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B-cell Receptor Pathway

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Lymphocytes are one of the five kinds of white blood cells or leukocytes, circulating in the blood. Although mature lymphocytes all look pretty much alike, they are extraordinarily diverse in their functions. The most abundant lymphocytes are: B-Lymphocytes (often simply called B-Cells) and T-Lymphocytes (likewise called T-Cells) (Ref.1). B-Cells are not only produced in the bone marrow but also mature there. Each B-Cell is specific for a particular antigen. The specificity of binding resides in the BCR (B-Cell receptor) for antigen. 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. B-Cell receptor complex usually consist of an antigen-binding subunit (the membrane immunoglobulin or MIg), which is composed of two IgHs (Immunoglobulin Heavy Chains) and two IgLs (Immunoglobulin Light Chains), and a signaling subunit, which is a disulfide-linked heterodimer of Ig-Alpha (CD79A) and Ig-Beta (CD79B) proteins. For the heavy chains of BCRs (antibodies), the gene segments are: 51 VH segments, each of which encodes most of the N-terminal of the antibody, including the first two (but not the third) hypervariable region, 25 DH (="diversity") gene segments, which encode part of the third hypervariable region, 6 JH (="joining") gene segments, encoding the remainder of the V region of the BCR (including the remainder of the third hypervariable region) and 9 CH gene segments, which encode the C region of the BCR (and the antibody derived from it). The C gene segments are 1 mu; encoding the C region of IgM, 1 delta for IgD4 gamma gene segments for the four types of IgG,1 epsilon for IgE and 2 alpha gene segments for the two types of IgA. All of these gene segments are clustered in a complex locus on chromosome 14. During the differentiation of the B-Cell (and long before any possible encounter with an antigen), the DNA in this locus is cut and recombined to make an intact gene for the heavy chain. This gene can then be transcribed into mRNA, which is, in turn, translated into the heavy polypeptide chain. All isotypes of mIg have very short cytoplasmic tails. Both mIgM and mIgD have a cytoplasmic domain, which are only 3 amino acids in length. The cytoplasmic tails of mIg are too short to be able to associate with intracellular signaling molecules. Since mIg is always associated with the Ig-alpha/Ig-beta heterodimer collectively forming B-Cell receptor complex (BCR), two molecules of this heterodimer associate with one mIg to form a single BCR. The Ig-alpha/Ig-beta heterodimer carries out the signal transducing function of the complex. The Ig-alpha chain has a long cytoplasmic domain containing 61 amino acids while the Ig-beta chain has a long cytoplasmic domain containing 48 amino acids (Ref.2).

BCR have a unique binding site. This site binds to a portion of the antigen called an antigenic determinant or epitope. The binding depends on complementarity of the surface of the receptor and the surface of the epitope. The binding occurs by non-covalent forces. In the absence of specific antigen, mature B-Cells survive in the peripheral circulation for only a few days. Cells which do not encounter antigen within this period of time undergo apoptosis. This is necessary in order to maintain an optimal circulation of B-lymphocytes in the peripheral circulation. When the receptor is on the cell surface of B-lymphocytes it functions to transmit intracellular signals that regulate cell growth and differentiation and it binds to antigen for the generation of the immune response (Ref.3).

Most B-Cell antigens are T dependent. In other words, the B-Cell requires direct contact by TH lymphocytes as well as exposure to TH lymphocyte cytokines in order to be fully activated. There are a few T independent antigens. One of the best-known examples of a T independent antigen is LPS (Lipopolysaccharide). At low concentrations, LPS stimulates the production of specific antibodies (LPS-specific) but at high concentrations it can cause the polyclonal activation of B-Cells. The polyclonal activation of B-Cells leads to the proliferation and differentiation of large numbers of B-Cells, regardless of their antigen specificity. Bacterial cell wall polysaccharides and bacterial flagellin can also serve as T independent antigens. The cell wall polysaccharides are characterized by possessing repetitive monosaccharide subunits while the bacterial flagellin is a repetitive polymeric protein (Ref.4). It is believed that these repetitive antigens stimulate B-Cells by extensively cross-linking membrane-bound Ig. The antibody response to these antigens is specific. This process does not require direct T-Cell contact but does require the presence of certain T-Cell cytokines. The signal initiated by binding of antigen to the B-Cell receptor complex causes growth and proliferation of the B-Cell and the creation of an amplified clone of effector cells that secrete the antigen-specific immunoglobulin. Activation of the B-Cell receptor by antigen also results in the production of memory cells that persist in circulation to produce a more rapid immune response after future challenges by the same antigen. The bound antigen molecules are engulfed into the B-Cell by receptor-mediated endocytosis. The antigen is digested into fragments, which are then displayed at the cell surface nestled inside a class II histocompatibility molecule (Ref.5).

References:
  1. Severinson E, Westerberg L
    Regulation of adhesion and motility in B lymphocytes.
    Scand. J. Immunol. 2003 Aug;58(2):139-44.
  2. Rheingold SR, Brown VI, Fang J, Kim JM, Grupp SA
    Role of the BCR Complex in B-Cell Development, Activation, and Leukemic Transformation.
    Immunol. Res. 2003;27(2-3):309-30.
  3. Calame KL
    Plasma cells: finding new light at the end of B cell development.
    Nat. Immunol. 2001 Dec;2(12):1103-8.
  4. Rojas Ramos E, Martinez Jimenez N, Reyes Salinas A
    The Th2 theory in allergy: present and future directions.
    Rev. Alerg. Mex. 2003 Mar-Apr;50(2):64-70.
  5. Silver K, Cornall RJ
    Isotype control of B cell signaling.
    Sci. STKE. 2003 May 27;2003(184):pe21.