Antigens And Their Receptors

An important characteristic of the immune system is that the cells are able to distinguish between those molecules that are normally present in the body, i.e. self and those that are not, i.e. non-self. This is a vital distinction. The term "non-self" may mean a foreign invader such as a microorganism or a protein expressed on a cell in an abnormal way.

This chapter is designed to introduce you to the terms used to describe those substances which stimulate an immune response - immunogens. It will discuss those characteristics which make a molecule a good immunogen and will distinguish between an immunogen and an antigen - a molecule or group of molecules which bind specific receptors but may not alone induce an immune response. We will look at an important group of self-antigens, which are coded for by genes of the major histocompatibility complex. In addition, we will examine the structure and function of those molecules on cells that are capable of recognising antigens.

2.1 Characteristics of antigens and immunogens

An immunogen is any molecule (or group of molecules) that can induce an immune response, whilst an antigen is any substance that can react with antigen-specific receptors found on the surface of certain white blood cells. Thus, an antigen differs from an immunogen in that although an antigen can interact in a specific way with the immune system, it cannot by itself stimulate an immune response; other stimuli are required. Thus, all immunogens are antigens but not all antigens are immunogens. Although these terms are interchangeable, it is common to refer to molecules as antigens even if they are immunogens. We shall follow this practice.

Immunology for Life Scientists, Second Edition. Lesley-Jane Eales. 2003 John Wiley & Sons, Ltd: ISBN 0 470 84523 6 (HB); 0 470 84524 4 (PB)

When an antigen is recognised by the immune system, it interacts with specific receptors on the surface of a group of white blood cells called lymphocytes. That part of an antigen which binds to these receptors is known as the antigenic determinant or epitope.

An antigen may be protein, lipid, carbohydrate or any combination of these. It may be soluble or particulate, simple or complex with many different antigenic determinants (e.g. a bacterium may have antigenic determinants on the cell wall, the flagellum or on pili). Although an antigen may have many different antigenic determinants each of which comprises a small number of amino acids (4-6) or sugar residues, the resulting immune response may comprise antibodies which recognise only a few of these. If the same antigen is introduced in two different people, the epitopes recognised may be quite different suggesting that the range of epitopes recognised is under genetic control.

Since antigens can be of almost any chemical composition, the proteins and carbohydrates present in the membranes of our cells may be antigenic if the cells are introduced into another person or an animal. It was just this principle that was exploited in the production of monoclonal antibodies. Injecting human cells into mice (where they are recognised as foreign) meant that mice produced antibodies to the different molecules on the surfaces of the cells. By fusing a single antibody producing B cell with a replicating, transformed, cell the product was an immortalised clone of cells constantly producing antibody of a single specificity. That allowed us to identify individual molecules (antigens) on the surface of cells and to use them to identify and classify different cell types. Thus, a molecule on the surface of a cell (i.e. inserted through the membrane of the cell) may also be referred to as a surface antigen.

2.1.1 Factors affecting immunogenicity

Various physical and biochemical characteristics affect a substance's immunogenicity. It is important to understand how an antigen's immunogenicity may be modified since this may for example affect the ability of a candidate vaccine to stimulate a protective response.

Foreignness

The immune system is designed to eliminate anything that does not belong in the normal healthy body, i.e. it is capable of distinguishing between ''self'' and ''non-self''; it can recognise things that are foreign to it. The more foreign a molecule is, the more likely it is that the immune system will react to it and the more immunogenic it will be.

It is important to remember that although a molecule may not be immunogenic in the normal host, if it is introduced into a different host, it may become so. For example, rabbit serum albumin injected into a rabbit will not be immunogenic. The same molecule injected into a dog will stimulate an immune response.

Size

The size of a molecule appears to affect its immunogenicity. Generally, substances with molecular weights greater than 100 kDa are potent immunogens, whilst those of less than 10 kDa may not stimulate an immune response at all.

Although some small molecules may contain antigenic determinants and can bind antigen-specific receptors on cells, they are not large enough to stimulate an effective immune response. However, these molecules may be made immunogenic by attaching them to a larger molecule known as a carrier. Under these circumstances, the small antigenic molecule is known as a hapten.

Chemical complexity

The chemical complexity of a molecule may affect its ability to stimulate an immune response. Large polymers of amino acids might be expected to be good immunogens (because of their size) but only prove to be so when they consist of a mixture of amino acids.

The type of amino acids present in a peptide also affects its immunogenicity. Aromatic amino acids make a molecule more immunogenic than non-aromatic molecules because non-covalent, hydrophobic, forces govern the interaction between an antigen and its specific receptor on a cell.

Route of administration

The type of immune response elicited by an immunogen may be very different at one particular site in the body compared to another. Thus, the route by which an antigen gains access to the immune system may affect its immunogenicity. For example an organism that normally causes infection when introduced in the lungs (a respiratory pathogen) may be destroyed by the acid in the gut if swallowed.

Dose

The dose of an antigen may also affect its ability to be immunogenic. Given at too high or too low a dose, the immune system may fail to respond to an antigen, which at the correct dose is immunogenic. This failure to respond is known as immunological tolerance.

Host genetic make-up

Since the immunogenicity of a molecule is determined by the size of the subsequent immune response, and an individual's ability to mount an immune response is genetically controlled, then the genetic make-up of the host must play a role in determining the relative immunogenicity of a molecule. This is demonstrated by the fact that some antigens, which stimulate an immune response in man are non-immunogenic in other animals.

All the factors affecting the immunogenicity of a molecule are summarised in Table 2.1.

Approaches used to increase immunogenicity

One of the aims of an immune response is to eliminate whatever has stimulated it, e.g. a microorganism. Obviously, in the case of infection, elimination must be quick and effective to prevent extensive damage to the host (pathology). However, where an immunogen is introduced specifically to stimulate a long-lasting immunity (e.g. in the case of immunisation), the longer it is present, the stronger and more long-lasting the resulting immune response will be. This persistence can be achieved by mixing the immunogen with an adjuvant.

There are a number of adjuvants which are commonly used, and whilst their precise method of action is not known exactly, they all increase the strength and longevity of an immune response to a particular immunogen. It is thought that this effect may be achieved in one or more of the following ways: increasing the effective size of the immunogen; enhancing the persistence of the immunogen; activating cells such as macrophages and lymphocytes.

Table 2.1 Factors affecting the immunogenicity of a molecule

Size

Foreignness

Complexity

Amino acids

Route of administration

Dose of antigen

Genetic make-up ofhost

Large molecules are better than small (>100 kDa)

The more foreign a molecule the better the immunogen

Heterogeneous amino acid composition improves immunogenicity

Aromatic amino acids make a molecule more immunogenic

Immunogenicity may be affected by route of administration, e.g. respiratory tract pathogens may be destroyed in the gut

Too high or too low a dose fails to stimulate a response and may prevent response on subsequent exposure

The generation of an immune response is under genetic control

Key points for review

• Antigens bind to specific receptors on immune cells.

• Immunogens bind to specific receptors on immune cells and provide the signals required to stimulate an immune response.

• A number of factors can influence whether or not a molecule is a good antigen including size, foreignness, molecular make-up, route of administration, dose and host genetic make-up.

• The effectiveness of an immunogen to stimulate an immune response may be enhanced by the use of an adjuvant.

2.2 The major histocompatibility complex

As explained previously, the membrane of a cell is composed of a lipid bilayer, which has proteins, glycoproteins and other compound molecules inserted in it. Such molecules may act as antigens when introduced to a foreign host (cell surface antigens). Probably the best example of this is the blood group antigens A, B and O. An individual of blood group A will have erythrocytes which express this antigen (A + ). If this individual is given group B blood (which expresses the B antigen B + ), their immune system will recognise the B antigen as foreign and will destroy the transfused blood. This is why it is vital to cross-match blood.

All other cells of the body have a variety of surface antigens, the nature of which are determined by the genetic make-up of the host. These tissue antigens are quite distinct in each individual and when an organ is transplanted, the donor must be matched to the recipient. If the tissues are not matched, the recipient's immune system will recognise the donor tissue antigens as foreign and will destroy the transplant.

These human leukocyte antigens (HLA) are the molecules that are identified when an individual is 'tissue-typed'. They are the products of a group of genes known as the major histocompatibility complex (MHC).

The MHC comprises a large number of separate genes and in man they occupy about 1/3000th of the total genome (Figure 2.1). The genes are divided into three classes. Class I includes the A, B and C region genes, Class II includes the D region genes and Class III includes those genes which produce some of the enzymes and control elements involved in antigen processing and presentation and genes coding for members of a group of serum proteins known as complement (see Section 3.1).

Figure 2.1 The major histocompatibility complex

The MHC comprises a large number of separate genes which, in man, occupy about 1/3000th of the total genome. The genes are divided into three classes: Class I includes the A, B and C region genes; Class II includes the D region genes; Class III includes those which produce some of the enzymes and control elements which form part of a group of serum proteins known as complement.

2.2.1 Class I MHC molecules

Antigens coded for by MHC Class I genes are found on the surface of all nucleated cells and platelets. The antigenically distinct molecules are coded for by different regions within the Class I genome (on chromosome 6). These regions are known as A, B and C and the molecules coded for by these regions are classed as A1, A2, B1, B2, etc. More than 100 alleles have been identified in the HLA-A and B loci so far.

Class I molecules have one glycosylated polypeptide chain encoded for by the MHC (Figure 2.2). This chain has a relative molecular weight of 45kDa and is anchored through the cell membrane. It is non-covalently linked with another molecule - 2 microglobulin (12kDa) - which is not coded for by the MHC and is not membrane bound. The heavy or - chain has five distinct regions or domains, three of which are extracellular and hydrophilic (the a1, a2 and a3 globular domains), one of which is transmembraneous and hydrophobic, and one of which is cytoplasmic and hydrophilic.

The majority of the differences which distinguish the Class I antigens from each other (i.e. the antigenic determinants) result from amino acid differences in the a1 and a2 domains. The existence of a number of antigenically distinct versions of the same molecule is known as polymorphism.

b2 microglobulin is a polypeptide chain with a single domain, which is structurally similar to MHC domains. This molecule plays a vital role in transporting newly synthesised MHC proteins to the cell surface.

Class I molecules are involved in stimulating an immune response by presenting processed antigen to those cells of the immune system capable of recognising them. This ability to present antigen is related to the structure of the molecule. Each of the a1 and a2 domains consists of four b strands and an a helix. Together these b strands form a b-pleated sheet, which acts as a platform that supports the a helices. This creates a groove or cleft, which forms the antigen-binding site of the molecule (Figure 2.3). The b2 microglobulin is key to the stability of the structure formed by the a1 and a2 domains.

Most of the polymorphism of Class I molecules is found within the antigen-binding cleft. These differences affect the ability of a particular MHC Class I molecule to bind a specific processed antigen and restrict the range of antigens presented. HLA-A alleles differ from each other by 20 to 30 amino acids. This affects the shape of the antigen-binding cleft allowing the alleles to bind a distinct range of peptides.

The peptide binding groove of Class I molecules is restricted at both ends, a feature that presumably dictates the binding of peptides of restricted size (8-10 amino acids). Also, the ends of the bound peptide are fixed in the binding groove allowing the peptide to arch away from it in the centre. Peptides, which share a particular sequence of amino acids with similar spacing and charge, will bind to the same Class I molecule.

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