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:
  • Antigens can be any substance.
  • Common types include proteins, polysaccharides, glycoproteins.
  • Antigens exist on the cell surface.
• Human Cell Antigens:
  • Comprised of proteins, glycoproteins, polysaccharides.
  • Examples include lipopolysaccharides or slimy capsules in gram-negative bacterial cells.
• Self vs. Foreign 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 MHC genes (Human Leukocyte Antigen proteins).
• Uniqueness of MHC (HLA) Genes:
  • Each person has a unique set of MHC genes.
  • MHC genes are inherited from both biological parents.
  • Major Histocompatibility Complex (MHC) stands for the genes involved.
• MHC Classes:
  • MHC class 1 genes: Inherited from both parents, typically 3 genes (i.e., 6 alleles).
  • MHC class 2 genes: Inherited from both parents, typically 4 genes (i.e., 8 alleles).
  • These genes are unique to individuals, except identical twins.
• Expression of MHC Genes:
  • MHC class 1: Expressed on all nucleated cells (except red blood cells and platelets).
  • MHC class 2: Expressed on phagocytic cells (neutrophils, eosinophils, macrophages).
• Role of MHC Genes:
  • MHC genes help the immune system ignore self-cells.
  • Autoimmune diseases occur when the immune system attacks self-cells.
• Autoimmune Diseases:
  • The immune system fails to distinguish self from non-self.
  • Results in the specific (adaptive) immune system attacking the body’s own cells.
  • Causes inflammation and tissue damage.
• Inheritance and Diversity:
  • MHC genes are located on chromosome six.
  • Thousands of allele combinations exist in the human genome.