Chpater 3_Nature of Antigens and the Major Histocompatibility Complex

Innate immunity

The body's ability to respond nonspecifically to infection by recognizing broad classes of molecular patterns found on pathogens.

Adaptive immune system

Recognizes very specific molecular regions from individual pathogens.

Lymphocytes

Cells responsible for specificity, diversity, and memory in adaptive immunity.

Antigen

A substance specifically recognized by the adaptive immune system.

Immunogen

A substance capable of causing an adaptive response.

Distinction between antigen and immunogen

All immunogens are antigens, but not all antigens are immunogens.

Factors influencing response to antigens

Biological properties of the individual, nature of the antigen, antigen processing with MHC molecules, and antigen presentation to T cells.

Host factors influencing immunogenicity

Age, health status, and genetics.

Effect of age on immune response

Elderly have decreased responses; neonates cannot fully respond due to immature immune systems.

Health conditions affecting immune response

Malnourished, fatigued, or stressed individuals are less likely to mount a successful immune response.

MHC genes

Genes that exert the most profound influence on immune response.

Requirement for stimulating adaptive immune response

A certain amount of antigen must be introduced into the body.

Very small amounts of antigen

They fail to reach the threshold required for adaptive response and are cleared by innate immunity.

Very large quantities of antigen

They can cause lymphocyte tolerance (ignorance toward the antigen).

Routes of antigen exposure

Intravenous, intradermal, subcutaneous, intramuscular, and oral.

Oral tolerance

A phenomenon where antigens delivered via the gastrointestinal tract are ignored by adaptive immunity to prevent responses against food.

Traits determining immunogenicity

Macromolecular size, foreignness, chemical composition and complexity, ability to be processed and presented with MHC molecules.

Molecular weight required for immunogenicity

At least 10,000 Da; most effective are >100,000 Da.

Role of foreignness in immunogenicity

The more taxonomically distant the antigen, the more likely it is immunogenic.

Effective immunogens

Proteins and polysaccharides.

Nonimmunogenic synthetic polymers

They are composed of simple repeating units with no complexity or folding.

Immunogenicity of proteins

They are complex, structurally diverse, and require B-cell and T-cell interactions for an effective antibody response.

Levels of protein structure

Primary, secondary, tertiary, and quaternary.

Primary structure of a protein

The linear sequence of amino acids in a polypeptide chain.

Secondary structure of a protein

Basic 3D shapes formed by folding, such as alpha helices and beta pleated sheets.

Tertiary structure of a protein

The overall 3D folding of a polypeptide, bringing distant amino acids together.

Quaternary structure of a protein

Two or more polypeptide chains forming a multimeric unit.

T cells recognition

Small peptides (primary structure) presented by MHC molecules.

B cells recognition

Exposed tertiary or quaternary structures on the protein surface.

Exposed tertiary or quaternary structures

Structures on the protein surface that are important for immune recognition.

Effective B-cell response

Requires help from T cells for signals for antibody production and memory.

Polysaccharides immunogenicity

Less immunogenic than proteins because they are smaller and cannot activate T cells.

Carbohydrates as immunogens

Act as immunogens in the forms of glycolipids and glycoproteins.

Examples of carbohydrate immunogens

A, B, and H blood group antigens (glycolipids), Rh and Lewis antigens (glycoproteins), and bacterial capsular polysaccharides.

Immunogenicity of pure nucleic acids and lipids

Not immunogenic unless attached to a suitable carrier molecule.

Autoimmune disease with DNA autoantibodies

Systemic lupus erythematosus (SLE).

Eliciting an immune response

A substance must be processed into small peptides and presented by MHC molecules to T cells.

Epitope

The specific portion of an immunogen recognized by B cells or T cells.

Types of B-cell epitopes

Linear epitopes (sequential amino acids) and conformational epitopes (folded structures).

T-cell epitope recognition

T cells recognize only linear epitopes displayed by MHC molecules.

Hapten

A small antigen that is not immunogenic by itself but becomes immunogenic when bound to a carrier.

Hapten binding to a carrier

Can initiate antibody production, allowing antibodies to later recognize the hapten alone.

Natural hapten example

Catechols in poison ivy that combine with skin proteins to form immunogens.

Drug hapten example

Penicillin, which can cause life-threatening allergic responses.

Famous hapten study conductor

Karl Landsteiner.

Landsteiner's discovery about antibodies

They recognize polarity, hydrophobicity, ionic charge, and 3D configuration of haptens.

Adjuvants

Substances administered with antigen to enhance the immune response.

How adjuvants work

They stimulate innate immune receptors and prevent antigen diffusion from the inoculation site.

Importance of adjuvants in vaccines

They enhance immunogenicity of antigens, especially recombinant proteins.

Vaccines that do not require adjuvants

Those with whole pathogens (live, weakened, or killed) that naturally provide immune danger signals.

Vaccines that often require adjuvants

Recombinant protein vaccines.

Autoantigens

Antigens that belong to the host; normally do not evoke a response but can cause autoimmune disease.

Alloantigens

Antigens from other members of the same species; important in tissue transplantation and blood transfusion.

Heteroantigens

Antigens from other species (animals, plants, microorganisms).

Heterophile antigens

Heteroantigens that exist in unrelated plants or animals but are identical or closely related in structure, causing cross-reactions.

Example of heterophile antigen cross-reactivity

Human blood group A and B antigens related to bacterial polysaccharides.

Formation of naturally occurring anti-A and anti-B antibodies

Through exposure to bacteria with similar polysaccharides.

Usefulness of cross-reactivity in diagnostics

Allows detection of diseases such as infectious mononucleosis.

Test for infectious mononucleosis based on heterophile antibodies

The Paul-Bunnell test, using sheep red blood cells.

Virus causing infectious mononucleosis

Epstein-Barr virus (EBV).

Epstein-Barr virus (EBV)

A virus that can interfere with clinical assays by cross-linking reagent antibodies, falsely elevating analyte levels.

MHC molecules

Major histocompatibility complex molecules that present peptides for recognition by T cells.

Human leukocyte antigens (HLAs)

The original name for MHC molecules.

Jean Dausset

The French scientist who named HLAs.

Location of MHC molecules

Found on all nucleated cells of the body.

Main immune function of MHC molecules

To carry peptide antigens for recognition by T cells.

T cells vs B cells in antigen recognition

T cells require antigens to be presented within MHC molecules, while B cells bind antigens directly.

Importance of MHC in transplantation

They determine whether tissue is histocompatible (accepted) or rejected as foreign.

Polymorphic MHC

Each allele varies greatly among individuals, improving survival against diverse pathogens.

Chromosome location of human MHC genes

Short arm of chromosome 6.

Categories of MHC genes

Class I, Class II, and Class III.

Class I gene loci

A, B, and C.

Class II gene loci

DR, DQ, and DP.

Class I molecule gene coding

Only one gene for each molecule.

Class II molecule gene coding

One α chain gene and one or more β chain genes.

Class III genes

Code for complement proteins (C4a, C4b, C2, B) and cytokines (e.g., TNF).

MHC classes involved in T cell recognition

Class I and Class II.

Expression of Class III molecules

No, they are secreted proteins with immune function.

Polymorphism in MHC system

Many alternate forms (alleles) of each gene exist.

Identified HLA-A alleles

6,082.

Identified HLA-B alleles

7,256.

Identified HLA-C alleles

5,842.

MHC uniqueness

Unlikely two people have the same MHC molecules due to high polymorphism.

Codominant MHC expression

All alleles inherited are expressed on cells.

Haplotype

A package of closely linked MHC genes inherited together from one parent.

Number of haplotypes inherited

Two (one from each parent).

HLA type uniqueness

Unique like a fingerprint due to the enormous diversity of alleles and haplotypes.

Possible Class I haplotypes

More than 1.7 billion.

HLA allele frequency differences

Can reveal ancestry or ethnic origins.

HLA uniqueness in transplantation

These antigens are highly immunogenic and hard to match.

Usefulness of MHC polymorphisms

They can help in disputed paternity testing.

Traditional HLA nomenclature definition

Serologically using antibodies.

Current HLA nomenclature definition

Through DNA sequencing of actual genes.

HLA DRB1*1301

The gene coding for the β chain of HLA DR1 antigen is number 13, subtype 01.

Class I MHC molecule expression

On all nucleated cells.

Class II MHC molecule expression

Primarily on antigen-presenting cells (APCs).

Cells with highest Class I expression

Lymphocytes and myeloid cells.

Cells with low/undetectable Class I expression

Liver hepatocytes, neural cells, muscle cells, sperm.

Mismatched liver transplants success

Sometimes succeed because hepatocytes have low Class I expression.

HLA-A and HLA-B

Most important Class I antigens for transplantation matching.