6/7/8- MHC and Antigens

Major histocompatibility complex (also known as HLA)

•Tightly linked cluster of 40-50 genes on chromosome 6 that encode a number of proteins

•Organised into regions that encode different classes of molecules (1-3)

•Associated with recognition of antigens and self/non-self recognition

•Play a role in transplantation acceptance

Naming the molecules

•HLA-A, HLA-B and HLA-C encode for MHC class 1

•HLA-G encodes for a non-classical type 1 molecule that protects the foetus

•HLA-DP, HLA-DQ and HLA-DR encode for class 2

•Class 3 not directly involved in antigen presentation- encode for serum proteins, complement proteins cytokines e.g. tumor necrosis factor

Two key properties of MHC

•Polygeneic- several genes within each class, each person posesses a different range of MHC molecules with different properties

•Polymorphic- multiple variants of each gene, different alleles within population, molecules have a broad specificity

•Every cell in the individual expresses the same set of MHC molecules

Functions of MHC

•Encode for cell surface glycoproteins, play a role in antigen presentation and T cell activation

•Class 1 presents on all nucleated cells

•Class 2 presents only on antigen presenting cells (B cells, macrophages, dendritic cells)

•Will result in killing of virally infected cell (cytotoxic), macrophage activation to kill bacteria (helper), B cell production of antibody (helper)

MHC class 1 structure

•Necessary for activation of cytotoxic T cells

•Heavy alpha chain with 3 domains- a1, a2, a3

•Light B2 microglobulin associated chain

•Antigenic peptides between 8-10 amino acids bind to the a1 and a1 domains

Class 2 structure

•Present antigens to helper T cells

•Two polypeptide chains- alpha and beta

•Peptide groove created within a1 and B1 domains

•Bind antigenic peptide of >13 amino acids

Expression of MHC molecules on cells

Anchoring of peptides within groove

•Class 1- peptide is bound (encased) at both ends to specific anchor residues, presents internal peptides e.g. derived from viruses

•Class 2- ends of peptide are unbound, side chains of peptide interact with anchor residues found in pockets along MHC molecule, presents external peptides e.g. derived from bacteria

MHC class 3 genes

• Encode soluble serum proteins, some complement proteins

• Tumour necrosis factor a and B

• Not involved in activation of T cells or transplatation

MHC gene diversity

• Individual alleles vary in their ability to present antigens from particular infections, may lead to more or less favorable outcome e.g. HIV

• Heterozygote advantage- individuals heterozygous for MHC alleles are more likely to have protective alleles

• Rare allele advantage- new infection may evolve to evade MHC alleles prevalent in a population, those with rare alleles are more likely to survive

• Diversity causes problems in transplantation- donor and recipient need to be as similar as possible

Where can antigens come from and what is an epitope

• Bacteria, infected cells, pollen

• Region on an antigen that triggers response in B or T lymphocytes

Immunogenicity vs antigenicity

• Immunogenicity- ability to induce B or T cell response

• Antigenicity- ability to combine specifically with the products of a B or T cell response e.g. antibodies or cell surface receptors

Four factors that determine immunogenicity

• Foreignness- any molecule that immature lymphocytes are not exposed to during development is later recognised as foreign

• Molecular size- best immunogens have size approaching 100k daltons, poor less than 10k

• Chemical composition- homopolymers tend to lack immunogenicity regardless of size, copolymers (different units) of sufficient size are immunogenic,also enhanced by aromatic amino acids

• Ability of immunogen to be processed and presented by an MHC molecule- large insoluble macromolecules are more immunogenic than small soluble ones are they are easier to phagocytose and process

B cell receptors

• Membrane bound immunoglobulin binds antigen but cannot generate signal

• Iga and IgB are transmembrane antigen associated nonspecific signalling molecules

• Each have single immunoreceptor tyrosine based activation motif (ITAM) in cytosolic tails

• Activate immune response by cell signalling after ligand binds to antibody

T cell receptors

• T cell receptors are made from an alpha beta heterodimer

• Antigens are presented to T cells by MHC molecules, whole complex binds to receptors, cannot initiate signalling

• Cell also contains associated CD3 complexes made up of polypeptides

• Acitvate T cells after ligans binds to receptor

Clonal selection theory

• Aims to explain diversity of antibodies formed during the initiation of the immune response

• States that in a pre-existing group of lymphocytes a specific antigen activates only its antigen specific cell to multiply and produce identical clones

• Lymphocytes circulate in blood and lymph and await their specific antigen

• Only recognise epitope that fits receptor, activation occurs in secondary lymphoid organs

• Once activated, produce clones with same epitopes

Immature lymphocytes

• Have not encountered antigen and lack fully developed antigen specific receptors

• Found in primary lymphoid organs

Naive lymphocytes

• Fully developed antigen receptors but have not encountered antigen

• Found in secondary lymphoid organs

• As they move around they interact with many dendritic cells and stop when the encounter antigen for which they express specific receptors

• This activation induces several responses in T cells- cytokine secretion, proliferation (clonal expansion), differenciation into effector and memory lymphocytes

Effector cells

• Activated helper and cytotoxic T cells, antibody secreting B cells

• Recognise antigens in lymphoid organs or peripheral non-lymphoid tissues and are activated to perform specific functions to eliminate microbes and prevent tissue damage

• CD4+ effector cells activate macrophages, B cells, inflammatory response

• CD8+ cells activate macrophages, kill infected cells

Memory lymphocytes

• Progeny of activated lymphocytes responsible for rapid secondary response if antigen is encountered again, will generate new effector cells

• Present in lymph circulation and are abundant in mucosal tissue, skin and lymphoid organs

• T cell response declines (apoptosis) after antigen is eliminated by effector cells to maintain state of equilibrium and homeostasis

Adjuvants

• Substances that enhance the immunogenicuty of an antigen when mixed with it and injected during vaccination

• Prolong antigen persistance at certain sites

• Result in increase in local inflammation and granuloma formation- dense, macrophage rich mass of cells

• Stimulate lymphocyte production non-specifically

Superantigens

• Class of antigens that results in excessive activation of the immune system by polyclonal T cell activation and massive cytokine release

• Do not bind to TCR but common structures on T cells (non-specific)

• Present on bacteria e.g. staphylococcal enterotoxins (SEs) and toxic shock syndrome toxin 1

• One in five T cells can be activated by superantigen which can lead to shock and death

Types and function of antigen presenting cells

• Process and present antigen to T cells to activate them

• Include dendritic cells, macrophages and B cells

• Capture the antigens and transport them to secondary lymphoid organs

• Provide primary signal- TCR binds to antigen-MHC complex

• Secondary signal- co-stimulatory molecules bind to receptors like CD28 on the T cell, required for activation

Antigen processing and presentation for extracellular antigens

• Derived from bacteria, foreign cells, toxins

• Usually dendritic cells detect entry of those materials and phagosytose them and package into vesicles

•Vesicles fuse with lysosomes to form phagolysosomes which fuses with vesicle containing MHC class 2 molecule

• Phagolysosome degraded by enzymes into peptides that fuse with the binding groove of MHC2

• This comples is transported to cell surface for display and is recognised by CD4+ cells (helper)

Antigen presentation pathway for intracellular antigens

• Pathogens e.g. viruses enter cell, cytoplasmic peptides derived from virus are tagged by the cell with a small molecule called ubiquitin

• The ubiquitin is recognised by the proteasome which digests the viral proteins into smaller peptides

• These are then transported to the endoplasmic reticulum by TAP (transporter associated with antigen processing) where they bind to MHC1 molecules

• This complex is displayed on the cell surface and recognised by CD8+ cells (cytotoxic)