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751212621

The document discusses the Major Histocompatibility Complex (MHC), detailing its role in immune response by presenting antigen fragments to T-cells. It outlines the structural differences between MHC Class I and Class II molecules, their pathways of antigen presentation, and the implications of MHC in autoimmune diseases and transplantation. Additionally, it highlights how various pathogens can manipulate MHC functions to evade host immune responses.

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5 views46 pages

751212621

The document discusses the Major Histocompatibility Complex (MHC), detailing its role in immune response by presenting antigen fragments to T-cells. It outlines the structural differences between MHC Class I and Class II molecules, their pathways of antigen presentation, and the implications of MHC in autoimmune diseases and transplantation. Additionally, it highlights how various pathogens can manipulate MHC functions to evade host immune responses.

Uploaded by

mc5gs9hr7f
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
Available Formats
Download as PPTX, PDF, TXT or read online on Scribd
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Antigen caplure by Loss of LC

Langerhans cells adhesivenes


(LC) s

Inflammatur
y
StoiuIuS

Migratio
n of
LC
›cn
ninur‹›

' Maturatio
n of
migrating
LC

I1OfJi
'
Activation
oi naive
T
lymphocytes
in draining
lymph
The immune system relies on
many regulatory mechanisms
that govern its ability to respond
to infectious agents and
neoplastic tissues, but no single
scheme is as much a cellular and
molecular
complex microcosm
biologic systems of as that
controlled by the Major
Histocompatibility Complex (Mhc).
The Mhc is a set of linked
genes, located on
chromosome 6 of the human,
chromosome 17 of the mouse,
and chromosome 20 of the rat,
that was first identified for its
effects on tumor or skin
transplantation and control of
immune responsiveness.
Although the control of
transplantation, autoimmunity, and
the other immune responses are
the phenotypic consequences of
the function of molecules encoded
in the Mhc, understanding the Mhc
becomes clear if we think of it in
molecular and cellular terms.
MHC molecules are cell surface receptors
that bind antigen fragments and display
them to various cells of the immune
system, most importantly T-cells that bear
up receptors.
The goal of this lecture will be to
the general principles of
outline
molecular organization and
function of both the genetic
regions that encode MHC
molecules and the functional
cell surface molecules
themselves.
A
The major function of the
molecules encoded by the
MHC is to facilitate the
display of unique
molecular fragments
on
the surface of cells
in an
B
arrangement that
permits their
The MHC
accomplishes
molecule ts major
role in

some cases
molecules)
nonpeptidic and the interaction
with T cells, usually via the ab
T-cell receptor (TCR).
The binding of peptides by
an MHC-I or MHC-II
molecule is the selective
event that permits the cell
expressing the MHC
molecule (the antigen-
presenting cell APC) to
sample either its own
proteins (in the case of
MHC-I) or the proteins
ingested from the
immediate
extracellular
environment (in the
case of MHC-II).
Class I
MHC Peptide-
binding cleft g Pride

u
2

§2
microglobul
in m
Transmembrane
region Disulfide
bond

lg domain
Class II MHC
—
Peptide-binding cleft Peptid
e

NN
§l

§2
Transmembra
ne region
D
is
ul
li
G C d
Class II are composed of 2 non-
covalen† associated peptides, a chain
and Ș chain.
The peptide binding clef† can
accommodate peptides up †o 30 amino
acids in leng†h.
C
Table 4-1. Features of Class I and Class ll MHC
Molecules

Polypeptide chains c‹ (44 47 kD) a (32-34 kD)


/2-MiCrogIobuIin (12 kD) § (29-32 kD)
Locations of o1 and a2 domains ‹x1 and §1 domains
polymorphic
residues
Binding site for c‹3 region binds CD8 §2 region binds CD4
T cell coreceptor
Size of Accommodates Accommodates
peptide-binding cleft peptides peptides
of 8-11 residues of 10-30 residues or
more
Nomenclature
Human HLA-A, HLA-B, HLA-C HLA-DR, HLA-DQ, HLA-
DP
Mouse H-2K, H-2D. H-2L
I-A, I-E
TH
1
Maciz›phage
acłivati‹xi:
d66tftJCłİ0fł 0ł
C0ł• Ph8g0Cyt050d
føț›e 8‹›ł›gef›

B T 2
œ
H
B c0lI antibgğysecretiori:
anybody binding to
antigæ
The MHC-I antigen presentation pathway is
most
easily thought of as an inside-out pathway by
which protein fragments of molecules
synthesized
by the cell are delivered to and bound by
the MHC- during its biosynthesis.
I molecule

In contrast the MHC-II antigen


presentation pathway is best more clearly
visualized as an outside-in one in which
ingested proteins are degraded by
enzymes in the endosomal— lysosomal
system and are delivered to the MHC-II
molecules in that degradative
The MHC-I and MHC-II molecules
show
also preferential restriction to T cells
of theor CD4-bearing subsets.
CD8-

This is related to the observation


binds to the nonpolymorphic o3 domain
that CD8
of molecules while CD4
interacts
membrane with domains of
proximal
There is little question
immune
that the system plays a decisive
role in host defense against
microbial pathogens, and it
should not have come as a
surprise to find that many
pathogens have the ability to
produce molecules that
modulate the host response.
The most striking results have been obtained
forviruses and MHC class I molecules.

(a) peptide binding to TAP (ICP47 of


herpes simplex) or peptide
translocation by TAP (US6 of human
cytomegalovirus);
(b) stable insertion of the class I heavy
chain into the ER membrane (US2
and US11 of human
cytomegalovirus and HIV vpu;
The most striking results have been obtained
forviruses and MHC class I molecules.

(c) release of assembled class I—


peptide
complexes from the ER (E19 of
adenovirus);
(d) inhibition of MHC class I heavy-
chain
gene transcription (adenovirus,
HIV);
(e) and
accelerated clearance of surface
class I
(HIV Nef).
The most striking results have been obtained
forviruses and MHC class II molecules.

Epstein-Barr virus produces a


that binds the human DR p chain.
molecule
The T-cell response to herpes
simplex in
unusual feature
humans has been of found
eliciting
to primarily
have
CD4+
cytotoxic
the cells, and not stimulating
much
in the way of a CD8+ CTL response.
The most striking results have been obtained
forviruses and MHC class II molecules.

Cells infected with herpes simplex


found
were to have a defect in the
stable
assembly of MHC class I heavy chain
—- Ș2m dimers and the export of
class I molecules to the cell surface,
which later was recognized to
resemble the situation in cells
lacking effective peptide import into
the ER as a result of mutations in
TAP-1 or -2.
The expression by the target cell of
class
MHC I molecules can, in certain
cases, protect the target from
killing by the NK effector events,
İ Ę' in
and target ceIIS çIĘ'fe¢ ]•V the
expression of normal MHC class I
cells are susceptible to such NK-cell
The genes encoding the chains of MHC
class I molecules and the and p
MHC class
chains of Il molecules are linked within
the
complex; the genes for Ș2-microgIobuIin
and invariant chain lie on separate
the
chromosomes.
Separate regions contain the genes
encoding the MHC class I and MHC class
II
molecules, and within these regions
there
are several genes for each chain.
-chain genes
called:

HLA-DR, -DP, and -


DQ.
The mechanisms of †issue damage in
autoimmune diseases are essentially
the
same as †hose †ha† opera†e in
pro†ec†ive
immunity.

Autoimmune responses are a natural


consequence of the open repertoires
of
bo†h B-cell and T-cell receptor †ha†
ellows †hem †o recognize any pe†hogen.
Juvenile Rhema†oid Ar†!
n. B27
• Another mechanism may by
through
†he binding of a
superan†igen
HSA matching be†ween †he donor and
-recipien†
a predictor of graf† survival in †he
kidney
allograft patient

HSA mis-matches mny cause chronic


pathologies in the allograft

I† is clear †ha† a negative HSA- A2


recipien†
receiving an allograf† expressing HLA-A2 wit
I ave a much higher
h risk of humoral
rejecti
the on vascular
of endothelium.

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