Meaning of Antigens:
Antigens, or Ag for short, are substances that can trigger an immune response within an organism. They can be of two types: self or non-self. The distinguishing characteristic of antigens is their ability to bind distinctively with antibodies or cell surface receptors. This property, known as antigenicity, is crucial in the immune system’s recognition process.
Antigens, which are able to induce adaptive immunity, are called immunogens. All immunogens are antigens unless their ability to stimulate an immune response is significant.
Nature of Antigens:
Antigens come in various forms, making the antigenic world incredibly diverse. They can be chemical substances like proteins or polysaccharides, biological entities like bacteria, fungi, parasites, and viruses, or even larger parasites. Essentially, anything foreign that enters the body can act as an antigen.
our immune system can recognize the macro-molecules of infectious agents, including proteins and polysaccharides. Among these, proteins are potent immunogens, while polysaccharides come second. In some cases, lipids and nucleic acids may also be considered antigens when they are associated with proteins or polysaccharides.
Additionally, various biological products such as milk, egg albumin, bee venom, snake venom, and pollen grains can serve as rich sources of antigens. Even different parts of bacterial cells, like flagella, pili, lipopolysaccharides, and capsular polysaccharides, can exhibit antigenic properties and provoke immune responses.
In rare instances, self-proteins may be misidentified as non-self by the body, leading to autoimmune diseases.
Classification of Antigens:
Antigens can be classified under two major categories, called:
(1) Exogenous and
(2) Endogenous antigens.
1. Exogenous antigens:
Exogenous antigens enter the host body from external environments, often in the form of pollutants, microorganisms, pollens, or drugs. These external agents can lead to communicable diseases, such as influenza or malaria.
2. Endogenous antigens:
Endogenous antigens reside within the individual’s body. They can be further categorized into:
Endogenous antigens are again classified under three sub-categories named as:
i. Xeno-genic or Heterogenic antigens
ii. Allogenic or Idiotypic antigens
iii. Autologous antigens.
i. Xeno-genic antigens:
These antigens are associated with tissue transplantation and serology. They are often referred to as heterogenic antigens due to their involvement with phylogenetically unrelated species.
When a piece of tissue or graft is transplanted to an individual, it may be treated as foreign, then those molecules are considered as xeno-antigens. Similar foreign recognition may be resulted in serology. Cross-reactions are very common in between antisera to certain erythrocytic surface antigens or some bacterial antigens.
Antisera is formed against surface antigens. Produced antisera cross-react with cells or body fluids of animals belonging to different species due to presence of mucopolysaccharide and lipid based chemical determinants.
ii. Allogenic antigens:
Allogenic antigens are genetically determined and polymorphic. They differentiate individuals within the same species and come into play during situations like blood transfusions or organ transplants.
These phenomena lead to incompatibility, agglutination and graft rejection. In case of human beings these types of antigenic determinants are located on erythrocytes, leukocytes, platelets, cell surface markers, serum proteins and histocompatibility antigens.
iii. Autologous antigens:
This category of antigens is rare and unnatural. In normal conditions, self-components are non-immunogenic. However, in certain abnormal situations, self-components can be considered as non-self or antigenic, leading to immune responses.
Antigens can also be classified into two broad categories:
1. Comparison of T-independent and
2. T-dependent antigens.
Essential Features of Antigens:
Antigens possess two fundamental features that define their role in the immune system:
- 1. Recognition as Foreign: Antigens must be recognized as foreign entities by the host’s immune system. The degree of immunogenicity is influenced by the foreignness of the antigen.
- 2. Antigen Processing and Presentation: Antigens must undergo specific physical and chemical changes after processing to stimulate the immune system effectively.
Factors that influence Immunogenicity (Antigenicity):
Immunogens are central to the immune system’s response to foreign invaders. The immune system actively seeks to recognize and eliminate antigenic effects. Several factors come into play in determining an antigen’s immunogenicity:
Somehow, the body must recognize a foreign substance in order to evoke an immune response:
There are some essential factors which influence the power of antigen:
Those are:
i. Molecular size,
ii. Structural stability,
iii. Degradability,
iv. Foreignness,
v. Chemical composition and heterogeneity,
vi. Antigen processing and presentation,
vii. Conformation and
viii. Accessibility.
i. Molecular size:
Larger molecules tend to be better antigens than smaller ones. Molecular size directly correlates with immunogenicity.
As for example, hemocyanin is an invertebrate blood protein with (6.7 x 103)kDa molecular size, is a potent antigen in nature. Serum albumin from other mammals (69 kDa) is a fairly good antigen but may also provoke tolerance, whereas the hormone angiotensin (1031 Da) is a poor antigen.
Sometimes, very small molecules may bind to large proteins and resulting in formation of active antigen which can evoke an immune system. The best immunogens tend to have a molecular mass approaching 100000Da.
ii. Structural stability:
The specific shape of a molecule or part of a molecule is essential for recognition by immune cells. Molecules lacking a stable structure are often considered poor antigens.
As for example gelatin is recognized as a poor protein due to its structural instability. This is being stabilized by cross-linking of the peptide chain with tyrosine or tryptophan.
The major protein of bacterial flagellum called flagellin is a weak antigen due to its unstable structure; it is being enhanced by polymerization. Proteins are much more stable antigens than starch (polysaccharide), lipids, carbohydrates and nucleic-acids.
iii. Degradability:
Easy degradation of an antigenic molecule is crucial for its antigenicity. Antigens that cannot undergo breakdown are not recognized as antigens.
For e.g., stainless steel pins and plastic joints are commonly implanted in the body without triggering an immune response. Different metals or organic polymers, plastic cannot be fragmented and processed to form suitable for triggering an immune response.
Conversely, since immune responses are antigen driven, foreign molecules are very rapidly destroyed on entering the body may not provide sufficient stable antigen fragments to stimulate an immune response.
iv. Foreignness:
Antigens must be non-self to the host. The greater the phylogenetic distance between species, the greater the antigenic disparity.
The degree of immunogenicity depends upon the degree of foreignness of the immunogen. When an antigen is introduced into an organism, greater the phylogenetic distance between two species, the greater the genetic (i.e. antigenic) disparity between them. But all foreign substances do not elicit immune response.
As for e.g. carbon granules evoke phagocytosis but not antibody production. But the bovine serum albumin (BSA) is an excellent immunogen when it is injected into a rabbit or other mammals but not at all an immunogen when it is introduced within the blood of cow itself.
A kidney graft from an identical twin will be readily accepted but a graft from an unrelated human will be rejected in about two weeks and a graft from a chimpanzee to a human will be rejected within a few hours due to disparity of protein structure and firmness with respect to evolutionary stand point view.
v. Chemical composition and heterogenity:
The chemical composition and structural complexity of a molecule affect its immunogenicity. Complex proteins tend to be more immunogenic than simple molecules. As for e.g. artificial or synthetic homopolymers tend to lack immunogenicity regardless of their size. Copolymers of sufficient size, containing two or more different amino acids are immunogenic.
The addition of aromatic amino acids, such as tyrosine or phenylalanine has immense effect on the immunogenicity of these synthetic polymer. As for e.g. a synthetic copolymer of glutamic acid and lysine requires a minimum molecular wt. of 30,000-40,000 for immunogenicity.
Besides chemical compositions, structural complexicity and heterogeneity of protein affect immunogenicity. Starting from nascent to final stage, proteins undergo four levels of organization called primary, secondary, tertiary and quarter- nary protein, which gradually add their structural complexity and impose effect on their immunogenicity (Fig. 4.3).
vi. Antigen processing and presentation:
Some antigens require processing and presentation to be recognized by immune cells effectively. There are intracellular (endogenous) and extracellular (exogenous) antigens which present different challenges to the immune system.
A foreign protein (antigen) to be recognized by a T-cell must be degraded into small antigenic peptides that form physical complex with Class I or Class II Major Histocompatibility Complex (MHC) molecules. This conversion of proteins into MHC associated peptide fragments is called antigen processing and presentation. This processing of antigens is mediated by different antigen cells of the body (Table 4.3).
Whether a particular antigen will be processed and presented together with Class I or Class II MHC, MHC is to be determined by which the antigen enters within a cell (Fig. 4.4).
Exogenous pathway (Cytosolic pathway):
Exogenous antigens are ingested by endocytosis or phagocytosis and then enter into the endocytic processing pathway. Antigen presenting cells (macrophages, dendritic cells, B-cells) degrade most of the ingested exogenous antigens into peptide fragments within the exogenous processing pathway.
Here, due to an acidic environment antigens are degraded into small peptides which then bind to the leaf within the Class II MHC molecules and MHC II bearing the peptide are then transported to the cell surface. The fragments of ingested antigens are presented with Class II MHC molecules on the membrane of antigen presenting cells.
T-cells displaying CD4+, recognize antigens associated with Class II MHC molecules and are thus said to be Class II MHC restricted. These cells are generally act as a TH (T-Helper) cells (Fig. 4.5).
Endogenous pathway (Endocytic pathway):
Endogenous antigens are produced within the host cell itself (e.g., in a virus infected cell), is degraded within the cytoplasm into peptides which then move into the endoplasmic reticulum where they bind with Class I MHC molecules.
The peptide Class I MHC complexes then move to the surface of the cell via Golgi complex. T-cell displaying CD8+ recognize antigen associated with Class I MHC molecules and are thus said to be Class I MHC restricted. These cells are generally act as Tc (T-Cytotoxic) cells (Fig. 4.5 and 4.6).
vii. Conformation:
Molecular conformation plays a significant role in determining immunogenicity. Changes in conformation can render an antigen ineffective. Most of the substances having their particular conformation in which that can be specifically identified by specific antibody.
An effective antigen may turn into an ineffective one due to their changed or altered form as because recognition by an antibody is a very specific feature. An antigenic determinant is denoted by a particular stretch of amino acids derived from different parts of a folded polypeptide sequence.
viii. Accessibility:
An immune response is highly dependent upon the accessibility of determinant group to the recognition arm of the immune system.