B Cells & Antibody Production

Introduction

Immunity is the ability of the body to produce lymphocytes or antibodies to destroy efficiently specific foreign substances such as antigens that has been detected in body. Immunity is basically defined as the mechanisms which develop the ability of individuals to recognize foreign substances (non self) and subsequently acts to neutralize, destroy, or metabolize the substances with or involvement of pathological consequences to the individual themselves. The immune system is also known as a diverse form of defense work together to complement each other. Immune system generally made up of three different components which are the physical components (e.g skin and mucous membrane), the cellular components (e.g leucocytes and reticulo-enditelial cells) and the non-cellular or nonparticulate components, which consists of excretory fluid (e.g sweat gland, tears, saliva, and trachea) and body fluids and cellular contents.

B cells are one of the lymphoid lineage in the immune system. B cells or also known as B lymphocytes produces antibodies when stimulated through plasma cells. This B cells exist as clones. B cells are produced and mature in the bone marrow and they have glycoprotein receptors on their cell surface membranes which bind specific antigens. This eventually makes B cells to act as an Antigen Presenting Cell (APC) to MHC I and MHC II. Mature B cells may become memory cells or plasma cells that secrete large quantities of antibodies. Besides that, B cells also functions in the production of interleukin such as the Interleukin I production.

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Antibodies are basic mediators of immunity to pathogens that survive and multiply in extracellular spaces and utilize the extracellular milieu to spread within host tissues. B cells are the primary effectors calls of the humoral immune response. Humoral immune response or also known as antibody mediated response is the method of antibody production (B cells). Humoral immune response also involves mainly B cells although stimulation by T cells is also necessary. Once B cells are activated, they produce antibodies which circulate in the body fluids via plasma and lymph. (Sell, 2001)

The Maturational Process of B Cells

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The maturation process in the bone marrow and involves variable region gene assembly and productive gene rearrangement leading to a large array of antibody diversity. The process also involves B cells progression through several stages associated with the elimination of autoreactive B cells by negative selection and finally the release to the periphery of mature B cells expressing membrane immunoglobulin M(mIgM) and mIgD. This process occur in an antigen independent fashion.(Pier.G.B., 2004)

Upon entry into the periphery, the mature B cells are ready to respond to their cognate antigen which leads to activation of the B cells and antibody production. This process involves a large number of B cells components, especially the mIg on the surface and associated structures that form the B cells antigen receptor (BCR) and the B cells coreceptor complex induced in signal transduction and B cells activation in responses to antigenic stimuli. B cells respond to antigen in both T cell dependent and T cell independent fashion, depending on the nature of the antigenic stimulus and the production of antibody secreting plasma cells depends heavily on B cells directly interacting with other cells and the production of cytokines to activate and drive the antibody respond. Figure 1: The maturation process of B cells

B cell receptor (BCR)

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The B cell receptor (BCR) consists in part of membrane-bound immunoglobulin and belongs to a class of receptors that includes the T cell receptor (TCR). All of these receptors contain a complex hetero-oligomeric, structure made up of a ligand binding subunits and signal transduction subunits. The intramembranous portion of mIg is usually 25 amino acids long and differs from the transmembranous region of the T cell receptor (TCR) which the latter contain several changed amino acids that are needed for interactions with other receptor proteins. This is due to the transmembranous region of mIg which lacks charged amino acids but instead has many hydroxyl-containing amino acids that interact with other polypeptides. (Pier.G.B., 2004)

In addition to mIg, the B cell receptor (BCR) contains the protein Ig α and Ig β which function as the signal transduction portion of the B cell receptor (BCR). BCR signal transduction is the key event in B cell activation. During the generation of B lymphocytes, pro-BCR mediated cell signal events involving of intermediates that causes Ca2+ levels to increase are required for cell survival and further maturation. In the stage of B lymphocytes development, the heavy (H) chain completely rearranged and associated with the surrogate light (L) chain, pre-BCR and λ5 as well as with Ig α and Ig β to form the pre-BCR. Cross linking of this pre-BCR complex can induce mobilization of both extracellular and intracellular calcium but cannot trigger phospholipace C (PLC) activation. (Pier.G.B., 2004)

This leads to the rearrangement of the immunoglobulin C chains leads to formation of the BCR, containing mIg, Ig α and Ig β. At this stage, B cells attain antigen specificity since it has functional immunoglobulin H and L chain genes. In the periphery mature, B cells are 4

ready to interact with antigen, become activated, differentiated, expand clonally and mature into antibody-secreting plasma cells.(Pier.G.B., 2004)

Humoral Immune Response The confrontation between antigens and lymphocyte usually occurs in the lymph modes, spleen or lymphoid tissue. If an antigen binds to the B-lymphocyte, humoral response is triggered. Humoral response is also known as antibody response. The human body has over 1 billion different types of B cells, each with its own specific antibody on the cell surface. The antibody on the surface of the B cells is actually a receptor for a specific antigen. (Campbell, 2005)

When an antigen binds to antibody on the B cells, the B cell becomes deactivated. The activated B cells then divides into a clone of cells. The bound antigen is absorbed into the B cells and fragmented.

Figure 2: Mechanism of action

MHC protein bind to the antigen fragment and present the antigen fragment on the surface of the B cells. Helper T cell with complementary receptors bind with the antigen fragment the surface of B cells. This stimulate the B cells to secrete Interleukin-1 which activates and stimulates helper T cells to release Interleukin-2.

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Interleukin-2 stimulates B cells to grow and divides into a clone of B cells with antibodies (receptors) identical to the antigen bound B cells.

This clone of B cells the differentiate into plasma cells that synthesise and secrete large amount of antibodies to bind with the specific antigen. The antibodies produced will circulate in the lymph and blood to all over the body to bind and destroy that specific antigen. The immune response just describe in the primary humoral response. Primary humoral response is the production of antibodies by B cells due to the first time exposure to the antigen. This response peaks 10 days after infection and fade off at the end due to action of suppressor cells.(Campbell, 2005)

Some of cells in the clone are differentiate into memory B cells. Memory B cells circulate body for months, year or lifetime. Memory B cells triggers secondary immune response. Those cells would rapidly divides into antibody producing cells if the body were attacked with the same antigen. Secondary immune response is rapid, longer, lasting and more effective. In this secondary immune response, memory B cells activated by antigen will divide rapidly to produce a large number of plasma cells. Hence large quantity of antibody is produced quickly. The high concentration of the antibody remains for a longer time in the blood. Humoral immune response(antibody mediated response) is the immune response that fight bacteria and viruses in body fluid with antibodies that circulated in the blood and lymph. (Campbell, 2005)

I. Antibody

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Antibody is an immunoglobulin capable of specific combination with the antigen. Antibodies exist as one or more copies of a Y-shaped unit, composed of four polypeptide chains. Each Y contains two identical copies of a heavy chain, and two identical copies of a light chain, named as such by their relative molecular weights. Antibodies can be divided into five classes: IgG, IgM, IgA, IgD and IgE, based on the number of Y units and the type of heavy chain. Heavy chains of IgG, IgM, IgA, IgD, and IgE, are known as gamma, mu, alpha, delta, and epsilon, respectively. The light chains of any antibody can be classified as either a kappa (κ) or lambda (λ) type (based on small polypeptide structural differences). However, the heavy chain determines the subclass of each antibody. (Coico, 2003)

The subclasses of antibodies differ in the number of disulfide bonds and the length of the hinge region. The most commonly used antibody in immunochemical procedures is of the IgG class because they are the major immunoglobulin (Ig) released in serum. The classical Y shape of IgG is composed of the two variable, antigen specific F(ab) arms, which are critical for actual antigen binding, and the constant Fc that binds immune cell Fc receptors and also serves as a useful for manipulating the antibody during most immunochemical procedures. The number of F(ab) regions on the antibody, corresponds with its subclass, and determines the valency of the antibody (loosely stated, the number of “arms” with which the antibody may bind its antigen). Direct-conjugated antibodies are labeled with an enzyme or fluorophore in the Fc region. II. Type of Antibody Name

Type

Description

Antibody Complexes

IgA

2

Found in mucosal areas, such as the gut, respiratory

Dimer

tract and urogenital tract, and prevents colonization 7

by pathogens.[10] Also found in saliva, tears, and breast milk. Functions mainly as an antigen receptor on B cells IgD

1

that have not been exposed to antigens. It has been shown to activate basophils and mast cells to

Monomer

produce antimicrobial factors. Binds to allergens and triggers histamine release IgE

1

from mast cells and basophils, and is involved in

Monomer

allergy. Also protects against parasitic worms. In its four forms, provides the majority of antibodyIgG

4

based immunity against invading pathogens. The only antibody capable of crossing the placenta to

Monomer

give passive immunity to fetus. Expressed on the surface of B cells and in a IgM

1

secreted form with very high avidity. Eliminates pathogens in the early stages of B cell mediated

Pentamer

(humoral) immunity before there is sufficient IgG.

Table 1: Show the different type of antibody.

Interaction Between B Lymphocytes and T Lymphocytes Activation of B cells and T cells involves a reciprocal dialogue between the two cells type, resulting in the activation of both cell type. During this dialogue, the B cells serve as an 8

Antigen Presenting Cell (APC) to activate the T Helper cell, while the T Helper Cell provide the B cells with activation signals essential for full B cell activation. As with T cell activation by other APC’s two signal are headed, signal one is delivered via the interaction of the MHC on APC’s and the T cell receptor(TCR) on T Lymphocytes, while the second or costimulating signal is usually delivered by the binding of CD80 and CD86 on B cells to CD28 on T cells. CD80 and CD86 also bind to Cytotoxin T Lymphocyte Antigen 4(CTLA-4) on T cells, but this result in a inhibitory signal on T cells.(Pier.G.B., 2004)

In addition, there is a recently describe set of additional co-receptor that is intimately involved in B cells and T cells interactions and important for induction of B cells immunoglobulin isotype switching, Inducible Costimulator (ICOS) on T cells and ICOS ligand on B cells.

Interaction of CD40 on B cells and CD40 ligand on T cells is also integral to B cells activation other sets of receptors and countereceptors are involved in T cells and B cells interactions. But, these other interaction only argument the response of the constimulatory ligands by futher stabilizing the T cells and B cells interaction and decreasing the threshold of B cell activation. The combined action of signal 1 and 2 leads to activation of the Lymphocytes which release cytokines that in turn active the B Lymphocytes.

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Figure 3:

Interaction between B cells and T cells.

Both B cells receptor(BCR) and T cells receptor(TCR) share these properties. They are integral membrane proteins. They are present in thousands of identical copies exposed at the cell surface. They are made before the cell ever encounters an antigen. They are encoded by genes assembled by the recombination of segments of DNA. They have a unique binding site. This site binds to a portion of the antigen called an antigenic determinant or epitope. The binding, like that between an enzyme and its substrate depends on complementarity of the surface of the receptor and the surface of the epitope. The binding occurs by non-covalent forces. BCRs and TCRs differ in their structure, the genes that encode them and the type of epitope to which they bind.

Apoptosis of B Cell Activation

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Activation and prevention overproduction of antibody and possible induction of autoimmune response, B cells must be killed. When B cells fails in any the maturation process they will die by mechanism known as apoptosis.

The early development of the immune response is also vital point for control B cells activation during the acts immune B cells can be induced. The inductionof apoptosis of B cells is therefore extremely important in the regulation of humoral immune response. B cells apoptosis can be initiated when the Major Histocompatibility Complex(MHC) class II already activated B cells is cross-linked. (Pier.G.B., 2004)

The function this regulatory mechanism mat be to dampen B cells-Mediated T cells activation once the immune response is activated. Furthermore, this mechanism of B cells apoptosis may constitute a fail-safe mechanism to eliminate antigen- nonspecific B cells activated interaction with activated helper T cells.

Conclusion

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B cells are lymphocytes that play a large role in the humoral immune response as opposed to the cell-mediated immune response that is governed by T cells. The abbreviation "B" comes from bursa of Fabricius that is an organ in birds in which avian B cells mature. The principal function of B cells is to make antibodies against soluble antigens. B cells are an essential component of the adaptive immune system. The clonal selection of B cells generates antibody-secreting plasma cells, the effector of cells of humoral immunity. Th efive major antibody classes differ in their distribution and function eithin the body. Binding of the antibodies to antigens on the surface of pathogens leads to elimination of the microbes by phagocytosis and complement-mediated lysis.

References

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Campbell. (2005). Biology. San Francisco: Benjamin Cummings. Coico, R. (2003). Immunology: A short Course(5th ed). New Jersey: John Wiley and Sons. Gerald B.Pier, Jeffrey B.Lyzack and Lee M.Wetzler. (2004). Immunology, Infection and Immunity. Washington DC: ASM Press. Lydyard,P.,Whelan,A. and Fanger,M.W. (2003). Immunology. London: Bios Scientific Publishers. Pharham, P. (2005). The Immune System(2nd ed.). New York: Garland Science, Taylor and Francis. Sell, S. (2001). Immunology,Immunopathology and Immunity. Washington DC: ASM Press. http://en.wikipedia.org/wiki/Antibody . (n.d.). Retrieved 13 October, 2009, from http://en.wikipedia.org/wiki/. http://en.wikipedia.org/wiki/B_cell . (n.d.). Retrieved 13 October, 2009, from http://en.wikipedia.org/wik.

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