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11. Antigen Processing and Presentation

11. Antigen Processing and Presentation TSOM- Term 3, Unified Exam 2
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what is the difference between recognition of processed antigen in T cells and B cells?
Unlike B lymphocytes, T lymphocytes recognize processed antigen in a context of epitope MHC molecules
What is the MHC I molecule composed of?
a single polypeptide chain plus a non MHC protein called the β2 microglobulin
are MHC I and β2 microglobulin coded for in the same DNA region?
no
what is the MHC II composed of?
2 polypeptide chains
α and β chain
how many coding regions are there for MHC II and what do they contain?
3 coding regions within MHC II loci:
each on contains gene coding for an α chain and one gene coding for a β chain
what are the domains of the MHC-I molecule?
there is one transmembrane heavy α chain with 3 domains:
α1, α2, α3
noncovalently bound to β2 microglobulin
the peptide binding cleft of the MHC class I is formed by what?
α1 & α2 domains
the extracellular region of MHC-II has how many domains?
each chain has 2 domains:
α1, α2 / β1, β2
which protein domains of the MHC-II molecule are involved in binding of the antigenic peptide?
α1
β1
what are the MHC gene products in humans called?
Human Leukocyte Antigen (HLA)
where are the MHC genes present?
Chromosome 6
what is the difference between achieving variability in BCR/TCR and in MHC?
in BCR/TCR variability is achieved in each individual by gene segments.
MHC variability is achieved by having multiple alleles
how many loci for each class of MHC does an individual have?
3
what are the loci found in MHC class I genes?
HLA.A
HLA.B
HLA.C
what are the loci found in MHC class II genes?
HLA.DP
HLA.DQ
HLA.DR
what is the variability of alleles for MHC gene loci?
each locus exists in several alleles in the human population
are MHC genes more or less stable than BCR genes?
more stable
they do not undergo somatic recombination like BCR or TCR
do MHC genes undergo somatic recombination?
No
draw the gene map of HLA on chromosome 6
how many loci does MHC I have?
6
how many of the MHC-I loci are polymorphic and involved in antigen presentation?
3
which MHC-I loci are highly polymorphic and involved in antigen presentation?
A
B
C
how many loci does MHC-II have?
6
how many MHC-II loci are polymorphic and involved in antigen presentation?
3
which MHC-II loci are polymorphic and involved in antigen presentation?
DP
DQ
DR
how many alleles are known for the MHC I loci?
A- 506
B- 872
C- 274
how many alleles does HLA DRA exist as?
2
how many alleles does HLA.DRB exist as?
>500
how many alleles exist for HLA DQA?
25
how many alleles exist for HLA DQB?
66
how many alleles exist for HLA DPA?
15
how many alleles exist for HLA DPB?
114
what is the inheritance and expression of the HLA locus?
each person has 2 copies of each locus (maternal + paternal) and both are expressed
what is the relationship of the expression of the alleles of MHC genes?
expression of HLA genes is codominant
how many of the HLA loci are expressed in an individual?
all loci are expressed in an individual
do people have the smae genes for HLA?
HLA loci is highly polymorphic, unlikely that 2 individuals will have the same genes for all the alleles
how many genes are there for HLA-DRA?
single gene, 2 alleles
how many genes are there for HLA-DRB?
4:
DR1
DRB3
DRB4
DRB5
most people have which HLA DR gene?
DRB1 only
some may have others
what is the tissue expression of MHC-I molecules?
unless there is a genetic defect, every individual expresses the protein product of each of these genes on the surface of all cells in the body (except RBC)
on which cells are MHC-1 not expressed?
RBC
what is the tissue expression of MHC-II ?
expressed primarily on antigen presenting cells:
-macrophages
-dendritic cells
-B Cells
when can MHC-II be expressed somewhere other than antigen presenting cells?
under certain conditions like stimulation by cytokines
what is the relationship between the expression of MHC-I and MHC-II?
MHCI and MHCII are expressed codominantly
what does MHC I present antigen to?
CD8 T cells
what does MHC II present antigen to?
CD4 T cells
where does CD8 bind MHC-I?
α3 domain of MHC-I
where does CD4 bind MHC-II?
CD4 binds to the β2 domain of MHC-II
how does MHC bind to different kinds of peptides?
not all peptides bind to MHC
Different MHC alleles bind to different peptides
what is the consequence of individuals having different MHC alleles?
may not respond to infections in the same way
what is the function of dendritic cells as APC?
present antigen to naive T cell
priming of T lymphocytes
what is the function of activated macrophages as APC?
present antigen to effector T cells (Th1)
what is the function of B-lymphocytes as APC?
present antigen to effector T cells (Th2)
what is the role of antigen presenting cells?
1. they capture and process antigens for presentation to T lymphocytes
2. they produce signals (cytokines) required for the proliferation and differentiation of lymphocytes
what is endogenous antigen derived from?
a pathogen multiplying inside the presenting cell- such as when the pathogen is intracellular- multiplying in the cytoplasm
what are some endogenous antigens?
viral antigens
tumor antigens
how are endogenous antigens presented and recognized?
via MHC I molecules and are recognized by CD8+ T lymphocytes
what are exogenous antigens?
they originate outside and are taken up by the presenting cell when extracellular pathogens are engulfed and killed inside phagolysosomes
how are exogenous antigens presented and recognized?
they are presented via MHC II molecules and are recognized by CD4+ T lymphocytes
what are the steps of exogenous antigen processing and presentation with MHC-II?
1. microbes engulfed and placed in phagosome
2. lysosomes fuse with the phagosome forming phagolysosome.
3. protein antigens from the microbe are degraded by proteases into 10-30 aa peptides
4. MHC-II synthesized in ER. invariant chain li (CD74) attaches to peptide binding groove of MHC-II molecules.
5. MHC-II molecules with bound li chain are now transported to the Golgi complex
6. Glogi places li-bound MHCII into vesicles
7. MHCII containing vesicles fuse with peptide containing phagolysosomes. li chain is removed and peptides are free to bind grooves of MHC-II
8. MHC-II molecules with bound peptides are transported to the cytoplasmic membrane where they become anchored
what is the purpose of invariant chain li/CD79?
attaches to the peptide binding groove of the MHC-II molecules so as to prevent peptides designated for binding to MHC-I molecules in the ER from attaching to MHC-II
Invariant chain li is cleaved to what and what happens next?
invariant chain li is cleaved to CLIP (class II associated invariant peptide).
processed peptide fragments are substituted for the CLIP proteins in the MHC II groove
what are the steps of endogenous antigen presentation by MHC-I?
1. endogenous antigen or phagocytosed exogenous antigen in the cytoplasm:
2. degradation by ubiquitin proteasome. ubiquitin protects the epitope from degradation.
3. peptides are transported into RER by TAP
4. peptides bind newly synthesized MHC-I
5. RER transports MHC-I+Peptide to Golgi
6. Golgi transports MHC-I+Peptide complex via exocytotic vesicle to cytoplasmic membrane where it becomes anchored.
What is TAP and what is its structure??
Transporter associated with Antigen Processing:
heterodimer of TAP1 and TAP2 chains
what does ubiquitin do in antigen presentation?
tags the foreign antigen for destruction and ensures production of epitopes
the major histocompatibility complex comprises what?
a stretch of tightly linked genes on chromosome 6 known as HLA genes
what are the protein components of MHC-I?
glycoprotein α chain with 3 extracellular domains and a transmembrane segment
single domain β2-microglobulin
MHC class II is composed of what?
2 non covalently associated glycoproteins, the α & β chains, coded by separate MHC genes
how are MHC gene products expressed?
co-dominantly
what is required for recognition by T cells and induction of an adaptive immune response?
antigens must be presented in the context of an MHC molecule
how are endogenous antigens processed/
via proteasomes, translocated into the ER via TAP proteins, then loaded in MHCI molecules in the ER before transport and presentation on the plasma membrane via the Golgi apparatus
how are exogenous antigens processed?
via hydrolytic enzymes in phagolysosomes then loaded in MHC molecules after fusion with MHC vesicles