What Makes an Antigen Effective? Understanding Antigenicity

Antigens are essential for our immune system‘s ability to identify and combat dangerous intruders. Understanding antigenicity, which is the property that causes an antigen to be effective, can help us understand disease prevention and treatment. This post will look at the important characteristics that influence antigen efficacy, including as structure, size, and origin. By grasping these principles, readers will gain a better understanding of how vaccines and medicines are intended to protect human health. Join us as we explore what makes an antigen truly effective.

Antigens are molecules that are recognized by the T-cell receptor when they are complexed with major histocompatibility complex (MHC) or by the immunoglobulin receptor of B cells. The term “antibody generator” is abbreviated to form the word “antigen.” Immunogens are chemicals that trigger an immune response, whereas antigens are compounds that bind to antibodies. The phrases “immunogen” and “antigen” are frequently used interchangeably. Haptens are antigens that can trigger an immune response but are not immunogenic. The term immunogenicity indicates the ability of an antigen to trigger an immune reaction in the form of a B-cell or T-cell response, whereas the term antigenicity means only the ability to combine precisely with the products of the above responses. Although every antigenic molecule can also be called immunogenic, not every immunogenic molecule is antigenic. One could therefore argue that haptens are not immunogenic.

Determinants of Antigenicity

The immunogenicity of a substance is determined by multiple parameters, of which

• Molecular size
• Foreignness
• Stability
• Chemical-structural complexity and other characteristics.

Molecular Size

Large molecular weight protein molecules are generally very allergenic. Generally speaking, chemicals with molecular weights of less than 5000 Da are not immunogenic, whereas substances with molecular weights of roughly 100,000 Da and above are highly immunogenic. High molecular weight proteins, such as bovine gamma globulin (MW 150,000 Da), have been used in experiments to take advantage of this characteristic and trigger an immunological response. By adsorbing substances with low molecular weight on inert particles like bentonite or kaolin, these substances can become antigenic.

Foreignness

A molecule has to be perceived as foreign, or nonself, in order to elicit an immune response. Depending on whether or not the molecule was exposed to the immune system during fetal development, the immune system classifies the molecule as either self or nonself.

The ability of the host to tolerate selfantigens is implied by foreignness. When the immune system is still developing, especially when lymphocytes are developing, self-antigens are encountered and tolerance to them is developed.

A molecule from one species will generally be more immunogenic to that of the other when exposed to it, the more asymmetrical two species are. For instance, chickens are more immunogenic to bovine serum albumin than goats are. If immunosuppressive medications are not utilized, a graft from an unrelated person will be rejected in around two weeks; whereas, a chimpanzee graft will be rejected in a matter of hours, regardless of the use of medications. On the other hand, a kidney transplant from an identical twin will be well received.

Chemical-Structural Complexity

The most potent immunogens are proteins, then polysaccharides. While lipids and nucleic acids can function as haptens, they are not effective at triggering a favorable immune response. The immunogenicity of a protein is influenced by its structural complexity. Chains containing just one amino acid or one sugar have little immunogenicity; however, when multiple amino acids or sugars are joined to form a single molecule, the immunogenicity is significantly increased.

In cell-mediated immunity, the way the peptide is identified and presented by the MHC cells determines how T cells will react to the peptide component of the proteins. Therefore, a protein’s immunogenicity—particularly in terms of triggering cellular immunity—is significantly influenced by its structure.

Lipid-specific antibodies are not very significant for immunity because they are hard to make. However, these antibodies contribute to the measurement of several drugs and lipid-based substances. These antibodies are first produced by treating lipids with haptens, before they conjugate with suitable carrier molecules, such as proteins (like hemocyanin or bovine serum albumin).

Stability

Certain polymers, metals, and chains of D-amino acids are examples of highly stable, nondegradable materials that do not trigger an immune response. This is due to the fact that antigen-presenting cells’ (APCs) internalization, processing, and presentation are always necessary in order to elicit an immune response. For this reason, extremely stable materials (like silicon) have worked well as nonimmunogenic materials for reconstructive procedures (like breast implants).

However, if a material is extremely unstable, it can disintegrate before an APC can be absorbed, turning it into an immunogenic agent. Furthermore, larger insoluble complexes elicit stronger immune responses compared to smaller soluble ones. This is because insoluble complexes are simpler for macrophages to phagocytose, break down, and present than soluble complexes.

Other characteristics

Biological system

The biological system has a significant impact on how well an antigen elicits an immune response. Certain chemicals elicit an immune response in one person but not in another (responders and nonresponders). This is because some people may not have the proper genes required for the APC to present antigen to the helper T (TH) cells, or they may have altered or missing genes that code for the receptors for antigen on B cells and T cells.

Dosage and route of the antigen

Immunogenicity of Antigens

• Dose and route of contact influence immunogenicity.
• Low doses don’t stimulate immune response due to insufficient lymphocyte contact.
• High doses fail to elicit tolerance.

Antigen Administration and Immune Response

• Booster doses of certain antigens are administered to enhance host immune response.
• Vaccines like DPT and DT are given to ensure protective antibody levels.
• Antigens are typically administered by parenteral route.
• Routes include intravenous, subcutaneous, intradermal, intramuscular, intraperitoneal, and mucosal.
• Subcutaneous route is generally more effective in eliciting an immune response than intravenous routes.

Adjuvants

Adjuvants enhance the immunogenicity of antigens by increasing the strength and duration of the immune response when mixed with and injected with the antigen.

• Adjuvants like alum and Fred’s water-in-oil prolong antigen persistence by forming depots at injection sites, precipitating antigen and slowly releasing droplets over time.
• Freund’s complete adjuvant, containing heat-killed mycobacteria, activates macrophages, increases IL-1 production and B7 membrane molecules, enhancing the immune response. It also increases class II MHC expression, presenting antigen to TH cells.
• Adjuvants like synthetic polyribonucleotides and bacterial lipopolysaccharides stimulate nonspecific lymphocyte proliferation, thereby initiating their action.

Antigenic Specificity

The antigen’s antigenic specificity is influenced by its antigenic determinants or epitopes.

Epitopes

• Defined as immunologically active region of an immunogen.
• Binds to antigen-specific membrane receptors on lymphocytes or secreted antibodies
• Interaction between immune system cells and antigens occurs at various levels.
• Two types: B-cell epitopes and T-cell epitopes.

B-cell epitopes

• B-cell epitopes are antigenic determinants.
• Can only combine with receptor if antigen molecule is native.
• Antibody and antigen surfaces are flat.
• Smaller molecules fit within antigen-binding site depression.
• Approximately six to seven sugar residues or amino acids long.
• Hydrophilic and often located at protein structure bends.
• Often found in regions of proteins with higher mobility, allowing slight shift for almost-right site fit.

T-cell epitopes

• T lymphocytes identify amino acids in proteins, not polysaccharides or nucleic acid antigens.
• Proteins are T-dependent antigens, polysaccharides are T-independent antigens.
• Antigenic determinants determined by protein’s primary amino acid sequence.
• T cells identify MHC molecules and peptide combination, but not free peptides.
• T-cell response is MHC limited, recognizing both antigenic determinant and MHC.
• T-cell epitopes, or antigenic determinants, are short, between 8 and 15 amino acids.
• Only parts of the antigen that attach to MHC molecules are considered antigenic determinants.
• Genetic heterogeneity in MHC molecules can cause different responses to stimuli.
• For a peptide to trigger an immune response, the person must possess MHC molecules capable of binding to the peptide.

Species Specificity

• Each species has unique tissues with specific antigens.
• Cross-reactivity exists between related species’ antigens.
• Species specificity indicates phylogenetic connection.
• Uses include tracking species evolution and forensic medicine.

Isospecificity

Isospecificity refers to the existence of isoantigens or histocompatibility antigens.

Isoantigens

• Isoantigens are antigens found in specific species members.
• Classification based on distinct isoantigens.
• In humans, erythrocyte antigens determine blood type classification.
• Blood groups crucial in transfusions, pregnancy vaccination, paternity issues.
• DNA fingerprinting techniques improve results.

Histocompatibility Antigens

• Unique biological determinants found in tissue cell plasma membrane.
• Human leukocyte antigen (HLA) causes homograft rejection.
• HLA typing crucial for organ transplantation.

Autospecificity

• Sequestered antigens like eye lens protein and sperm are exceptions.
• Immune system doesn’t encounter ocular tissue or sperm.
• Unintentional or experimental discharge of tissues into blood or tissues makes them immunogenic.

Organ Specificity

• Antigens specific to brain, kidney, and lens tissues.
• Shared in human and sheep brains.
• Antirabies vaccines from sheep brain may trigger immunological response.
• Potential neural tissue damage may lead to neuroparalytic problems.

Heterophile Specificity

• Heterophile antigens are similar in tissues from different species.
• Antibodies against one species’ antigens can cross-react with others.
• Used for diagnosing infectious disorders.
• Serological assays include Weil-Felix reaction, Paul-Bunnell test, and cold agglutination tests.

Haptens

• Haptens are antigenic but not immuneogenic compounds.
• They cannot activate helper T cells due to their inability to bind to MHC proteins.
• Haptens are univalent and cannot activate B cells alone.
• They activate B cells when covalently linked to a “carrier” protein.
• Haptens interact with IgM receptors on B cells, resulting in the internalization of the hapten-carrier protein complex.
• Activated helper T cells produce interleukins, stimulating B cells to create antibodies against hapten.
• Animals inoculated with hapten-carrier combination develop antibodies.
• Antibodies target hapten determinant, carrier protein epitopes, and novel ones.
• Hapten-carrier molecule binds to B cell surface immunoglobulins.
• B and TH cells process and present fragments.
• Synthesis of hapten-carrier conjugates leads to allergic reactions to medicines.

Superantigens

• Superantigens interact with APC MHC class II molecules and T-lymphocyte receptor Vb domains.
• Interaction activates more T cells (10%) than traditional antigens (1%).
• Includes staphylococcal enterotoxins, toxic shock syndrome toxin, exfoliative toxins, and some viral proteins.

Source: Textbook of Microbiology and Immunology, 2/e Subhash Chandra Parija

Reference:

• Antigen  : https://en.wikipedia.org/wiki/Antigen
• Interesting thing I just found on two biological terms: “antigen” and “antibody” ; https://www.reddit.com/r/etymology/comments/33t0q9/interesting_thing_i_just_found_on_two_biological/