Functional Proteins of the Acquired Immune System

Antibodies

Antibodies are proteins that bind specifically to epitopes on antigen surfaces neutralizing them or opsonizing them for phagocytosis. Each antibody has a unique specifity and binds to a distinct epitope, however all antibodies possess the same basic structure and are referred to as immunoglobulins. Immunoglobulins are composed of two identical heavy chains and two identical light chains. There are two types of light chains, K and X, but each immunoglobulin contains only one type of light chain. The heavy chains are connected to one another and the light chains are connected to the heavy chains by disulfide bonds. The light chain has a constant (C) and variable region. The constant region is encoded by either a K or X gene. The variable region is encoded by two genes that are translated into a large V and a smaller J segment. There is a cluster of 70 or more V genes and 5 J genes. After transcription of the C, J, and V segments, recombinases link the mRNA together and the combined CJV mRNA is then translated into a complete light chain. Heavy chains are produced in a similar fashion except there is a D segment in the variable region between the V and J segments and there are five potential constant regions, y, a, 6, and £ (Fig. 2.3).

When the complete immunoglobulin molecule is digested by papain, one FC fragment and two FAb fragments are produced. The FAb fragment composed of a light chain and the variable region of a heavy chain is the portion of the antibody that determines its specificity and binds to the antigen. Since each immunoglobulin monomer has two FAb fragments, its antigen binding valency is two. The FC fragment consists of the constant region of the two heavy chains, and by binding to specific cell surface antibody receptors it determines the biological role of the antibody. Immunoglobulins are classified into IgG, IgM, IgA, IgD, and IgE isotypes based on the type of heavy chain each contains (y, a, 6, and £ respectively). These isotypes and receptors specific to each one determine the antibody's distribution within the body. Isotypes also differ with regards to half-life and ability to fix complement.

IgG is the most abundant antibody found in the serum and diffuses more readily into other body compartment than other isotypes. IgG is secreted as a monomer by terminally differentiated B cells called plasma cells. IgG can bind to and neutralize antigens as well as act as an opsonin. Macrophages possess high affinity IgG receptors, FcyRI, capable of binding free monomeric IgG. This receptor appears to be involved in macrophage mediated antibody dependent cell-mediated cytotoxicity (ADCC). The low affinity receptors, FcyRII and FcyRIII, are found on a wide variety of cells. These receptors bind to aggregated antibody (i.e., immune complexes). Although the strength of each individual receptor/antibody interaction is low, multiple antibodies binding provides high binding avidity. The concept of multiple antibodies binding at once is important because receptor occupancy alone does not initiate most cell functions. For some cell actions to occur, whether degranulation, phagocytosis, or extracellular killing, multiple receptors must be occupied allowing them to aggregate and interact. This process of interaction between aggregated receptors is referred to as crosslinking. FcyRII receptors are involved in phagocytosis by macrophages and neutrophils as well as degranulation of eosinophils while FcyRIII mediates NK cell ADCC and immune complex clearance by macrophages. In addition to the above abilities, IgG can fix complement but C1 requires binding of two IgG molecules for activation.

IgA is found primarily in secretory fluids where it defends surfaces such as the GU, GI, and respiratory tracts from infection. Plasma cells below the basement membranes of these epithelia secrete dimers of IgA. The IgA molecules are bound to one another within the plasma cell by a protein called the J-chain. The dimeric structure gives it an antigen binding valency of four. After secretion by a plasma cell, the IgA dimer binds to a poly-Ig receptor on the basal surface of the epithelial cell. This complex is then internalized and transported to the apical surface. At the apical surface of the epithelial cell, a portion of the poly-Ig receptor is cleaved from the complex and the IgA dimer with the remaining part of the poly-Ig receptor known as the secretory piece is released onto the mucosal surface. Once secreted, the secretory piece appears to protect the dimer from degradation. Dimeric IgA acts by binding to and neutralizing an antigen before it can invade the body. A small amount of monomeric IgA is produced and secreted into the tissue beneath the mucosa apparently functioning to neutralize those antigens that manage to evade the secreted

IgA.

IgM is also known as macroglobulin because its circulating pentameric form has a very high molecular weight compared to other immunoglobulins. The pentamer, which is held intact by a J-chain similar to that found in IgA, gives it an antigen binding valency of ten and also allows one complete IgM molecule to fix complement. Each FAb fragment has low binding affinity; however because of its valency intact IgM has a high binding avidity. IgM is typically the first antibody type produced in the humoral response. Although its theoretical valence is ten, in reality it rarely binds more than five antigens due to steric hindrance. However, IgM is still very effective at agglutinating antigens and its ability to activate complement helps to destroy antigens. In addition to its pentameric form, monomeric IgM is also produced. These IgM monomers are produced with a hydrophobic region attached to the constant region that allows it to insert into the surface of mature naive B cells as a receptor. IgD is also expressed on mature naive B cells as a receptor, and it is almost exclusively found here. Little is known regarding the function of IgD.

IgE concentrations in the serum are very low. Mast cells express FceRI, a very high affinity receptor for IgE. Monomeric IgE binds to these receptors on circulating mast cells. When enough antigen binds to the IgE on the mast cell surface it aggregates the FceRI receptors close to one another allowing crosslinking. After crosslinking occurs, the mast cell degranulates. This is the basis for the type I hyper-sensitivity reaction.

T Cell Receptors (TcR)

Just as B cells express IgM and IgD antibodies on their surface to serve as receptors, T cells also express receptors on their surface each with specificity for a different antigen. However, unlike antibodies that recognize epitopes on intact antigens, T cell receptors can only recognize processed antigen bound to an MHC. The T cell receptor is composed of an a and a p subunit. The a subunit is analogous to the constant region of the immunoglobulin while the p subunit determines binding specificity of the receptor. The formation of the a and p chains, again similar to antibody production, involves a series of recombinations which allows a limited number of genes to produce a very large number of receptors each with a different antigen binding specificity. The TcR is associated on the T cell surface with a protein designated CD3.

Once the processed Ag-MHC complex binds to the cleft formed by av and pv CD3 transduces the signal of binding to the cell interior initiating a series of reactions that elicit a specific effect dependent on the type of T cell.

The major histocompatability complex, known as human leukocyte antigen in humans, was first described in the context of transplant rejection. There are two types of MHC. MHC type I, corresponds to HLA-A, B, and C, and is found on all nucleated cells. The MHC-I is composed of a heavy peptide with three globular domains designated a1, a2, and a3. A smaller peptide called p2 microglobulin is noncovalently linked to the larger peptide completing the MHC-I complex. A binding cleft for the processed antigen is formed between the a1, and a2 domains. The peptides that bind to this cleft are processed in the cytosol.

MHC-II corresponds to HLA-DR, DQ, and DP in humans and is found primarily on antigen presenting cells (B cells, dendritic cells, and macrophages). MHC-II is composed of two peptides, an a and p chain. Each chain has two globular domains. The a1 and p1 domains form the binding cleft for MHC-II. Peptides that bind to this cleft are processed within intracellular vesicles.

As previously mentioned processed peptide must be bound to a MHC for the TcR to recognize the antigen. There is further restriction to TcR recognition of Ag. For T cells to interact with an antigen presented by MHC-I they must have a protein called CD8 associated with the TcR. CD8 interacts with MHC-I to stabilize the TcR and processed peptide allowing antigen recognition to occur. CD8 is associated with the TcR on cytotoxic T cells. Inflammatory and helper T cells have CD4 associated with their TcR rather than CD8. CD4 interacts with MHC-II stabilizing the TcR and peptide that again allows antigen recognition to occur.

Acquired Immune Responses

It would be highly inefficient for the body to produce thousands of immune cells specific to every antigen an individual might encounter in its lifetime. In addition to the energy expenditure maintaining this large number of immune cells would incur, it would also occupy a large amount of space. The immune system overcomes these limitations by clonal selection and expansion. According to the theory of clonal selection, once an immune cell encounters the antigen it is specific to it undergoes a series of divisions producing roughly a thousand immune cells within about three days. Each of these cells is capable of producing the appropriate response to that particular Ag whether a humoral or cell-mediated response is needed. The secondary lymphoid organs are positioned so that they efficiently filter the extracellular fluid, blood, and material that crosses mucosal surfaces for foreign antigens. Once an antigenic compound is sequestered within one of these peripheral lymphoid organs, the secondary lymphoid organs are arranged to efficiently present the antigen to initiate the appropriate immune response. In addition to the anatomic location and histologic organization of the secondary lymphoid organs, lymphocytes circulate continuously through the peripheral lymphoid tissues. They migrate from one lymph node to another then return to the venous system on their way to the spleen. If the cell does not encounter its specific antigen it will leave the vascular compartment to repeat the journey. In these ways the odds that the lymphocyte will encounter an antigen it is capable of responding to are increased. A subset of cells derived from clonal expansion do not become effector cells. Instead these cells become memory cells and migrate to the bone marrow until the antigen is encountered again. Upon reexposure to the antigen these memory cells allow for more rapid immune responses.

0 0

Post a comment