Antigens

Antigens and Antigen Receptors

Antigens are molecules that initiate the immune response and can be bound by antibodies.

Learning Objectives

Distinguish between antigens and antigen receptors

Key Takeaways

Key Points

  • An antigen is a molecule that initiates the production of an antibody and causes an immune response.
  • Antigens are typically proteins, peptides, or polysaccharides. Lipids and nucleic acids can combine with those molecules to form more complex antigens, like lipopolysaccharide, a potent bacterial toxin.
  • An epitope is a molecular surface feature of an antigen that can be bound by an antibody. A paratope is the molecular surface feature of an antibody that binds to an epitope.
  • Antigens are classified as exogenous (entering from outside) endogenous (generated within cells ), an autoantigen, a tumor antigen, or a native antigen.
  • Antigenic specificity is the ability of host cells to recognize an antigen by its unique molecular structure, such as the relationship between antigen epitopes and antibody paratopes.

Key Terms

  • antigen: A substance that induces an immune response, usually foreign, but self antigens and internally produced antigens exist as well.
  • autoantigen: Any antigen that stimulates auto antibodies in the organism that produced it. These are “self” antigens that are involved in autoimmune disease pathogenesis.

Examples

Fluorescein, along with other haptens such as biotin, is used in various cell and molecular biological techniques. Fluorescein is often conjugated to a protein to allow scientists to examine its location using a fluorescent microscope.

In immunology, an antigen is a substance that evokes an immune response. Formally they are defined as a substance that causes the production of antibodies specific to that antigen, however they also cause T cell mediated immune responses, and may lead to an inflammatory response. The substance may be from the external environment or formed within the body. The immune system will try to destroy or neutralize any antigen that is recognized as a foreign and potentially harmful invader.”Self” antigens are usually tolerated by the immune system; whereas “non-self” antigens can be identified as invaders and can be attacked by the immune system.

Molecular Structure of Antigens

At the molecular level, an antigen is characterized by its ability to be “bound” at the antigen-binding site of an antibody. Antibodies tend to discriminate between the specific molecular structures presented on the surface of the antigen. Antigens are usually either proteins, peptides, or polysaccharides. This includes parts (coats, capsules, cell walls, flagella, fimbrae, and toxins) of bacteria, viruses, and other microorganisms. Lipids and nucleic acids are antigenic only when combined with proteins and polysaccharides. For example, the combination of lipids and polysaccharides are lipopolysaccharides (LPS), which are the primary component of gram negative bacterial endotoxin. LPS forms the cell wall of gram negative bacteria and causes a powerful immune response when bound. Cells present their immunogenic-antigens to the immune system via a major histocompatibility (MHC) molecule. Depending on the antigen presented and the type of the histocompatibility molecule, several types of immune cells can become activated due to an antigen.

Antigens have several structural components of interaction that may be bound by different classes of antibodies. Each of these distinct structural components is considered to be an epitope, also called an antigenic determinent. Therefore, most antigens have the potential to be bound by several distinct antibodies, each of which is specific to a particular epitope. The antigen binding receptor on an antibody is called a paratope, and is specific to the epitope of the antigen. Using the “lock and key” metaphor, the antigen itself can be seen as a string of keys – any epitope being a “key” – each of which can match a different lock.

Types of Antigens

Antigens are categorized into broad classes of antigens based on their origin. So many different molecules can function as an antigen in the body, and there is considerable diversity even within these categories.

These are the main classes of antigens that are involved in immune system activation. Their diversity is analogous to the immense diversity of the diseases that the immune system works to overcome.

Exogenous Antigens

Exogenous antigens are antigens that have entered the body from the outside, for example by inhalation, ingestion, or injection. Exogenous antigens are the most common kinds of antigens, and includes pollen or foods that may cause allergies, as well as the molecular components of bacteria and other pathogens that could cause an infection.

Endogenous Antigens

Endogenous antigens are that have been generated within previously-normal cells as a result of normal cell metabolism or because of viral or intracellular bacterial infection (which both change cells from the inside in order to reproduce). The fragments are then presented on the surface of the infected cells in the complex with MHC class I molecules.

 Autoantigens

Autoantigens are normal “self” protein or complex of proteins or nucleic acid that is attacked by the host’s immune system, causing an autoimmune disease. These antigens should, under normal conditions, not be the target of the immune system, but due to mainly genetic and environmental factors, the normal immunological tolerance for such an antigen has been lost.

Tumor Antigens (Neoantigens)

These antigens are presented by MHC I or MHC II molecules on the surface of tumor cells.These antigens result from a tumor-specific mutation during malignant transformation of normal cells into cancer cells. Despite expressing this antigen, many tumors have developed ways to evade antigen recognition and immune system killing.

Native Antigens

A native antigen is an antigen that is not yet processed by an APC to smaller parts. T cells cannot bind native antigens, but require that they be digested and processed by APCs, whereas B cells can be activated by native ones without prior processing.

Complete Antigens and Haptens

Haptens are molecules that create an immune response when attached to proteins.

Learning Objectives

Describe haptens and complete antigens

Key Takeaways

Key Points

  • Haptens are incomplete antigens that do not cause an immune response upon binding because they cannot bind to MHC complexes.
  • Haptens may bind with a carrier protein to form an adduct, which is also a complete antigen.
  • While haptens don’t directly cause immune responses, they may sensitize the body towards hypersensitivity and autoimmune responses.
  • Haptens may inhibit antibody immune responses by binding with antibodies in place of the actual antigen until there aren’t enough antibodies left to bind to the complete antigen.

Key Terms

  • adduct: A complex molecule formed by the combination of two or more molecules, such as a complete antigen created by a hapten and a carrier.
  • hapten: Any small molecule that can elicit an immune response only when attached to a large carrier such as a protein.

Antigens are basic molecules that induce an immune response when detected by immune system cells. Antigens may be either complete or incomplete based on the nuances of their molecule structure.

Haptens

A hapten is essentially an incomplete antigen. These small molecules can elicit an immune response only when attached to a large carrier such as a protein; the carrier typically does not illicit an immune response by itself. Many hapten carriers are normal molecules that circulate through the body. When haptens and carriers combine, the resulting molecule is called an adduct, the combination of two or more molecules. Haptens cannot independently bind to MHC complexes, so they cannot be presented to T cells.

The first haptens used were aniline and its carboxyl derivatives (o-, m-, and p-aminobenzoic acid). One well-known hapten is urushiol, the toxin found in poison ivy and a common cause of cell-mediated contact dermatitis. When absorbed through the skin from a poison ivy plant, urushiol undergoes oxidation in the skin cells to generate the actual hapten, a reactive molecule called a quinone, which then reacts with skin proteins to form hapten adducts. Usually, the first exposure causes only sensitization, in which there is a proliferation of helper and cytotoxic T cells. After a second exposure, the proliferated T cells can become activated, generating an immune reaction and producing the characteristic blisters of poison ivy exposure.

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Fluorescein Molecule: Fluorescein is an example of a hapten used in molecular biology.

Some haptens induce autoimmune disease. An example is hydralazine, a blood pressure-lowering drug that occasionally causes lupus erythematosus (an autoimmune inflammatory disorder) in certain individuals with genetic predispositions to the disease. This also appears to be the mechanism by which the anesthetic gas halothane can cause life-threatening hepatitis and penicillin-class drugs cause autoimmune hemolytic anemia. Other haptens, such as flourescein, detect proteins with which they form adducts. This makes them a common part of molecular biology lab techniques.

Complete Antigens

A complete antigen is essentially a hapten-carrier adduct. Once the body has generated antibodies to a hapten-carrier adduct, the small-molecule hapten may also be able to bind to the antibody, but will usually not initiate an immune response. In most cases this can only be elicited by theonly the hapten-carrier adduct. Sometimes the small-molecule hapten can block immune response to the complete antigen by preventing the adduct from binding to the antibody, a process called hapten inhibition. In this case, the hapten acts as the epitope for the antigen, which binds to the antibodies without causing a response. If this happens with enough haptens, there will not be enough antibodies left to bind to the complete antigen, thus inhibiting the antibody response.

Antigenic Determinants and Processing Pathways

Antigen epitopes make it possible for the immune system to recognize pathogens.

Learning Objectives

Describe antigenic determinants and pathways of processing

Key Takeaways

Key Points

  • An epitope (also known as an antigenic determinant) is part of an antigen that is recognized by the immune system, specifically by antibodies and B and T cells. Other immune cells like APCs cannot recognize epitopes (only PAMPS and DAMPS).
  • Antigenic determinants (epitopes) are divided into conformational epitopes and linear epitopes.
  • Antigen processing occurs within a cell and results in fragmentation of proteins, association of the fragments with MHC molecules, and expression of the peptide -MHC molecules at the cell surface where they can be recognized by the T cell receptor on a T cell.
  • Antigen processing may be done through either the endogenous pathway (viral proteins from within an infected cell) or through the exogenous pathway (engulfing a pathogen and isolating its antigen from within the APC).
  • The endogenous pathway uses MHC class I and binds to cytotoxic T cells, while the exogenous pathway uses MHC class II and binds to helper T cells.
  • Some viruses can prevent antigen processing by disrupting movement of MHC within the cell.

Key Terms

  • Linear epitopes: These consist of the primary amino acid structure of a protein that makes up the larger antigen.
  • The Exogenous Pathway: Phagocytized pathogens are broken down from within the cell and their broken-down antigens bind with MHC II, which then is expressed on the surface of the antigen-presenting cell.

An epitope, also known as an antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, and T cells. The latter can use epitopes to distinguish between different antigens, and only binds to their specific antigen. In antibodies, the binding site for an epitope is called a paratope. Although epitopes are usually derived from non-self proteins, sequences derived from the host that can be recognized are also classified as epitopes. Epitopes determine how antigen binding and antigen presentation occur.

Types of Antigenic Determinants

The epitopes of protein antigens are divided into two categories based on their structures and interaction with the paratope.

  • A conformational epitope is composed of discontinuous sections of the antigen’s amino acid sequence. These epitopes interact with the paratope based on the 3-D surface features and tertiary structure (overall shape) of the antigen. Most epitopes are conformational.
  • Linear epitopes interact with the paratope based on their primary structure (shape of the protein’s components). A linear epitope is formed by a continuous sequence of amino acids from the antigen, which creates a “line” of sorts that builds the protein structure.

Antigenic determinants recognized by B cells and the antibodies secreted by B cells can be either conformational or linear epitopes. Antigenic determinants recognized by T cells are typically linear epitopes. T cells do not recognize polysaccharide or nucleic acid antigens. This is why polysaccharides are generally T-independent antigens and proteins are generally T-dependent antigens. The determinants need not be located on the exposed surface of the antigen in its original form, since recognition of the determinant by T cells requires that the antigen be first processed by antigen presenting cells. Free peptides flowing through the body are not recognized by T cells, but the peptides associate with molecules coded for by the major histocompatibility complex (MHC). This combination of MHC molecules and peptide is recognized by T cells.

Antigen-Processing Pathways

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Antigen-Binding Site of an Antibody: Antigen-binding sites can recognize different epitopes on an antigen.

In order for an antigen-presenting cell (APC) to present an antigen to a naive T cell, it must first be processed so itacan be recognized by the T cell receptor. This occurs within an APC that phagocytizes an antigen and then digests it through fragmentation (proteolysis) of the antigen protein, association of the fragments with MHC molecules, and expression of the peptide-MHC molecules at the cell surface. There, they are recognized by the T cell receptor on a T cell during antigen presentation. MHC molecules must move between the cell membrane and cytoplasm in order for antigen processing to occur properly. However, the pathway leading to the association of protein fragments with MHC molecules differs between class I and class II MHC, which are presented to cytotoxic or helper T cells respectively. There are two different pathways for antigen processing:

  • The endogenous pathway occurs when MHC class I molecules present antigens derived from intracellular (endogenous) proteins in the cytoplasm, such as the proteins produced within virus-infected cells. Generally, proteosomes are used to break up the viral proteins and combine them with MHC I.
  • The exogenous pathway occurs when MHC class II molecules present fragments derived from extracellular (exogenous) proteins that are located within the cell. First, pathogens are phagocytized, then endosomes within the cell break down antigens with proteases, which then combine with MHC II.

Some viral pathogens have developed ways to evade antigen processing. For example, cytomegalovirus and HIV-infected cells sometimes disrupt MHC movement through the cytoplasm, which may prevent them from binding to antigens or from moving back to the cell membrane after binding with an antigen.