Antibody Structure Lec5 PDF

Molecular Mechanism of Antibody Synthesis  Ig Genes Are Assembled from Separate Gene Segments During B Cell Development After stimulation by antigen and helper T cells, B cells can switch from making IgM and IgD to making other classes of Ig—a process called class switching. In addition,...

Molecular Mechanism of Antibody Synthesis  Ig Genes Are Assembled from Separate Gene Segments During B Cell Development After stimulation by antigen and helper T cells, B cells can switch from making IgM and IgD to making other classes of Ig—a process called class switching. In addition, the binding affinity of these Igs for their antigen progressively increases over time—a process called affinity maturation. Each light-chain V region, for example, is encoded by a DNA sequence assembled from two gene segments—a long V gene segment and a short joining segment, or J gene segment. Each heavy-chain V region is similarly constructed by combining gene segments, but here an additional diversity segment, or D gene segment, is also required.  In the “germ-line” DNA the cluster of five J The V–J joining process involved in gene segments (green) is separated from making a human k light chain. the C-region coding sequence (purple) by a short intron. During the development of a B cell, a randomly chosen V gene segment (V3 in this case) is moved to lie precisely next to one of the J gene segments (J3 in this case). The “extra” J gene segments (J4 and J5) and the intron sequence are transcribed (along with the joined V3 and J3 gene segments and the C-region coding sequence) and then removed by RNA splicing to generate mRNA molecules with contiguous V3, J3, and C sequences, as shown. These mRNAs are then translated into κ light chains. The human heavy-chain locus. Each heavy-chain V region is similarly constructed by combining gene segments, but here an additional diversity segment, or D gene segment, is also required V(D)J recombination is mediated by an enzyme complex called V(D)J recombinase, which recognizes recombination signal sequences in the DNA that flanks each gene segment to be joined. Although the process ensures that only appropriate gene segments recombine, a variable number of nucleotides are often lost from the ends of the recombining gene segments, and one or more randomly chosen nucleotides are also inserted. This random loss and gain of nucleotides at joining sites is called junctional diversification, and it greatly increases the diversity of V- region coding sequences created by V(D)J recombination. Antigen-driven Somatic Hypermutation Fine-Tunes Antibody Responses After an infection or vaccination, there is usually a progressive increase in the affinity of the antibodies produced against the pathogen. This phenomenon of affinity maturation is due to the accumulation of point mutations in both heavy-chain and light-chain V-region coding sequences. B cells mutate at the rate of about one mutation per V- region coding sequence per cell generation. Because this is about a million times greater than the spontaneous mutation rate in other genes and occurs in somatic cells rather than germ cells, the process is called somatic hypermutation.  Very few of the altered Igs generated by hypermutation will have an increased affinity for the antigen. However, the antigen will stimulate preferentially those few B cells that do make BCRs with increased affinity for the antigen. Most other B cells in the germinal center will die by apoptosis. B Cells Can Switch the Class of Ig They Make When a B cell switches from making IgM and IgD to one of the secondary classes of Ig, an irreversible change occurs in the DNA—a process called class switch recombination. The activated B cells are undergoing somatic hypermutation in germinal centers, the combination of antigen and cytokines derived from helper T cells stimulates many of the B cells to switch from making membrane-bound IgM and IgD to making IgG, IgE, or IgA, in the process of class switching. Activation-induced deaminase (AID) is also required for activated B cells to switch from IgM and IgD production to the production of the other classes of Ig, as we now discuss. T lymphocytes T CELLS AND MHC PROTEINS Like antibody responses, T cell–mediated immune responses are exquisitely antigen specific, and they are at least as important as antibodies in defending vertebrates against infection. Indeed, most adaptive immune responses, including most antibody responses, require helper T cells for their initiation. Most important, unlike B cells, T cells can help eliminate pathogens that have entered the interior of host cells, where they are invisible to B cells and antibodies. T cell responses differ from B cell responses in at least two crucial ways. First, a T cell is activated by foreign antigen to proliferate and differentiate into effector cells only when the antigen is displayed on the surface of an antigen-presenting cell (APC), usually a dendritic cell in a peripheral lymphoid organ. One reason T cells require APCs for activation is that the form of antigen they recognize is different from that recognized by the Igs produced by B cells. Whereas Igs can recognize antigenic determinants on the surface of pathogens and soluble folded proteins, for example, T cells can only recognize fragments of protein antigens that have been produced by partial proteolysis inside a host cell. Newly formed MHC proteins capture these peptide fragments and carry them to the surface of the host cell, where T cells can recognize them.  The second difference is that, once activated, effector T cells act mainly at short range, usually contacting the cells they influence, either within a secondary lymphoid organ or after they have migrated to a site of infection. Effector B cells, by contrast, secrete antibodies that can act far away. Effector T cells interact directly with another host cell in the body, which they either kill (if it is an infected host cell, for example) or signal in some way (if it is a B cell or macrophage, for example).  There are three main classes of T cells—cytotoxic T cells, helper T cells, and regulatory T cells. When activated, they develop into effector cells, each class having its own distinct activities. Effector cytotoxic T cells directly kill cells that are infected with an intracellular pathogen. Effector helper T cells help stimulate the responses of other immune cells—mainly macrophages, dendritic cells, and B cells. Effector regulatory T cells suppress the activity of other immune cells. After functioning, some effector T cells become memory T cells. T Cell Receptors (TCRs) Are Ig-like Heterodimers Each chain has a large extracellular part that is folded into two Ig-like domains one variable and one constant. A Vα and a Vβ domain form the antigen-binding site. Unlike Igs, which have two binding sites for antigen, TCRs have only one. A typical T cell has about 30,000 TCRs on its surface. Activated Dendritic Cells Activate Naïve T Cells (A) Immunofluorescence micrograph of a mouse dendritic cell in culture. These APCs derive their name from their long processes, or “dendrites.” (B) Scanning electron micrograph of T cells bound to the surface of an activated dendritic cell in a mouse lymph node. d: uch as a face in Activated Dendritic Cells Activate Naïve T Cells Naïve T cells, including naïve helper and cytotoxic T cells, T cell sa proliferate and differentiate into effector cells and memory he cells only when they see their specific antigen on the uding surface of an activated dendritic cell in a peripheral actor-κB lymphoid organ. olecules, ovide n. These The three general types of proteins on the surface of an activated dendritic cell involved in activating a T cell. crete ). ecific aling cting T Th1, Th2,