Nature of Ag and the MHC

What is an immunogen?

An immunogen is anything capable of starting a specific immune response that results in antibodies or activated cells, which can then react with it.

What is an antigen?

An antigen (Ag) can react with antibodies or activated immune cells, but cannot always induce them.

What is the difference between an immunogen and an antigen?

An immunogen can induce an antigen response and then react with an antibody. An antigen (Ag) can react with an antibody, but cannot always induce them. The two terms are often used as synonyms.

How does age affect the immune response?

Older individuals have a decreased response to antigenic stimulation. Neonates have an immune system that is not yet fully developed.

What overall health factors can influence the immune response?

Malnutrition, fatigue, and stress can all negatively affect the immune response.

How does route of inoculation influence the immune response?

The route matters — options include intravenous, intradermal, subcutaneous, and oral. Different routes affect how the immune system encounters and responds to an immunogen.

How does dose affect the immune response?

The larger the amount of immunogen one is exposed to, the greater the immune response. However, very large doses can actually induce tolerance (no response).

What is genetic capacity (predisposition) in terms of the immune response?

The presence or absence of particular genes makes some individuals more susceptible to certain diseases. Genetic makeup influences the ability to mount an immune response.

What factors determine immunogenicity?

Macromolecular size and foreignness. The more taxonomically different from the host, the more successful it is as an immunogen.

How does macromolecular size affect immunogenicity?

A substance must be at least 10,000 Daltons to be recognized; most active antigens are at least 100,000 Daltons.

How does foreignness affect immunogenicity

The more taxonomically different from the host, the more successful it is as an immunogen. Proteins are generally better immunogens than carbohydrates.

What minimum size must a molecule be to be recognized as an immunogen?

At least 10,000 Daltons. Most active antigens are at least 100,000 Daltons.

Why are proteins considered great antigens?

Due to their variations and 3-D structure. The immune system reacts with peptide fragments (approximately 6–15 amino acids), not the whole protein. These fragments are presented to T and B cells, triggering a CMI or humoral response.

What type of immune response do protein antigens trigger?

They are T-cell dependent — they require a T helper cell, result in both IgM and IgG production, and generate memory cells.

Types of Antigens: Polysaccharides/Lipids

Why is pure polysaccharide considered a weak immunogen?

Pure polysaccharides tend to have long, repeating subunits (e.g., bacterial capsule) and are not well recognized by T cells.

What type of immune response do polysaccharide antigens trigger?

They are T-cell independent — they activate B cells without T helper cells, produce IgM only, and generate no memory cells.

Epitopes

What is an epitope?

The key portion of an antigen recognized in the immune response. Also called a determinant. Each epitope is capable of causing a specific immune response and binding to the antibody produced from that reaction.

What is a linear (sequential) epitope?

An epitope made up of amino acids following one another in a single chain — sequential in structure.

What is a conformational epitope?

An epitope that has folding of one or more chains, allowing amino acids from different segments of the antigen to come into close proximity.

Haptens

What is a hapten?

A small molecule (less than 10,000 MW) that does not elicit an immune response by itself. It is a nonimmunogenic material that creates new antigenic determinants when combined with a carrier molecule.

Can haptens react with antibody?

Yes — haptens can react with antibody even without being complexed to a carrier molecule. When bound to carriers, they contribute to the development of an interconnected lattice that serves as the basis for precipitation and agglutination reactions.

What is a classic example of a hapten?

Poison ivy. The chemical (urushiol) acts as a hapten that, when combined with skin proteins (the carrier), triggers an immune response.

Adjuvants

What is an adjuvant?

A substance mixed with an antigen to enhance the immune response. Adjuvants can make immunization more effective by targeting APCs, protecting immunogens from degradation, and allowing a longer response time that attracts more immune cells to the injection site.

What are examples of adjuvants used in vaccines?

Aluminum salts (used in the HBV vaccine) and MF59, a water-oil emulsion (sometimes used in flu vaccines).

How do adjuvants work?

They target APCs, which are important to the adaptive immune response. They protect immunogens from degradation, allow a longer response time, attract more immune cells to the injection site, and accelerate the immune response while increasing the duration of protective immunity.

Relationship of Antigens to the Host

What are autoantigens?

Antigens that belong to the host (self). They do not usually evoke an immune response. Loss of tolerance to autoantigens results in autoimmune disease.

What are alloantigens?

Antigens from other members of the same host species (e.g., encountered in transplantation or blood transfusion). The antibodies formed against them are called alloantibodies.

What are heteroantigens?

Antigens from other species, such as animals, plants, or microorganisms.

What are heterophile antigens?

Antigens that exist in plants or animals but are identical to or closely related in structure to antigens from a different species, such that antibody to one will cross-react with the antigen of the other. Examples: antigen from pneumococci bacteria cross-reacting with type B blood group antigen; used in the lab test for infectious mononucleosis.

Major Histocompatibility Complex (MHC) — Overview

What is the Major Histocompatibility Complex (MHC)?

A set of genes linked to the genetic capability that allows the body to mount an immune response. In humans, these genes code for human leukocyte antigens (HLA), which are found on all nucleated cells in the body and play a pivotal role in the development of humoral and cellular immunity.

What is the main function of MHC molecules?

To bring antigens inside the body to the surface of cells for recognition by T cells. When combined with antigen on the surface of cells, they activate T cells.

What role do MHC molecules play in transplantation?

They determine whether transplanted tissue is histocompatible and accepted, or recognized as foreign and rejected.

MHC Genes and Classes

Where are MHC genes located in humans?

On the short arm of chromosome 6.

What are the three classes of MHC genes?

Class I: found at three loci (A, B, and C). Class II: found at the D region (DR, DQ, and DP). Class III: found between Class I and II; codes for C4A, C4B, C2, and Factor B complement proteins.

Which MHC classes are involved in antigen recognition?

Classes I and II are involved in antigen recognition and influence the antigens to which T cells respond.

What does MHC Class III do?

It is composed of secreted proteins that have immune functions but are not expressed on cell surfaces. It codes for components of the complement system (C4A, C4B, C2, Factor B).

How many alleles do HLA genes have?

HLA-A has over 2,000 different alleles; HLA-B has over 2,600 different alleles; HLA-C has over 1,500 different alleles.

What is an HLA haplotype?

Because MHC genes are closely linked, the grouping inherited together is called a haplotype. One haplotype is inherited from each parent. The probability of two people having the same HLA type is very low due to billions of possible variations — this creates problems for organ matching but is useful for paternity testing.

Structure of Class I MHC Molecules

Where are Class I MHC molecules expressed?

On all nucleated cells. Expression is highest on lymphocytes and myeloid cells, and lowest (or undetectable) on liver hepatocytes, neural cells, muscle cells, and spermatozoa. (This is why liver transplants do not require tissue matching.)

What is the structure of a Class I MHC molecule?

A transmembrane (alpha) glycoprotein dimer made up of two noncovalently linked polypeptides: an alpha chain with 3 domains, and beta-2 microglobulin. They form a peptide-binding cleft.

Which HLA molecules are most important to match for transplantation and why?

HLA-A and HLA-B, because there are greater numbers of these molecules present.

Structure of Class II MHC Molecules

Where are Class II MHC molecules found?

Primarily on antigen-presenting cells (APCs): B lymphocytes, monocytes, macrophages, dendritic cells, and thymic epithelium.

What are the major Class II MHC molecules?

DP, DQ, and DR. They are made up of two noncovalently bound polypeptide chains encoded by separate genes in the MHC complex.

Role of MHC Molecules in the Immune Response

What is the main role of Class I and Class II MHC molecules?

Antigen presentation. Degraded peptides are transported to the plasma membrane (surface) of the APC where T cells recognize them. T cells can only "see" and respond to antigen when it has been degraded (processed) and combined with an MHC molecule.

What two main types of pathogens do Class I and Class II deal with?

Bacteria (exogenous antigens) — handled by Class II. Viruses (endogenous antigens) — handled by Class I.

Which T cells do Class I MHC molecules present antigen to, and what response does this trigger?

Class I presents endogenous peptides (from viruses, tumors, some parasites) to CD8+ (cytotoxic) T cells, triggering a cytotoxic reaction.

Which T cells do Class II MHC molecules present antigen to, and what response does this trigger?

Class II presents processed exogenous peptides (e.g., bacteria) to CD4+ (helper) T cells, which are involved in antibody production.

What is required for a T cell response to occur?

Peptide fragments must be able to bind to the MHC molecule AND be recognized by the T cell receptor (TCR).

Class I MHC — Antigen Processing Pathway (Endogenous)

Where are Class I MHC molecules made, and where do they contact processed antigen?

They are made in the rough endoplasmic reticulum (ER) and contact processed antigen there.

What are TAP1 and TAP2?

Transporters Associated with Antigen Processing. They transport antigenic peptides to the endoplasmic reticulum, where those peptides bind to MHC Class I molecules.

How long are the peptides presented by Class I MHC molecules?

Approximately 8 to 11 amino acids in length.

What happens after a peptide binds to the Class I MHC molecule?

The MHC I–peptide complex is transported to the surface of the cell via the Golgi apparatus, where it binds to the CD8+ T cell receptor (TCR).

What percentage of peptides processed by Class I MHC actually cause a response, and how many copies of each Class I molecule can a cell have?

Only about 1% of processed peptides cause a response. A single cell may have 100,000–200,000 copies of each Class I molecule, which increases the number of peptides that can be processed and displayed.

Class II MHC — Antigen Processing Pathway (Exogenous)

How does the Class II MHC antigen processing pathway work?

Antigen is taken in via phagocytosis/endocytosis. Endosomes containing enzymes digest the antigen into peptide fragments. MHC II molecules are synthesized in the endoplasmic reticulum and associated with a protein called the invariant chain (Ii). The Ii is cleaved to form a fragment called CLIP, which is exchanged for the antigenic peptide. The MHC II–peptide complex is then transported to the cell surface, where it interacts with the CD4+ T cell receptor (TCR).

What is the invariant chain (Ii)?

A protein associated with MHC Class II molecules as they are synthesized in the endoplasmic reticulum. It is cleaved to form a fragment called CLIP, which holds the peptide-binding groove until the real antigenic peptide is loaded.

What is CLIP?

A fragment produced when the invariant chain (Ii) is cleaved. CLIP occupies the MHC II binding groove and is exchanged for the actual antigenic peptide before the complex moves to the cell surface.

Clinical Significance of MHC

What is the clinical significance of MHC molecules?

They are important in tissue transplant procedures (Classes I and II can induce graft rejection) and appear to play a role in the development of autoimmune diseases.

What diseases are associated with specific HLA alleles?

Ankylosing spondylitis (B27, very strong association); Celiac disease (DQ2, very strong; DQ8, strong); Rheumatoid arthritis (DR4, clear association); Type 1 diabetes (DQ8, strong; DQ2, clear association).

What HLA allele is very strongly associated with ankylosing spondylitis?

HLA-B27 (very strong association — +++).

What HLA alleles are associated with celiac disease?

DQ2 (very strong association, +++) and DQ8 (strong association, ++).

What HLA allele is associated with rheumatoid arthritis?

DR4 (clear association, +).

What HLA alleles are associated with Type 1 diabetes?

DQ8 (strong association, ++) and DQ2 (clear associatio