Lecture 10 - MHCs Flashcards
What type of molecules are MHC receptors
glycoproteins
an antigen fragment can trigger immune response only if it is
bound to an MHC molecule
What consequence does MHC control of antigen presenting have
determines animal’s susceptibility to infectious or autoimmune diseases
three classes of MHC gene loci
I, II, III
Genes in class I codes for
MHC I molecules that are present on all nucleated cells
Genes in class II codes for
MHC II molecules that are restricted to professional APCs
Genes in class III codes for
a diverse mixture of proteins, many of which are
important in innate immunity, such as complement proteins
MHC I distribution
most nucleated cells except mammalian red cells, gametes, neurons, trophoblast cells
MHC II distribution
B cells, macrophages, DC
MHC I function
present antigen to cytotoxic T cells
MHC II function
present antigen to T helper cells
MHC I result
T cell mediated toxicity
MHC II result
T cell mediated help
HLA
human leukocyte antigen
DLA
dog leukocyte antigen
BoLA
bovine leukocyte antigen
ELA
equine leukocyte antigen
H-2
mouse leukocyte antigen
B
chicken leukocyte antigen
MHC Class Ia
Expressed on most nucleated cells. Only polymorphic class I molecules
MHC Class Ib
Reduced expression and tissue distribution compared
with class Ia molecules. These bind to a limited range of ligands. Receptors for PAMPs
MHC Class Ic
MICA and MICB, involved in signaling to NK cells but do not bind antigenic peptides
MHC Class Id
bind to PAMPs
Structure of MHC class Ia molecule
2 long chains
MHC class Ia 2 chains
- long heavy a chain
- short B2-microglobulin chain
long heavy a chain
three extracellular domains; a transmembrane domain; a cytoplasmic domain
short β2-microglobulin chain
attached to the extracellular region of the heavy α chain
Where do small peptides bind on long heavy a chain
groove, antigen binding site formed by a1 and a2 domains
Heavy a chain is ____ while B2-microglobulin chain is ____
polymorphic; monomorphic
B2 microglobulin chain serves to
stabilize the structure
Peptides that bind to MHC I are
8-10 amino acids long; anchored at both ends and fit completely within the binding groove
The amino acids at each end of peptide must conform to
particular motif
Why can AA in middle of peptide be variable
do not interact with AA within the groove
MHC I molecules present _____ which are derived from proteins manufactured by or within the cell
endogenous peptides
Endogenous peptides can be
normal proteins or viral proteins if the virus is replicating inside the cell
Steps of the endogenous pathway of MHC I
1. ____ binds to the cytoplasmic protein and targets it to ____
2. ____ is a cellular organelle that is a hollow cylinder and ___ proteins into short peptides
3. _____ bind cytosoloic peptides from the proteasome and transport them to the _____ of the ____
4. Peptide is trimmed to 9 aa by the ____ and binds to an empty ____ in the ER
5. ____ move to Golgi and transported in ____ to cell surface. _____ available for recognition by ______ cell
- Ubiquitin, proteasome
- Proteasome; degrades
- Transporter for Antigen processing (TAP); lumen; ER
- ER resident aminopeptidase (ERAP), MHC I
- MHC I + peptide; exocytic vesicle; Antigen MHC I; CD8+ T cell
A normal cell displays about ____ loaded MHC I on its cell surface at any one time
100,000
Because of ____, different ___ of MHC are displayed at any one time
polymorphism; alleles
Why can MHC I on cell surface display samples of all endogenous proteins manufactured
each allele binds to a different peptide
MHC class II present only on
APCs
MHC II 2 chains
a and B chain
MHC II a chain
three domains - extracellular α1 and α2, a transmembrane domain and a cytosolic domain
MHC II B chain
three domains - extracellular β1 and β2, a transmembrane domain and a cytosolic domain
What chains form peptide binding groove on MHC class II
a1 and B1 chains
Peptides binding to MHC II
1. ____ of MHC II molecule is open
2. A peptide of 13-20 aa can be presented, with 9 aa ___ and rest ____
3. Around __ MHC II alleles must present ___; they are not very ____
4. They have broad aa requirements based on _____
- Peptide groove
- inside groove; protruding on sides
- 12; all antigens; specific
- charge, hydrophobicity
EXOGENOUS PATHWAY OF MHC II
1. ___ internalizes the antigen via ___ or ___.
2. ____ digest the antigen into short peptides.
3. MHC molecule is synthesized in the _____
4. _____ of MHC II come together and form a ___.
5. ____ fill the peptide groove while the MHC II is transported through the ___.
6. ____ of the RER fuses with the _____ containing the antigen peptides.
7. The ____ is partially digested leaving a small peptide ____.
8. CLIP is removed by ____, a peptide exchanger molecule, and antigen peptide binds to the ____.
9. MHC II with ____ is transported to membrane and presented.
- APCs; phagocytosis; endocytosis
- Lysozomal enzymes
- RER
- a and B chains; groove
- Invariant; golgi
- Exocytic vesicle; endosomephagolysosome
- invariant chain; CLIP (class II associate Ii peptide)
- DM; MHC II groove
- antigen in groove
What is MHC restriction
Only antigen fragments that can bind in the groove of a MHC molecule can trigger an immune response.
A foreign molecule that cannot bind to at least one MHC molecule will not
trigger an adaptive immune response
What determines susceptibility to infectious and autoimmune diseases
specific MHC alleles
MHC heterozygotes are at an advantage because
they can respond to a greater range of antigens
Why are there not more than 6 different MHC I and 12 different MHC II in an individual
increases risk that MHC molecules could bind and present more self antigens
No single MHC haplotype confers
major survival advantages on individual animals
BoLA-Aw7 linked to
resistance to bovine leukosis (bovine leukemia virus)
BoLA-A*16 linked to
resistance to mastitis
BoLA DR locus linked to
resistance to Dermatophilus sp.
ELA-A9 linked to
susceptibility to equine recurrent uveitis
ELA-A3, ELA-A15, ELA-Dw13 linked to
development of sarcoid tumors (likely induced by bovine papilloma virus)
Class I MHC present endogenous antigens
to CD8+ T cells
Class II MHC molecules present exogenous antigens
to CD4+ T cells
Class I MHC molecules present ___ antigens
endogenous
