Determinants of Antigenicity

Determinants of Antigenicity

A number of factors have been identified that make a substance immunogenic. Some of the important determinants of antige-nicity include:

1.        Molecular size

2.        Foreignness

3.        Chemical-structural complexity

4.        Stability

5.        Other factors

Molecular Size

In general, protein molecules with large molecular weight are highly antigenic. Substances with molecular weights of about 100,000 Da and more are highly immunogenic, while substances with molecular weights of less than 5000 Da are generally not immunogenic. This property has been exploited in experimen-tal studies by using high molecular weight proteins like bovine gamma globulin (MW 150,000 Da) to induce an immune reac-tion. Substances with low molecular weight may be made anti-genic by adsorbing these on carrier particles, such as bentonite, kaolin, and other inert particles.

Foreignness

To be immunogenic, a molecule must be recognized as nonself, i.e., foreign. The molecule is considered self or nonself by the immune system depending on whether or not the molecule was exposed to the immune system during fetal development.

Foreignness implies ability of the host to tolerate self-antigens. Tolerance to self-antigens develops by contact with them in the initial phases of the development of immune sys-tem, particularly during the development of lymphocytes.

In general, the more distantly related two species are, the greater the immunogenicity of a molecule from one species will be when exposed to the other. For example, the bovine serum albumin is more immunogenic in a chicken than in a goat. A graft from an unrelated human will be rejected within about 2 weeks unless immunosuppressive drugs are used, but a graft from a chimpanzee will be rejected within hours even if drugs are used. In contrast, a kidney graft from an identical twin will be accepted readily.

Chemical-Structural Complexity

Proteins are the most potent immunogens followed by polysaccha-rides. Nucleic acids and lipids are not efficient in eliciting a good immune reaction, although they may act as haptens. Structural complexity of a protein contributes to its immunogenicity. Chains of single amino acids or single sugars are poorly immunogenic, but if different amino acids or sugars are combined in the same molecule, the immunogenicity is greatly enhanced.

In cell-mediated immunity, the response of T cells to the peptide component of the proteins depends on how the pep-tide is recognized and presented by the MHC cells. Therefore, the structure of protein plays an important role in its immuno-genicity, especially in inducing cellular immunity.

The lipid-specific antibodies are not easily produced; hence, they do not play a major role in immunity. However, these antibodies have a role in the measurement of certain lipid-based molecules and drugs. These antibodies are produced first by treat-ing lipids with haptens and then conjugating with suitable carrier molecules, such as the proteins (e.g., hemocyanin or bovine serum albumin).

Stability

Highly stable and nondegradable substances (e.g., some plastics, metals, or chains of D-amino acids) are not immunogenic.

This is because internalization, processing, and presentation by antigen-presenting cells (APCs) are always essential to mount an immune response. Therefore, very stable substances (such as silicon) have been successful as nonimmunogenic materials for reconstructive surgeries, such as breast implants.

On the other hand, if a substance is very unstable, it may break up before an APC can be internalized, and hence become immunogenic. In addition, large, insoluble complexes are more immunogenic than smaller, soluble ones. This is because macrophages find it easier to phagocytose, degrade, and pres-ent the insoluble complexes than the soluble complexes.

Other Factors

◗ Biological system

Biological system also plays an important role in determining the immunological efficiency of an antigen. Some substances are immunogenic in one individual but not in others (i.e., responders and nonresponders). This is due to the fact that individuals may lack or have altered genes that code for the receptors for antigen on B cells and T cells, or they may not have the appropriate genes needed for the APC to present anti-gen to the helper T (T_H) cells.

◗ Dosage and route of the antigen

The dose of antigen and the route by which it comes into contact with the immune system also influence immunoge-nicity of the antigen. Very low doses of antigen do not stimu-late immune response, either because too few lymphocytes are contacted or because a nonresponsive state is elic-ited. Conversely, an extremely high dose also fails to elicit tolerance.

Repeated administration of antigens (booster doses) may be required to enhance immune response of the host to certain antigens. This is particularly important in case of vac-cines where a prerequisite immune level needs to be attained. Hence the booster doses of vaccines, such as DPT (Diphtheria, Pertussis, Tetanus), DT (Diphtheria, Tetanus), etc., are given to ensure good protective levels of antibodies. Generally, antigens are administered by the parenteral route to produce good level of antibodies. The antigens can be given by (a) intravenous, (b) subcutaneous, (c) intradermal, (d) intramuscular, (e) intra-peritoneal, and (f) mucosal routes. Usually, the subcutaneous route of administration proves to be better than intravenous routes at eliciting an immune response.

◗ Adjuvants

Adjuvants are the substances that when mixed with an anti-gen and injected with it boost the immunogenicity of the anti-gen. Adjuvants increase both the strength and the duration of immune response. Adjuvants boost immunogenicity of anti-gens in several ways:

    Adjuvants like aluminum potassium sulfate (alum) and Freund’s water-in-oil adjuvant prolong the persistence of antigen by forming a depot at the injection site. Alum

      precipitates the antigen and releases it a little at a time. The water-in-oil emulsion forms small droplets with the antigen and also releases these slowly over time.

      Freund’s complete adjuvant contains, in addition to the emulsifying factors, heat-killed mycobacteria. The bacterial components activate macrophages and increase both the production of IL-1 and the level of B7 membrane molecules, which enhances the immune response. The increased expression of class II MHC increases the ability of APC to present antigen to T_H cells. B7 molecules on the APC bind to CD28, a cell-surface protein on T_H cells, triggering costimulation, an enhancement of the T-cell immune response.

        Some adjuvants, like synthetic polyribonucleotides and bacterial lipopolysaccharides, stimulate nonspecific lym-phocyte proliferation and bring about their action.