Antigen Processing and Presentation Flashcards
(24 cards)
How does activation of lymphocytes in adative immune responses happen?
1) Ag presentation - T cells recognise epitopes from Ag processed and presented by APC
EITHER
2) T cells activates B cells to produce Abs
OR
2) T cells activates Cytotoxic T cells (CTLs)
3) CTLs recognise and kill target cells
How does T cells recognise Ags?
1) Specifically recognise Ags presented into groove of self MHC molecules
2) By Antigen Presenting Cells (APC)
How does the peptide binding site bind to many different peptides in MHCs?
1) MHC class I that present peptides are derived from intracellular proteins
2) MHC class II peptides presented are derived from exogenous proteins
What is MHC promiscuity?
Each MHC molecule can bind to numerous different peptides and peptides can bind to numerous MHC molecules
Why are TCRs and peptide known to be degenerate despite being highly specific?
1) Each TCR can recognise multiple peptides
2) TCR degeneracy (cross-reactivity) is potential causative factor for autoimmune diseases
What is the HLA region in chromosome 6?
1) MHC molecules are encoded by a cluster of genes
2) Polygeny - Class I: HLA-A, HLA-B, HLA-C
Class II: HLA-DP, HLA-DQ, HLA-DR
3) Maximum of 9 types of Ag presenting molecule allow interaction with wide range of peptides
What is MHC polygenism referring to?
Several MHC class I and class II genes encoding different types of MHC molecule with range of peptide-binding specificites
What is polymorphism?
1) Multiple alleles of same genetic locus, giving different dene products
2) MHC are most polymorphic proteins
Are MHC molecules co-dominantly expressed?
1) Yes
2) Genes in MHC are tightly linked and usually inherited in unit - MHC haplotype
What is a MHC haplotype?
1) We inherit 1 set of MHC alleles from each parent
2) Each set of alleles is referred to as haplotype
3) So individual inherits maternal and paternal haplotype - alleles co-dominantly expressed (both maternal and paternal MHC genes are expressed in same cells)
How is allelic variation shown within MHC molecule?
1) Occurs at specific sites
2) Allelic variability is clustered in specific sites within domains furthest from membrane (amino terminal domain)
3) Regions of highest variability are clustered in peptide binding groove
How does polymorphism in MHC affect peptide Ag binding?
1) Changes in pockets, walls and floor of peptide binding cleft alter peptide MHC interactions and determine which peptides bind
2) Products of different MHC alleles bind a different repertoire of peptides
Why do population need to express variants of each type of MHC molecule?
1) Population of microorganisms reproduce faster than humans
2) To counteract superior flexibility of pathogens - human populations possess variants of each type of MHC
3) Variant MHC may not protect every individual from every pathogen
4) However, existence of large no. of variants means that population is prevented from extinction
How are exogneous Ags uptaken?
1) Membrane Ig receptor mediated uptake
2) Complement receptor mediated phagocytosis
3) Pinocytosis
4) Fc receptor mediated phagocytosis
What is the exogenous pathway?
1) Cathepsin B, D and L proteases are activated by decrease in pH
2) Proteases produce around 24 aa long peptides from Ags
3) MHC Class II containing vesicles fuse with Ag containing vesicles, peptide is loaded and exported to cell surface
4) Cathepsin L degrades Invariant chain - CLIP blocks groove in MHC molecule
5) Newly synthesised MHC class II is translocated from ribosomes held by invariant chain to keep it stable and unable to bind peptides
What is the role of the invariant chain CLIP (Class II associated Invariant chain Peptide)?
1) Blocks MHC molecule binding site
2) Invariant chain stabilises immature MHC II by non-covalently binding
What is the process of making CLIP?
1) Invariant chain (li) binds in groove of MHC class II molecule
2) Ii is cleaved initially to leave fragment bound to class II molecule and to membrane
3) Further cleavage leaves short peptide fragment, CLIP, bound to class II molecule
How does HLA-DM and HLA-DR assist in removal of CLIP?
1) Resembles structurally an MHC II but cannot bind Ag
2) HLA-DM - Single pocket in ‘groove’ insufficient to accommodate a peptide
3) HLA-DR - multiple pockets in groove sufficient to accommodate a peptide
How does HLA-DM catalyse the removal of CLIP?
1) Replaces CLIP with peptide Ag
2) Discovered using mutant cell lines that failed to present Ag
3) Sequence in cytoplasmic tail retains HLA-DM in endosomes (cannot reach cell surface)
How does degradation in the proteasome happen?
1) Cytoplasmic cellular proteins, including non-self proteins are degraded continuously by multi-catalytic barrel shaped protease of 28 subunits
2) Defective/damaged proteins are targeted for proteasome recognition by covalent link with several copies of small peptide - ubiquitin
3) Proteasome recognise ubiquitin tag, cleaves proteins after hydrophobic and basic aas and release peptides into cytoplasm
What is the role of Transporter Antigen Processing (TAP)?
1) Transport of peptides across ER membrane
2) Transporter has preference for >8 aa peptides with hydrophobic C termini
How does MHC class I mature and load?
1) Calnexin binds to nascent class I alpha chain until beta2-M binds
2) beta2-M binds and stabilises floppy MHC
3) Tapasin, calreticulin, TAP 1 and 2 form complex with floppy MHC
4) Cytoplasmic peptides loaded onto MHC and structure becomes compact: MHC-peptide sent to cell surface
What are BCRs?
1) B cells receptors
2) BCRs are membrane-bound Abs (mAbs)
3) B cells are APC - Antigen Presenting Cells
4) They process and present Ags to T cells
What is linked recognition?
1) Th cell is activated by the same Ag (not necessarily same epitope) that is recognised by B cell and provides ‘help’ to B cell activation
