Major Histocompatibility Complex Flashcards
What does MHC stand for?
Major Histocompatibility Complex
Lymphocytes (B and T cells) are
‘adaptive’ immune cells
b and t cells are life […]
life long
what percentage pf leukocutes are Lymphocytes?
20 -40 % of total leukocytes
Prior to interactions with antigen, lymphocytes are…
… naive
Immature B and T cells are
… small, motile non
phagocytic cells and morphologically
identical (although each has a unique receptor)
Prior to interactions with antigen (naïve), lymphocytes are in…
… G0 (quiescent) but can be induced into cell cycle via Ag stimulation
As they progress through cell-cycle they
proliferate and differentiate
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Lipids / nucleic acids need to be
linked to proteins or polysaccharides to be immunogenic
Proteins are the most
potent immunogen
WHAT MAKES A GOOD IMMUNOGEN?
1) Foreigness
2) Molecular size
3) Chemical composition
4) ABility to be recognised.
Describe foreigness of immunogens?
must be recognised as non-self (B and T cell are educated to recognise ‘self’
whats the best molecular size?
> 100 kDa best; 5 – 10 kDa poor
B and T cells differ in …
… antigen recognition
describe chemical composition of immunogens?
homopolymers
copolymers (2 different amino acids)
B cells interact with soluble (and processed) antigen via…
… the B cell receptor
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epitopes must be …
… accessible as Ag may be free in solution
T cells interact with
internally processed Ag (peptide associated with MHC molecules on the surface of antigen presenting cells - APC or ‘altered-self’ cells.
Thus T cells must be…
… shown processed antigen to become activate
Two classes of T cells (broadly)…
T cytotoxic cells (CD8 +)
T helper cells (CD4+)
T cytotoxic cells (CD8+) function?
they are killer cells involved in Ag-specific cell killing of altered self cells.
T helper cells (CD4+) function?
secrete cytokine - coordinate immune response
what is required for t cell activation?
Complex ligand-receptor integrations at the T cell plasma membrane
are required for T cell activation (immunological synapse)
go look at slide 7
what is the Cluster of Differentiation (CD molecules)?
Categorisation scheme of
cell surface molecules
(glycoproteins)
how many cd molecules curntly found?
371
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Cluster of differeitation allows for…
…the identification
of leukocyte subsets
fluorescent conjugated
CD specific antibodies label
cells that express a
particular CD molecule
(immunophenotype)
where is CD3 expressed?
on t cell surface
what is cd3
the signalling component part of the T cell receptor complex
what is CD4
co-receptor for MHC-II expressed by T helper cells
What is CD45
common leukocyte antigen
What is CD8
co-receptor for MHC-I expressed by T cytotoxic cells
what is CD19
B cell receptor component
What is CD25
interleukin-2 (IL-2) receptor
when is cd25 upregulated?
up-regulated during activation
MHC are
polymorphic antigen (Ag) presenting proteins
MHC are polymorphic antigen (Ag) presenting proteins but and are
cell markers of self
MHC bind
processed Ag at the cell surface for t cells to recognise
t cells require the presentation of
processed antigen for activation
how amny classes of mhc
MHC-I
MHC-II
where are MHC-I present?
on almost all nucleated cells
what do MHC-I present?
present endogenous peptide to T
cytotoxic cells (CD8+)
what do MHC-II present?
present exogenous peptide to T helper cells (CD4+).
Structurally homologous both have a
peptide binding groove
Where are MHC-II present?
present on APC
(antigen presenting cells)
MHC class-I are present on all..
… nculeated cells.
MHC class-I presents…
…endogrnous peptide which includes self, altered self (malignant( and viral (allows infected cells to be detected).
MHC-I binds
CD8 molecules on T cytotoxic cells.
MHC I how many sub units?
two sub-units (α & β chains)
Biding cleft α1-α2 can bind
peptide 8-13 residues
mhc class 1 has a
β2-microglubulin
MHC class 2 is present on
antigen presenting cells
Alpha-chain has …
… three extra cellular domains. a1 a2 and 3 with a transmembrane segment and cytoplasmic tail
mhc 2 binds
cd4 molecules on t helper cells
mhc class 2 presents
exogenous peptide from bacteria / yeast
MHC-II binds CD4 molecule on T helper cells
which produce…
cytokine, inflammatory response and stimulates Ig
class switching in B cell
mhc class 2 how many subunts
two subunits ( a and b chains)
in mhc 2, alpha and beta chains have two
extra cellular domains (a1 / a2. and b1 / b2 with transmembrane segments and cytoplasmic tails.
Biding cleft α1-β2 can bind
peptide 12-18 residues
(open ended)
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MHC polymorphisms alters
the peptide / MHC affinity creating stronger or weaker
interactions
peptide / mhc association is
degenerate
Integrations within the
cleft are:
- Dipole-dipole
- Hydrogen bonding
- London dispersion
- Hydrophobic
residue alteration can alter…
… complementary sticky
patches at key areas
certain MHC alleles are assoicates with and increase risk of
certain disease including viral infections and autoimmune disease
Certain MHC alleles are associates with and increased risk of certain
disease including viral infections and autoimmune disease
Give some examples of this?
- HLA-DR4associated with rheumatoid arthritis & type-1 diabetes
- HLA-DQ2associated with increase risk of coeliac disease
- HLA-DQB1associated with narcolepsy
- HLA-B57associated with greater HIV control (slower progression)
Lack of outbreeding in cheetah
populations predispose to
viral disease (limited MHC polymorphism)
Tasmanian devil transmissible facial
tumour
- rare example of …
…transmissible tumour, transmitted by biting
MHC genes are coded by
… the Human Leukocyte Antigen (HLA) complex
gene cluster at Ch.6 p21.1 to p21.3 .
what are the most variable regions of HLA loci?
HLA-B and HLA-DRB1
The HLA locus contains:
MHC-I genes: (A, B and C)
MHC-II genes: (DP, DQ and DR)
MHC-III genes: (some complement proteins and
cytokines)
DR = ?
antigen presenting
DP and DQ are involved
with
antigen processing
HLA antigen are co-dominant = both
maternal and paternal alleles are expressed
MHC genetic diversity is
inherited (no somatic recombination)
becaue MHC gene are closely linked
the chances of genetic crossover are rare (meiosis)
Thus class-I and class-II
MHC genes are
inherited together (linked).
-> haplotype
We each express how many MHC-I alleles?
We each express six MHC-I alleles (HLA-A, HLA-B and HLA-C from each
parent)
MHC genes are closely
linked
In organ / tissue transplantation MHC act as antigen, thus donor and recipient need to be
matched
In organ / tissue transplantation MHC act as
antigen
HLA-A, HLA-B and HLA-DR compatibility is
assessed before donation
we each express ow many MHC-II alleles?
six to eight MHC-II (HLA-DP, one HLA-DQ and one or two HLA-DR from each parent
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Antigen is presented at
the cell surface via MHC molecules
what do intracellular processes do?
Intracellular processes cleave protein into peptide fragments, which
associate with MHC and is presented at plasma membrane
Intracellular processes cleave protein into peptide fragments, which
associate with MHC and is presented at plasma membrane.
What then?
Two major peptide antigen process mechanisms occur
Endogenous antigen
processing occurs in
all nucleated cells; couples
peptide to MHC-I for CD8 T cell presentation
Exogenous antigen
+ processing occurs in…
APC; couples peptide to MHC-II for CD4+ T cell presentation
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In ER the MHC-II molecule is
complexed with the ‘invariant chain’ in the
peptide binding cleft (MHC-II li)
In ER the MHC-II molecule is complexed with the ‘invariant chain’ in the peptide binding cleft (MHC-II li).
What the purpose of this?
prevents binding of endogenous peptide
Invariant chain is
cleaved creating MHC-II CLIP complex
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There are several crucial points of interaction for …
… MHC-II / peptide compelx (anchor points)
position 4 must have
a negative charge
position 9 must be
hydrophobic
peptide binding to MHC-II is
degenerate
Negatively charges and
hydrophobic anchor points are…
… alligned
Exogenous antigens arise from…
… intracellular pathogens (virus, tumour, antigen)
Self or viral antigen – these are degraded in
… the proteosome
MHC-I / peptide complex brought into
ER
MHC-I / peptide complex brought into via protein called
TAP
MHC-I / peptide complex brought into via protein called TAP.
Then,
loaded onto MHC I molecule and exported to plasma membrane (cell surface),
MHC-I / peptide complex brought into via protein called TAP.
Then, loaded onto MHC I molecule and exported to plasma membrane (cell surface),
Then,
… presented to T cell
Endogenous peptides enter ER via
Transport associated with Antigen Processing (TAP) protein
MHC-I in ER is associated with
calreticulin and tapasin proteins which act as chaperones for peptide loading
Once peptide is loaded, MHC-1 and peptide complex are
… exported to the plasma
membrane
This process occurs in all
nucleated cells
CD8+ T cell presentation
what is the Endogenous Antigen Processing and Presentation process
1) A peptide delivered by TAP binds to the class I heavy chain, forming the mature MHC class I molecule
2) The class I molecule dissociates from calreticulin, tapasin, and TAP and is exported from the endoplasmic reticulum
The anchor points for MHC-I are..
…. better define (set rules)
MHC I postion 2 must be
charged (N term)
MHC I posiiton 9 must be
hydrophobic (C term)
Degenerate peptide binding to
MHC-I
Are MHC-II open or closed ended?
open ended
Unlike MHC-II (open-ended) MHC-1 are
closed-ended
Second (N-term) and last (C-term) residues of the peptide must be
charged and hydrophobic (8mer and 9mer fit cleft perfectly)
Larger peptides (11mer
13mer) cause
a bulge in the middle
The larger the peptides are the greater the…
… steric hindrance with respect to TCR interaction
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