antibody on initial exposure but 3-5 days later IgMisotype appears in serum and reaches its peak at between 10- 14 days. Antibody levels start to decline thereafter till it reaches the pre-immunisation or baseline levels. In lag phase also referred to as latent or inductive phase, on introduction of antigen, it is seen as the foreign substance and cells start to proliferate and distinguish in response to antigen generally 3-5 days. This is consequently followed by log or exponential phase in which B cells different in plasma cells which produce antibody of IgM type. In third phase which is the plateau or steady state phase there is no net increase in antibody production as antibody synthesis is balanced by decay and this happens between 10-14 days. Final stage decline or decay, rate at which antibodies are degraded outweighs synthesis and this brings decline in level of antibody in body till it reaches baseline or pre-immunization state. This is what occurs in primary response to the antigen. Though, a subsequent or secondary exposure to same antigen results in quicker response due to immunologic memory. Lag phase is shorter while log phase responds quickly to presence of the antigen. There appears to be no steady state and response proceeds to decline stage that is not as rapid and antibody persists for months and even for years or lifetime.

Qualitative Changes and Cellular Events during Primary and Secondary Response:

Qualitative changes which occur during primary and secondary response involve isotype of antibody. The IgMisotypes are predominant antibodies produced but in secondary response, isotypes present are IgA, IgG and IgEisotypes and IgGisotypes are predominant antibodies. There is affinity maturation of IgG antibody that implies that initial response to low doses of antigen is low but it progresses with time. This description is described by clonal selection theory. Increased affinity leads to avidity and higher affinity is much probable to result in cross reactivity. Avidity refers to strength with which the antibody binds to antigen. Antibodies are multivalent in their reactions with multivalent antigens, therefore creating stronger bond. Though, remember that univalent antibody fragment could bind to the single antigenic determinant therefore avidity of the antibody for its antigen depends on affinities of individual antigen binding sites for epitopes on the antigen.

Cellular events though earlier defined are seen in phases of both primary and secondary immune response; where in lag phase B cells distinguish in plasma cells, followed by exponential increase in antibody concentration, then plateau and decline phases. In secondary response, all distinguished B and T cells after encountering antigen die off and some become memory cells. When challenged again by the antigen it is not only naive T and B cells which are activated but also memory cells and that is reason for a short lag period in secondary response.

Antigen/antibody interactions: role of lymphoid tissues and thymus in immune-response

Immune responses are not performed in any single organ, but in broad variety of structures collectively called as lymphoid tissue. Lymphoid tissue can be usually categorized as central (or primary), and peripheral (or secondary). Central lymphoid tissues are those which serve as source of immunocompetent cells, these cells then migrate to peripheral lymphoid tissues that are sites of immune responses. Primary lymphoid tissues are tissues in which lymphocytes are generated and distinguish in mature naive lymphocytes; these are bone marrow for B cells, and bone marrow and thymus for T cells. Secondary lymphoid tissues are tissues in which immune responses are initiated, and lymphatic vessels which connect them to tissues and bloodstream and therefore to sites of infection.

Major function of immune system is to defend body against the wide variety of pathogenic infectious agents with greatly differing natures that is fungi, viruses, bacteria, protozoa and parasitic worms. Complexity of this task needs the sophisticated repertoire of mechanisms for recognition of, and defense of body against, these pathogens. This is attained by the array of cells (and molecules that they secrete) that are dispersed throughout body and cooperatively constitute immune system.

Many of mature cells circulate in bloodstream and are dispersed throughout tissues of body, while some also congregate in specialized lymphoid tissues. Also, to generate effective immunity, different cell types cooperate with each other by means of direct interactions between cell surface molecules and via molecules that they secrete.

What are Lymphocytes?

They arise from lymphoid progenitors in bone marrow mammalian B cells fully develop here, while T cell precursors migrate to thymus for selection and maturation. Bone marrow and thymus are therefore called as primary lymphoid organs. Three major kinds of lymphocytes are known as B cells, T cells and NK (natural killer) cells. Mature B and T cells circulate in bloodstream and lymphatic system, spending some time in secondary lymphoid tissues, i.e. spleen, lymph nodes and mucosa-associated lymphoid tissues (MALT). Two morphological kinds of resting lymphocytes can be differentiated: B cells and majority of T cells are small lymphocytes with the thin rim of cytoplasm surrounding nucleus, while natural killer cells and some T cells are larger, have more cytoplasm and separate cytoplasmic granules, and are called as large granular lymphocytes. B and T lymphocytes are completely liable for adaptive or acquired immunity that is ability to recognize each pathogen in specific way and to mount faster and bigger response on repeated exposure to the specific pathogen (immunological memory). This is because B and T cells express surface receptors that specifically bind to materials which are foreign to body (called as antigens). Receptors of the single lymphocyte are identical to each other and recognize a single antigen.

What are B-Lymphocytes?

Cells of immune system that are specialized to make antibodies are termed B-lymphocytes, they are generated in bone marrow of adult mammals. Without B-cells and antibodies they make, one can only survive if given frequent gamma-globulin injections. B cells comprise 5-15% of human blood lymphocytes. Main function of the B cell is to secrete soluble recognition molecules known as antibodies that particularly bind to antigen recognized by that B cell. These antibodies (also called as immunoglobulins) are, in fact, secreted form of the B cell's surface antigen receptors and bind to exactly same antigen. A B cell will only create antibodies when it has been activated by binding antigen; this activation procedure also generally needs help from T cells. Activated B cell undergoes multiple divisions and some of the resulting cells distinguish in antibody-secreting cells. These are called as plasma cells, and they have copious rough endoplasmic reticulum involved in antibody synthesis.

Different classes of antibody predominate at different compartments of body (IgM being intravascular, IgG the main antibody of blood and tissues, IgA in secretions). Mucosa related lymphoid tissue comprises of lymphoid tissue at numerous mucosal sites (bronchus, gut, urogenital tract). Though, these are all connected functionally as subpopulations of B cells home to the tissues specifically. The response created at one site will induce immune responses to same antigen at other sites.

Main structural difference between antibodies of different classes is in non-antigen binding portion of molecules, known as Fc region, that is constant in structure between antibodies of same class produced by different B cells. The significant feature of antigen recognition by B cells is that these lymphocytes, and antibodies they generate, bind to antigens in their natural or naive form that is as they take place as constituents of pathogens.

What are T-Lymphocytes?

Approx 70% of human blood lymphocytes are T cells. The major functions of T lymphocytes are to apply effects on other cells, either regulating activity of cells of immune system or killing cells which are infected or malignant. Like B lymphocytes, T cells have surface antigen receptors, but there is no secreted form of this equivalent to antibodies. In addition, T cells can't recognize antigens in their native forms, but only when they are presented on surface of antigen-presenting cells (APCs). Antigen receptors of most T cells (alpha-beta T cells) are made up of two polypeptides known as alpha and beta chains, and they interact with peptides derived from degradation (processing) of foreign antigenic proteins. These peptides are bound to molecules of major histocompatibility complex (MHC) on surface of APCs. Interaction in T-cell antigen receptors and the peptide-MHC complexes binds the T cell to the surface of the APC, therefore targeting T cell to apply effects on APC. There are two kinds of MHC molecules, known as class I and class II, those present antigen peptides to alpha-beta T cells expressing surface proteins CD8 or CD4, respectively. This is due to CD8 binds to MHC class I and CD4 binds to MHC class II.

Development of T-Lymphocytes in Thymus:

As soon as receptor rearrangement has happened, T and B cells are able to respond to antigen and induce the immune response. Though, cell activation is firmly regulated to make sure that only damaging antigens elicit the reaction. Regulation mainly comprises initiation of T lymphocyte activation. This needs that antigen is presented to T cell within peptide binding groove of the self MHC molecule. This is due to T-cell receptor doesn't just recognizing antigenic epitope, but also the complex of the peptide in connection with self-MHC molecule. The delicate procedure of positive selection of T cells which can react with self-MHC and peptide sufficiently to induce immune responses takes place in thymus. These cells could at time not be very MHC-reactive to extent that would cause self-tissue destruction.

Cells which emerge from thymus and bone marrow having undergone gene rearrangement are naive that is they have not yet came across their specific antigen within the immune response. These cells populate secondary lymphoid tissues of tonsils, lymph nodes, spleen, and mucosa related lymphoid tissue. As there are only a few naive T and B cells capable of reacting particularly with the foreign particle, to encounter their specific antigen, there has to be the system to bring them together. Lymphoid tissues give the microenvironment for this procedure. Additionally to T and B lymphocytes, they have competent antigen-presenting cells and are capable to generate the cytokines essential to preserve T and B lymphocytes. Lymphoid tissues state adhesion molecules in the ordered array, permitting cells to move throughout the tissue and increase possibility of lymphocytes being brought in contact with antigen. Lymphoid organs communicate with the tissues by means of lymphatic and blood vessels.

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