Detailed Notes on Antigens

Antigens

Introduction to Antigens

• Antigens are foreign substances or components of organisms that can include pathogens (bacteria and viruses), chemicals, toxins, and pollens.
• They induce a specific immune response and subsequently react with the products of this response.
• Essentially, any substance against which an antibody is produced is considered an antigen.

Antigenicity and Immunogenicity

• Antigenicity: The ability of an antigen to specifically combine with the final products of the immune response, such as secreted antibodies or surface receptors on T cells. It's the ability to bind to an antibody or T cell receptor.
• Immunogenicity: The ability to induce a humoral or cell-mediated immune response.
• All immunogenic molecules are also antigenic, but the reverse is not always true.

Antigen vs. Immunogen

Tolerogen

• A foreign antigen that suppresses immune response or produces immune tolerance. Tolerance is the prevention of an immune response against a particular antigen, such as a self-antigen.
• An antigen that invokes specific immune non-responsiveness due to its molecular form. If its molecular form changes, a tolerogen can become an immunogen.

Allergen

• A substance that causes an allergic reaction.
• Foreign or apparently harmless molecules that induce an abnormal immunological response.
• Reactions may occur after exposure through ingestion, inhalation, injection, or skin contact.

Classification of Antigens

• Antigens are classified based on their origin:
  • Exogenous
  • Endogenous
  • Auto-antigens

Exogenous Antigens

• Antigens that enter the body from the outside via inhalation, ingestion, or injection.
• They are taken into antigen-presenting cells (APCs) through endocytosis or phagocytosis and processed into fragments.

Endogenous Antigens

• Antigens generated within the cell due to normal cell metabolism or viral/intracellular bacterial infection.

Autoantigens

• Self-antigens that stimulate the immune system to produce auto-antibodies in the organism.

Types of Antigens (Based on Origin)

Exogenous Antigens Examples

• Bacterial antigens:
  • Somatic antigen (O): Part of the cell wall in gram-negative bacteria.
  • Capsular antigen: Usually polysaccharide.
  • Flagellar Ag (H): A protein made of flagellin.
  • Fimbrial Ag: Surface antigens in fimbriated bacilli.
  • Antigen secreted by bacteria: Exotoxins (enzymes).

Endogenous Antigens Examples

• Human tissue antigens:
  • Blood group antigens: A, B, and Rh antigens.
  • Histocompatibility antigens: Glycoprotein molecules on all nucleated cells.
    • Major histocompatibility complex antigens (MHC).
    • Human leukocyte antigen (HLA).

Autoantigens

• In some cases, an animal may mount immune responses against normal body components, leading to autoimmune responses.
• Examples:
  • Hormones (thyroglobulin).
  • Structural components (basement membranes).
  • Complex lipids (myelin).
  • Intracellular components (mitochondrial proteins).
  • Nucleic acids.
  • Nucleoproteins.
  • Cell surface proteins.

Tumor Antigens (Neoantigens)

• Proteins or other molecules found only on cancer cells and not on normal cells.
• Presented by Major Histocompatibility Complex (MHC) I on the surface of tumor cells.

Native Antigens

• Antigens that are not processed by antigen-presenting cells (APCs).
• T-cells cannot bind to these antigens without processing.
• B-cells can be activated by such antigens even without processing.

Types of Antigens Based on Immune Response

Complete Antigens/Immunogens

• Antigens that elicit a specific immune response.
• They can induce an immune response by themselves without any carrier particles.
• Usually proteins, peptides, or polysaccharides with high molecular weight (greater than 10,000 Daltons).

Incomplete Antigens/Haptens

• Antigens that cannot generate an immune response by themselves.
• Usually non-protein substances that require a carrier molecule to form a complete antigen.
• Haptens have a low molecular weight (usually less than 10,000 Da) and fewer antigenic determinant sites (one).
• The carrier molecule bonded to the hapten is a non-antigenic component (protein or polysaccharide molecule).

Antigen Recognition Molecules and Binding

• Types of antigens are recognized by receptors in the immune system:
  • B-cell receptors (BCR):
    • Transmembrane proteins on the surface of B cells.
    • Secreted to plasma as antibodies IgM and IgD.
  • T-cell receptors (TCR):
    • Protein complex found on the surface of T-cells or T lymphocytes.
    • Composed of alpha and beta chains.
    • Recognize fragments of antigens as peptides bound to the MHC on the surface of APCs.
  • Major Histocompatibility complex (MHC class I and class II):
    • Essential for the presentation of peptides.
    • Bind peptide fragments derived from pathogens and display them on the cell surface for recognition by the appropriate TCR or T cell receptors.

MHC Class I and II Pathways

• MHC Class I Pathway
  • Cytosolic protein is processed through the proteasome.
  • Peptides are transported via TAP.
  • Peptide-MHC association occurs.
  • Expression on the cell surface allows recognition by CD8 T cells through TCR.
• MHC Class II Pathway
  • Extracellular protein undergoes antigen uptake.
  • Antigen processing occurs through the endosome.
  • Lysosomal proteases cleave the antigen and invariant chain (li).
  • Peptide-MHC association happens in the ER.
  • Expression on the cell surface allows recognition by CD4 T cells through TCR.

Essential Features of Antigens

• Molecules must be recognized as foreign to stimulate the immune system.
• Processing places physical and chemical restrictions on the types of foreign molecules.
• Most effective antigens are:
  • Large (over 10,000 MW).
  • Rigid.
  • Chemically complex.

Structure of an Antigen

• The molecular structure determines its ability to bind to the antigen-binding site of an antibody.
• Antibodies differentiate based on specific molecular structures on the antigen's surface.
• Most antigens are proteins or polysaccharides, including coats, capsules, flagella, toxins, and fimbriae of bacteria, viruses, or other microorganisms.
• Lipids and nucleic acids are antigenic when combined with proteins or polysaccharides.
• All immunogenic antigens have a specific structural component called an epitope or antigenic determinant.
• The number of epitopes varies and determines the number of antibodies a single antigen can bind to.
• The region on antibodies that interacts with antigens is called a paratope.
• Epitope and paratope structures are specific and fit like a lock and key.

Chemical Nature of Immunogens

• Proteins: Most immunogens are proteins (pure proteins, glycoproteins, or lipoproteins).
• Polysaccharides: Pure polysaccharides and lipopolysaccharides are good immunogens.
• Nucleic Acids: Poorly immunogenic unless single-stranded or complexed with proteins.
• Lipids: Generally non-immunogenic, although they may be haptens.

Factors That Influence Antigenicity

• Molecular size: Large molecules are better antigens.
• Complexity: The more complex, the better.
• Structural stability: Rigid molecules are better.
• Degradability
• Foreignness

Molecular Size Examples

• Hemocyanin (6.7x10 KDa): A potent antigen.
• Serum albumin (69 KDa): A fairly good antigen.
• Hormone angiotensin (1031 Da): A poor antigen.
• Very small molecules may bind to large proteins, provoking an immune response.

Complexity and Rigidity

• Simple repetitive polysaccharides (e.g., starch) are poor antigens.
• Complex bacterial lipopolysaccharides (LPS) are good antigens.
• Complex proteins are better antigens than large repeating polymers.
• Rigid molecules are good antigens.

Structural Stability

• The immune system must recognize a molecule's shape to recognize it as foreign.
• Highly flexible molecules with no fixed shape are poor antigens (e.g., gelatin).
• Flagellin, a major protein of bacterial flagella, is structurally unstable and a weak antigen.

Degradability

• Not all foreign molecules stimulate an immune response.
• Inert organic polymers lack antigenicity due to their uniformity and inertness.
• Unstable foreign molecules that are rapidly destroyed may not provide sufficient antigen to stimulate a response.

Foreignness

• Suppression of cells reacting with normal body components (self-antigens) occurs because these cells are exposed to self-antigen when immature.
• Examples:
  • Trauma to testes (or vasectomy) can lead to anti-sperm antibodies.
  • Extensive cell destruction (heart attack) can lead to anti-mitochondrial antibodies.

Antigenic Determinants and Cross-Reactivity

• Epitope: Immunologically active region of an immunogen (or antigen) that binds to antigen-specific membrane receptors on lymphocytes or secreted antibodies; also called antigenic determinants.
• Antigenic determinants are regions in an antigen molecule involved in the reaction with antibodies.
• Antigens with two or more antigenic determinants can induce antibody production.

Epitope

• The part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells.
• The specific piece of the antigen to which an antibody binds.
• Two types:
  • B cell epitope: Recognized by the B cell receptor.
  • T cell epitope: Recognized by the T cell receptor.

Types of Epitopes (Based on Structure)

Linear Epitopes

• Continuous stretches of amino acids sufficient for binding.
• Found in polysaccharides and both native and denatured proteins.
• Specificity depends upon primary sequence.
• Typical size: 5-6 subunits.

Conformational Epitopes

• Discontinuous, involving multiple subunits brought together by protein folding.
• Found only in native (globular) proteins.
• Specificity depends upon conformation, or three-dimensional shape (tertiary and quaternary structure).
• Typical size is hard to pinpoint, but sequences of up to 16 amino acids have been shown to interact with their complementary paratope.

Antigen-Antibody Complex

• A molecule formed by binding multiple antigens to antibodies.
• The interaction is highly specific and determined by the amino acid sequence in the epitope and paratope.
• The complex is formed by an antigen-antibody reaction, leading to responses like complement deposition, opsonization, and phagocytosis.
• Immune complexes regulate antibody production as the binding of antigen to cell receptors activates signaling cascades.
• Deposition of the immune complex can lead to autoimmune diseases like arthritis and scleroderma.