Antigens

An antigen is defined as any substance that can be bound by antigen-receptors and stimulate an immune response.  Antigen-receptors are a main component of antibodies, and the term antigen is derived from the premise that it is an antibody generator.  Antigen receptors are also found on B cells (B lymphocytes), and T cells (T lymphocytes).

Different types of molecules can be antigens, for example: proteins, peptides, lipids, saccharides, and nucleic acids.

Self-antigens are produced within the body, and T and B cells are normally considered self-tolerant and therefore do not stimulate an immune response to self-antigens.  T and B cells develop self-tolerance during their maturation in whtat is termed the negative selection process in which T and B lymphycytes that bind too tightly to self-antigens are destroyed.  Self-antigens exist on and within the body’s own cells.  At times cancerous cells display proteins not normally expressed by mature healthy cells, and these are called tumor specific antigens (TSA).  Endogenous antigens can be self-antigens, though can also be antigens that are produced during bacterial or viral infections.

Non-self (or exogenous) antigens are produced outside the body and can be parts of bacteria, viruses, parasites, fungi, and sometimes plants or other animals (e.g., pollen, cat dander).

Terms associated with antigens are:

Antigenic specificity – is a term that refers to the ability of antigen receptors on antibodies, B and T cells to recognize and bind to specific antigens.  This is an important premise of specific (adaptive) immunity.

Allergen – a molecule that can induce an allergic reaction in individuals that have developed Type I Hypersensitivity Reactions to that particular substance (e.g., peanuts, strawberries, pollen, penicillin, shellfish, cat dander).

Epitope – the portion of the antigen that is bound to by antibodies.

Hapten – is a small molecule that can only be bound by an antibody, only if it is attached to a larger molecule.

Superantigen – antigens that are able to induce immune cells to release a large amount of cytokines (a cytokine storm) that can be detrimental due to the strength of the ensuing inflammatory response.

Major Histocompatibility Complex (MHC)

There is a large locus on chromosome 6, which contains a set of polymorphic genes that code for the MHC molecules (glycoproteins) that are essential for the specific (adaptive) immune system.  MHC molecules are responsible for presenting antigens (both self and non-self) on cell surfaces to T and B cells, to allow for immune system surveillance.  This process allows for T and B cells to launch a specific (adaptive) immune response in order to protect the body against pathogens.

The name Human Leukocyte Antigen (HLA) was originally used, as it is the name of the first identified MHC molecules.  There are 3 classes of HLA genes within the MHC locus on chromosome 6, Class I, Class II and Class III.  Class I and Class II are involved in presenting and displaying antigens to T and B cells as part of the specific (adaptive) immune system.

MHC Class I molecules are expressed on the surface of all nucleated cells (i.e., all cells including platelets, with the exception of RBCs).  As part of their role, MHC Class I molecules locate to the cell surface to display and present both endogenous and exogenous antigens to the T cell receptors (TCRs) of CD8 (Cytotoxic) T cells.

MHC Class II molecules are expressed on the surface of all antigen-presenting (APC) cells (e.g., monocytes, macrophages, dendritic cells) and B cells.  MHC Class I molecules present both endogenous and exogenous antigens to TCRs of CD4 (Helper) T cells.

Proteasomes are used to generate self-antigens (e.g. peptides) from cytosolic proteins for MHC molecules to display and present.

Phagosomes, lysosomes, and endosome enzymes are used to generate exogenous antigens that can be displayed and presented by MHC molecules..

Humans inherit MHC class I genes and MHC class II genes, many of which are polymorphic.  Individuals inherit 2 sets of each of these genes (one set from each biological parent).  Therefore, each nucleated cell is characterized by the expression of 3-6 different MHC class I molecules and each APC is depicted by the expression of 3-12 different MHC class II molecules.

The genetic and phenotypic differences between the MHC alleles is most prominent in the antigen-binding region and the T cell receptor (TCR) binding regions.  The amount of variation in MHC alleles is thought to be driven by pressure from the wide-range of infectious agents.

The MHC polymorphic genes code for 1000s of different Class I and Class II alleles, meaning that each person (specifically, each non-genetically identical human) has a unique set.  This massive variation in MHC Class I and Class II expression from one person to the next is compounded as the MHC genes are codominant, so are expressed from both sets of inherited chromosomes leading to 10s of 1000s of different possible combinations.  As we will see in subsequent sections, this can make avoiding organ transplant rejection challenging.

Autoimmune Diseases

Autoimmune Diseases are characterized by inappropriate adaptive immunity responses and reactions against self-antigens.  Self-antigens that are mistakenly recognized and targeted by the adaptive immune system, are sometimes termed auto-antigens.  To date, many autoimmune diseases have been investigated.  Some of the more common autoimmune disease include:  Type I diabetes mellitus (T1D), Multiple Sclerosis (MS), systemic lupus erythematosus (SLE, lupus), rheumatoid arthritis, Addison’s disease, Grave’s disease, pernicious anemia, alopecia areata, psoriasis, Sjörgren’s syndrome, celiac disease,  inflammatory bowel diseases (Crohn’s disease and ulcerative colitis.  We will explore these in more detail in subsequent sections.

Summary

• Introduction to Antigens:
  • Definition:  any substance capable of being bound by antigen receptors and stimulating an immune response
  • Antigens can be any substance: proteins, peptides, lipids, saccharides, nucleic acids
  • Common antigen types include proteins, polysaccharides, glycoproteins.
  • Antigens typically exist on the cell surfaces.
  • Antigen Receptors: are the main components of antibodies, and are also found on B and T lymphocytes
  • Antigen Specificity:  allow for specific recognition and ability of antigen receptors on antibodies, T and T cells to recognize and bind to specific antigens
• Human Cell Antigens:
  • Comprised of proteins, glycoproteins, polysaccharides.
• Self vs. Foreign (Non-self) Antigens:
  • The body differentiates between self and foreign antigens.
  • Self-antigens help immune cells recognize what belongs to the body.
  • Self-antigens are coded by Major Histocompatibility Complex (MHC genes), originally termed Human Leukocyte Antigen (HLA) genes.
  • Self-tolerance develops during T and B lymphocyte maturation (through negative selection, a process in which T lymphocytes that bind too strongly to self-antigens are induced to undergo apoptosis)
  • Antigen receptors are found on B and T lymphocytes as well as on antibodies
  • Examples of foreign (non-self) antigens include lipopolysaccharides (LPS) or slimy capsules in gram-negative bacterial cells
  • Foreign (non-self) antigens are found on viruses and other organisms (e.g., bacteria, fungi, plants and animals), and can trigger the immune response
  • Tumor Specific Antigens (TSAs):  Some cancer cells display proteins not normally expressed on the surface of mature cells, which can trigger the immune response
  • Allergens:  antigens that induce allergic reactions (Type I hypersensitivity Reactions)
  • Haptens:  small molecules that only bind to an antibody when attached to a larger molecule
  • Epitopes:  Antibody Binding Portion – the specific part of the antigen to which antibodies bind
  • Superantigens:  induce immune cells to release large amounts of pro-inflammatory cytokines (cytokine storm)
• Uniqueness of MHC (HLA) Genes:
  • Each person has a unique set of MHC genes found in a large locus on chromosome 6.
  • MHC genes are inherited from both biological parents and are essential for enabling the adaptive immune response.
  • Major Histocompatibility Complex genes are polymorphic and code for a diverse set of glycoproteins.
• MHC Classes:
  • MHC class I genes: Inherited from both parents, typically 3 genes (i.e., inherit two sets, one from each parent, so 6 alleles).
  • MHC class II genes: Inherited from both parents, typically 4 genes (i.e., inherit two sets, one from each parent, so 8 alleles).
  • These genes are unique to individuals, except identical twins.
• Expression of MHC Genes:
  • MHC class I: Expressed on platelets and all nucleated cells (not expressed by RBCs).
  • MHC class II: Expressed on phagocytic cells (neutrophils, eosinophils, macrophages).
  • There are three classes: Class I, II, and III
• Role of MHC Genes:
  • MHC genes help the immune system ignore self-cells.
  • MHC class I proteins:
    • expressed on all nucleated cells
    • present endogenous and exogenous antigens to T cell receptors (TCRs) on CD8 (Cytotoxic T cells)
  • MHC class II proteins:
    • are expressed on Antigen Presenting Cells (APCs) e.g., monocytes, macrophages, dendritic cells and B lymphocytes
    • present endogenous and exogenous antigens to T cell receptors (TCRs) on CD4 (Helper T cells)
  • Proteasomes:  Generate self-antigens for MHC display from cytosolic (endogenous) proteins
  • Phagosome, Lysosome, and Endosome Enzymes: Generate antigens for display by MHC molecules
• Autoimmune Diseases:
  • The immune system fails to distinguish self from non-self.
  • Considered an inappropriate immune response
  • Autoimmune diseases occur when the immune system attacks self-cells (specifically by targeting self-antigens, also known as auto-antigens).
  • Results in the specific (adaptive) immune system attacking the body’s own cells.
  • Remember that adaptive the immune system contains memory B and T cells, making an autoimmune disease, a chronic disease
  • Causes inflammation and tissue damage.
  • Common Autoimmune Diseases include:  Type I Diabetes Mellitus, Multiple Sclerosis, Systemic Lupus Erythematosus (SLE)
• Inheritance and Diversity:
  • The MHC locus is polymorphic, meaning that thousands of allele combinations exist in the human genome.
  • Genetic and phenotypic differences are most prominent in the antigen-binding regions
  • Each person has a unique set of MHC genes (except for identical twins).
  • Successful organ transplants require a match of MHC alleles