Molecules Mediating Cell-Cell Recognition

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Nicholas Bradley
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1 Molecules Mediating Cell-Cell Recognition The immune system produces a powerful response to foreign molecules, but does not attack its own molecules. To avoid attacking self, the body has established several mechanisms. The immune response can differentiate between pathogenic organisms (bacteria, viruses, parasites and fungus) and human cells. Pathogen-associated Molecular Patterns (PAMPs) and Pattern Recognition Receptors (PRR) Pathogens express pathogen-associated molecular patterns (PAMPs) that are common to groups of pathogens, but are generally not found on human cells. Examples of PAMPs include parts of bacterial cell walls, such as certain lipopolysaccharide (Gram-negative bacteria), techoic acid (Gram-positive bacteria) and peptidoglycans (bacteria); flagellin in bacterial flagella; and various viral RNA molecules. In the past years DAMPs (Damage-associated molecular patterns) have been added to the list of molecules that can initiate the innate response. DAMPs include nuclear and cytosolic components than can provoke a non-infectious inflammatory response, for example after tissue injury or in gout. Pattern recognition receptors (PRR) found on the surface of macrophages, neutrophils and dendritic cells bind the PAMPs as part of the innate immune response. Molecules with pattern recognition ability may also be soluble, like lysozymes and the complement components. Antigens and Antigen Receptors Antigens are substances that bind to receptors on immune cells. Entire microbes or parts of microbes may act as antigens. The term antigen is derived from its function as an antibody generator. Chemical components of bacterial structures such as flagella, cell walls and bacterial toxins, viral capsules, pollen, and incompatible blood cells and tissue transplants can all act as antigens. Typically,

2 just small parts of a large antigen molecule act as the triggers for immune responses. These small parts are call epitopes orantigenic determinants. Antigens are most often large, complex molecules such as proteins, however, nucleic acids, lipoprotein, glycoprotein and some polysaccharides may also act as antigens. Simple, repeating subunits, like cellulose and most plastics are not usually antigenic. Antigenicity is the ability to combine specifically with the secreted antibodies and/or surface receptors on T-cells. T and B lymphocytes, also called T and B cells, are the mediators of the adaptive immune response. They are lymphocytes with receptors that bind to antigens. Individual T and B cells recognize only one antigenic determinant. This is like a lock and key system where only one key can open the lock. The antigenic determinant is the key. The lock is the receptor on the T or B cell. This T cell receptor (TCR) or B cell receptor (BCR) only fits that one key and opens it (activates it) to initiate an immune. Because T and B cells only recognize one antigen, each T and B cell is said to be antigen-specific. One feature of the human immune system is its ability to recognize and bind to a least a billion different antigens. Before an antigen enters the body, a small number of T and B cells that can recognize and respond to that intruder are ready and waiting. The diversity of antigen receptors in both T and B cells results from shuffling and rearranging gene segments. This process is called genetic recombination. As the lymphocytes are developing in the bone marrow or thymus, gene segments are put together in different combinations. The situation is similar to having a deck of 52 cards and dealing out three cards. If you did this over and over you could generate many more than 52 sets of three cards. Because of genetic recombination, each T and B cell has now created a unique gene that codes for its unique antigen receptor. Because this random rearrangement of gene segments could produce a TCR or BCR against self antigens, B and T cells must be selected for self-recognition and tolerance. While developing in the bone marrow, B cells that have an antigen receptor that recognizes self-antigens are deleted. T cells that have an antigen receptor that recognizes self-antigens are deleted in the thymus. However, to function properly T cells do not just

3 recognize antigen alone. They must have the ability to recognize antigen in association with their own MHC complex. Major Histocompatibility Complex (MHC) Located in the plasma membrane of all nucleated body cells are thousands of transmembrane glycoproteins called major histocompatibility complex (MHC) antigens. Because they were first identified on leukocytes they are also called human leukocyte antigens (HLA). Unless you have an identical twin your MHC antigens are unique. MHC molecules mediate interactions of leukocytes with other leukocytes or body cells. Their normal function is to mark your cells as self cells, as T cells will recognize those MHC molecules that do not match your own as foreign. Such recognition can be one of the first steps in any adaptive immune response. Protein molecules are continually made and broken down in a cell. Each MHC molecule combines with a small part of a protein present in the cell (epitope), similar to a hot dog (epitope) in a bun (MHC). The MHC then displays this complex on its membrane surface. The epitope that is presented can either be self or nonself. MHC molecules will become transmembrane molecules only after they associate with an epitope. The membrane bound MHC fall into two subgroups. Class I MHC (MHC-I) are inserted into the plasma membrane of all nucleated cells of the body. Class II MHC (MHC-II) are only present on antigen-presenting cells (APCs) such as macrophages and B cells. Class I MHC molecules combine with endogenous (intracellular) self peptide fragments in the rough endoplasmic reticulum and should not react with cytotoxic T cells. If a nonself peptide is present inside the cytosol of the cell, such as during viral infection or cancerous transformation, the foreign epitope will associate with Class I MHC. In this situation cytotoxic T cells may now recognize that this cell is a threat and needs to be destroyed. Class II MHC molecules combine with exogenous (extracellular) peptide fragments that have been phagocytosed or endocytosed in vesicles. Lysosomes fuse with these vesicles and cleave the uptaken protein into smaller peptides. These epitopes now are loaded in the class II MHC molecules. Helper T cells with the appropriate receptors bind with class II MHC/epitope molecules. During development, T

4 cells that recognize self-protein epitopes associated with MHC are eliminated during a process called clonal deletion. Therefore, only MHC molecules complexed with a foreign peptide will bind to T cell receptors (TCRs). Antibodies Unlike T cells, B cells do not recognize antigen associated with MHC. Their B cell receptor (BCR) binds to antigen that is circulating freely in the body fluids. Involvement of a B cell in an adaptive immune response is called an antibody-mediated immune response. This is because when activated, B cells produceantibodies. Antibodies are Y shaped molecules consisting of four polypeptide chains; two identical heavy chains and two identical light chains. The end of each arm of the antibody is the variable region and is the part the binds with the antigen with a lock and key specificity. The variable region is unique to only those antibodies produced from one activated B cell. Thousands of variable regions exist. The rest of the antibody is theconstant region. Different from the variable region of the antibody, only five different constant regions exist: IgG, IgM, IgE, IgD, and IgA. The constant regions are referred to by the Greek letters gamma, mu, epsilon, delta and alpha. When the region is on an immunoglobulin molecule it is referred to as Ig. Therefore, immunoglobulin is another term for antibody. These constant regions, also called isotypes, are identical between antibodies. Therefore every different antibody with an IgM constant region will have the same exact IgM constant region, even though the antibodies have different antigen specificity on its variable region. There is no variability in the constant region. Antibodies may exist as single molecules (IgG, IgE and IgD) or may link with another like antibody to form a dimer (IgA) or five like antibodies may join as a pentamer (IgM). Single IgG function well to neutralize, immobilize, clump together, or mark pathogens; dimer IgA are secreted in body fluids; and pentamer IgM activates complement. Each immunoglobulin type is found with different types of infection or location.

5 The actions of the classes of immunoglobulins differ somewhat, but all of them act to disable antigens in some way. Actions of antibodies include the following: 1. Neutralizing antigen of some bacterial toxins and prevents attachment of some viruses to body cells. 2. Immobilizing cilia or flagella of motile bacteria thereby limiting their spread into nearby tissues. 3. Agglutinating or clumping together pathogens by antigenantibody cross-linking. 4. Activating the classical pathway of the complement system 5. Enhancing the activity of phagocytes by marking the pathogen as foreign (opsonization). 6. Binds to immune cells and stimulates chemical secretion Classes of Immunoglobulins (Igs) and Their Immune Function

specific B cells Humoral immunity lymphocytes antibodies B cells bone marrow Cell-mediated immunity: T cells antibodies proteins

specific B cells Humoral immunity lymphocytes antibodies B cells bone marrow Cell-mediated immunity: T cells antibodies proteins Adaptive Immunity Chapter 17: Adaptive (specific) Immunity Bio 139 Dr. Amy Rogers Host defenses that are specific to a particular infectious agent Can be innate or genetic for humans as a group: most microbes