7 - Adapt 1: Antigen Recognition Flashcards
The adaptive immune system is capable of distinguishing how many antigens/epitopes?
Millions
Which immune response is specific?
Adaptive
The adaptive response relies on ____ of receptors on T lymphocytes.
pre-existing diversity
How many antigen receptors are expressed on each clone?
Only one specific antigen receptor.
How many antigen receptors are expressed on lymphocytes as a population?
> 5 x 10^7 different antigen receptors
The acquired immune response relies on ____ and ____ of clones that express the antigen receptors that can bind the specific relevant antigen.
selection and expansion
What are the four basic elements of clonal selection theory?
- Selection - Antigen selects pre-existing cell surface receptor made by a single cell.
- Clones - Selection of a precursor gives rise to clones that all make the same receptor.
- Origin of receptor genes - Randomized receptor that is subject to mutation that is transmitted by somatic inheritance to all descendants.
- Self/nonself - Self-reactive cells are killed upon interaction with self antigen early in life.
What is an antigen?
Any molecule that can be recognized by the adaptive immune system (ex. can be bound by a T cell receptor).
What do antigens bind to?
Both MHC molecules and TCRs.
What is an immunogen?
Something that initiates an immune response.
Most immunogens are …
proteins.
(Pure proteins, lipoproteins, or glycoproteins).
In general, proteins are very good…
immunogens.
List the 5 properties of antigens.
- Foreignness
- Molecular size
- Chemical nature and composition
- Physical form
- Degradability
Describe how foreignness is a property of antigens.
An antigen must be a foreign substance. Autologous (self antigens) are ordinarily not immunogenic, but under certain circumstances may act as auto-antigens. Not all foreign things are immunogenic.
Describe how molecular size is a property of antigens.
Active immunogens have high a molecular mass (>14kDa).
E.g., tetanus toxoid, egg albumin, thyroglobulin are highly antigenic. Insulin (5.7kDa) is either non-antigenic or weakly antigenic.
Under what circumstance might self-antigens become immunogenic?
Thyroglobulin (don’t ask how this is all it said).
Describe how chemical nature is a property of antigens.
The more chemically complex and organic the substance is, the more immunogenic it will be (mainly proteins).
Describe how physical form is a property of antigens.
Particulate antigens are more immunogenic than soluble ones.
Denatured antigens are more immunogenic than the native form.
Describe how degradability is a property of antigens.
Antigens that are easily phagocytosed or degraded (proteases) are more immunogenic.
E.g., T-dependent antigen requires to be phagocytosed, processed and presented to helper T cells by APC.
How do T cells see pathogens?
T cells can only “see” antigens in the context of other cells. They interact with other cells (infected cells, B cells, and phagocytes) and recognize pathogen-derived antigens in the context of MHC molecules with antigen specific receptors.
What cells do not express MHC?
Red blood cells.
Describe the peptide binding region of class I and II MHC molecules.
The peptide binding region exhibits polymorphism, meaning there is lots of variation in the peptide sequence.
How many allelic variants of MHC are there in humans?
Several hundred, one copy is inherited from each parent.
How many class I MHC molecules are expressed per person?
Up to 6
How many class II MHC molecules are expressed per person?
About 12
How does the limited group of MHC molecules present the vast diverse array of possible antigen peptide fragments?
A given MHC molecule can bind numerous different peptides, and some peptides can bind to several different MHC molecules.
Also gene polymorphism.
What are anchor residues?
The amino acids that are within the binding site of an MHC molecule.
What cell types do class I MHC molecules present to?
CD8 T cells
What do anchor peptides do?
They “anchor” peptides into the MHC binding groove.
What type of molecules do class I MHC proteins present?
Peptides derived from endogenous intracellular proteins.
What type of molecules do class II MHC proteins present?
Extracellular antigens or phagosomal pathogens
What cell types do class II MHC molecules present to?
CD4 T cells
What do MHC class III genes encode for?
Complement and inflammation proteins. These genes are within the MHC locus but are not expressed on MHC molecules.
What molecules are expressed on the MHC locus?
- Class I MHC genes
- Class II MHC genes
- Class III MHC genes
How many major classes of molecules are encoded on the MHC locus?
3
Do humans and mice have the same layout of MHC genes?
NOOOOO
How many sets of MHC class II genes do humans have?
Humans = 3 sets
How are allelic forms of MHC genes inherited?
They are inherited in linked groups called haplotypes.
How many haplotypes of MHC genes does every individual inherit?
One haplotype from each parent.
How are MHC alleles expressed?
Codominantly.
Both maternal and paternal MHC genes are expressed in offspring cells.
What is the benefit of codominant MHC expression.
It gives the best chance for an organism to have SOME capability of presenting all the possible antigen peptides it encounters.
What are the differences in the peptide binding domain between class I and II MHC molecules?
Class I = α1/α2
Class II = α1/β1
What are the differences in the nature of the peptide binding groove between class I and II MHC molecules?
Class I = Closed at both ends
Class II = Open at both ends
What are the differences in the size of bound peptides between class I and II MHC molecules?
Class I = 8 to 10 aa
Class II = 13 to 18 aa
What are the differences in the nature of the bound peptides between class I and II MHC molecules?
Class I = Extended structure in which both ends interact with MHC groove but middle
arches up and away from MHC molecule
Class II = Extended structure that is held at a constant elevation above the floor of the MHC groove
What are the differences in the motifs involved in peptide binding between class I and II MHC molecules?
Class I = Anchor residues at both ends of peptide; generally hydrophobic at carboxy-terminus
Class II = Conserved residues distributed along the length of the peptide anchor
How do MHC alleles affect transplants?
It can also make transplantation somewhat difficult, as humans are heterozygous at each locus.
Nonmatching MHC patterns will result in rejection of transplanted tissues.
The MHC region is …
polygenic.
MHC molecules present both ___ and
___ antigens.
intracellular and extracellular
Which class of MHC molecules presents self-proteins?
Class I
How can the immune system check if cells are self and generally healthy?
Class I MHC presents intracellular antigens.
Can show which cells have been infected with viruses or are abnormal and display those peptides on class I and activate CD8+ T cells.
Which class of MHC molecules help direct a response against threats?
Class II
Where is MHC class I expressed?
Throughout the body on all nucleated cells.
Where is MHC class II expressed?
Antigen presenting cells: macrophages, B cells, dendritic cells.
What kind of processing does MHC class I require?
Cytosolic or endogenous.
What kind of processing does MHC class II require?
Exogenous processing.
Describe the endogenous pathway of antigen processing and presentation. (sorry)
- Peptides are transported from the cytosol to the rough endoplasmic reticulum (RER)
- Transporter associated with antigen processing (TAP) molecules in the RER membrane move the fragments
- MHC class I molecules synthesized on ribosomes on the RER anchor in the RER membrane after their translation
MHC class I binding depends on how many amino acids?
As few as two amino acids.
What molecules help peptide/MHC class I assembly?
Chaperones
What trims long peptides to a suitable size for MHC class I grooves?
ER aminopeptidase ERAP1
Peptides are generated from internalized antigens in …
endocytic vesicles.
Where are MHC class II molecules produced and exported to?
Produced in the ER
Exported in vesicles to the Golgi
What is the function of invariant chain (Ii, CD74)?
- It guides transport of class II MHC molecules to endocytic vesicles.
- It prevents peptides from binding to the groove too early in the ER.
- It uses sorting signals to direct the MHC class II vesicles that contain molecules to endocytic compartments.
What is Ii (invariant chain) degraded to?
Class II-associated invariant chain (CLIP)
Where does degradation of Ii (invariant chain) occur?
In endocytic compartments by proteolytic activity.
What is the function of HLA-DM?
It exchanges CLIP out of the groove for a peptide fragment.
What happens in an MHC II late endosome?
The invariant chain is digested, leaving only a portion behind (CLIP).
Once the extracellular peptides enter that endosome, clip can be removed and the peptides can become bound to the MHC.
