Download MHC class II Pathway

IMMUNOLOGY
LectureMajor Histocompatibility Complex(MHC) and organ
Transplantation
By
Dr.Sana'a Khudhur
Major Histocompatibility Complex(MHC)
The major histocompatibility complex (MHC) :is a locus on a
chromosome 6 comprised of multiple genes encoding histocompatibility
antigens. MHC is also called human leukocyte antigen (HLA).
Important properties of MHC
1-Cluster of genes found in all mammals.
2-Its products play role in discriminating self/non-self.
3-Participant in both humoral and cell-mediated immunity.
4-MHC Act As Antigen Presenting Structures.
5-In Human MHC is Found on Chromosome 6 referred to as HLA
complex.
6- MHC genes are highly polymorphic.
7-Bind peptide: recognized by T cells: Th__MHCII , Tc__MHCI.
8- MHC structure determined by X-ray crystallography.
Human HLA Gene Complex
In man, the MHC locus is designated as HLA (Human Leukocyte Antigen).
HLA=Human Leukocyte Antigen.
Genes Of MHC Organized In 3 Classes (figure 1)
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Class I MHC genes
1-Glycoproteins expressed on all nucleated cells.
2-Major function to present processed Ags to TC .
3-The Class I region consists of HLA-A, HLA- B, and HLA-C loci.
Class II MHC genes
1-Glycoproteins expressed(found on the surface )on
professional antigen presenting macrophages( M), B-cells,
Dentritic cells (DCs), langerhans cells.
2- The Class II region consists of the D region which is subdivided into HLADP, HLA-DQ, and HLA-DR sub regions (several HLA-D loci determine the
class II MHC proteins i.e. DP, DQ and DR).
3-Major function to present processed Ags to TH.
4-Helper T-cells recognize antigens on antigen-presenting
cells only when the antigens are presented on the surface
of cells in association with class II MHC.
5-Class II antigens react with the CD4 molecule on the
helper T-cells which secrete cytokine.
Class III MHC genes
Products that include secreted proteins that have immune
functions. Ex. Complement system, inflammatory molecules. Class III
molecules are encoded by genes located between those that encode class I
and class II molecules.
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Table 1:Human HLA complex
MHC Genes Are Polymorphic
Inherited as 2 sets (one from father, one from mother):
1-Haplotype refers to set from mother or father.
2- MHC Products Are Highly Polymorphic.
3-Vary considerably from person to person .
Inheritance Of HLA Haplotypes
MHC protein
MHC class I protein molecule
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MHC I occurs as an α chain composed of three domains—α1, α2, α3. The
α1 rests upon a unit of the non-MHC molecule β2 microglobulin . The α3
subunit is transmembrane, anchoring the MHC class I molecule to the cell
membrane(figure 1).
Figure1: MHC class I protein
molecule
MHC class II protein molecule
MHC II is formed of two chains, α and β, each having two domains—α1
and α2 and β1 and β2—each chain having a transmembrane domain, α2
and β2, respectively, anchoring the MHC class II molecule to the cell
membrane.The peptide-binding groove is formed of the heterodimer of α1
and β1(figure 2).
Figure 2: MHC class II
protein molecule
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MHC Class III
Class III molecules have physiologic roles unlike classes I and class II, but
are encoded between them in the short arm of human chromosome 6. Class
III molecules include several secreted proteins with immune functions:
components of the complement system (such as C2, C4), cytokines (such as
TNF-α and heat shock proteins (hsp).
Antigen processing and presentation
Antigen processing:
Proteolytic cleavage of proteins into small fragments(antigen peptides)
that can bind to MHC molecules on antigen presenting cells.
Antigen presentation: Presentation of antigen peptides to T cell receptor
on T cells. Different antigen degradation and processing pathways produce
MHC-peptide complexes.
Peptides are processed and presented by two classical pathways:
Endogenous” peptides associate with Class I molecules.All nucleated cells are
able to present with Class I.

In MHC class I any nucleated cell normally presents cytosolic
peptides, mostly self peptides derived from protein turnover and
defective ribosomal products.

During viral infection, intracellular microorganism infection, or
cancerous transformation, such proteins degraded in the proteosome
are as well loaded onto MHC class I molecules and displayed on the
cell surface.
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MHC class I pathway:
Proteins in the cytosol are degraded by the proteasome, liberating
peptides internalized by TAP channel in the endoplasmic reticulum, there
associating with MHC-I molecules .
MHC-I/peptide complexes enter Golgi apparatus, enter secratory vesicles,
fuse with the cell membrane, and externalize on the cell membrane
interacting with T lymphocytes( figure 3,4).
Figure 3: MHC class I pathway
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Figure 4: MHC class I pathway
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MHC class II Pathway
“Exogenous” peptides associate with Class II molecules
Only specialized APCs may present with Class II, such as macrophages, B
cells and dendritic cells, and thymic epithelial cells.
In MHC class II phagocytes such as macrophages and immature dendritic
cells uptake entities by phagocytosis into phagosomes which fuse with
lysosomes whose acidic enzymes cleave the uptaken protein into many
different peptides interaction with the particula. These are trafficked to and
externalized on the cell surface(Figure 5).
Figure 5: MHC class I I pathway
Biologic importance of MHC
1-Role in immune response through MHC Restriction
MHC Restriction
MHC restriction means that different T cells are restricted to either Class I or
Class II MHC antigens The T cell receptor will recognise a peptide only
when it is bound to a particular MHC molecule(Figure 6).
 Cytotoxic T cells are restricted to Class I antigens present on nucleated
body cells, thus play a role in protecting against virus-infected cells or
cancerous cells.
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 Helper CD4 cells are restricted to Class II MHC antigens present on
immune cells, thus play a role in increasing the humoral immune
response and protecting against bacterial,parasitic infection and toxin.
exogenous pathway
endogenous pathway
B cell help
CD4 T
CD8 T
TcR
MHC I
ab
CD8
TcR
CTL
kill
CD4
MHC II
pathogen
virus-infected or
tumor cell
Macrophage or other
professional APC
MHC I restriction
MHC II restriction
Figure 6: MHC restriction
3-Role in organ transplantation,the success of organ transplantation
determind by the compatibility of the MHC genes of the donor and
recipient.
4-MHC gene and proteins important in autoimmune disease which occur in
people who carry certain MHCgene.
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Transplantation and Graft Rejection
Types of grafts
1) Autografts :
The transfer of an individual’s own tissues from place to place e.g.
Skin grafts (regularly accepted).
2) Isografts :
Transfer of tissues between genetically identical personse.g.
Identical twins ( accepted permanently).
3) Allografts (homograft):
- Transfer of a graft between genetically different members of
same speciese.g from one human to another.
- Rejection occur if donor and recipient are not matched.
4) Xenograft (heterograft):
- Transfer of tissues between different species
- Always rejected
Transplant rejection
The rapid and very potent cell-mediated immune response to
the transplanted tissue results from a large number of T cells that
are specifically reactive to non-self.
Mechanism Of Graft Rejection
1) Both TH and TC are activated
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- TC cells destroy graft cells by direct contact
-TH cells secrete cytokines that attract and activate
macrophages, NK cells and polymorphs leading to cellular
infiltration and destruction of graft (Type IV)
- B cells recognize foreign antigens on the graft and produce
antibodies which bind to graft cells and:
. Activate complement causing cell lysis.
. Enhance phagocytosis, i.e. opsonization (Type II).
. Lead to ADCC by macrophages, NK,PML(Type II).
-Immune complex deposition on the vessel walls induce platelets
aggregation and microthrombi leading to ischemia and necrosis of
graft (Type II).
Types Of Graft Rejection
1) Hyperacute rejection:
- It occurs hours after transplantation
- In individual with preformed antibodies either due to - blood groups
incompatibility or previous sensitization by blood transfusion, previous
transplantation
2) Acute Rejection:
- It occurs 10 to 30 days after transplantation
- It is mainly T-cell mediated
3) Chronic or late rejection:
- It occurs over a period of months or years.
- It may be cell mediated, antibody mediated or both.
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Graft Versus Host (GVH) Reaction
Immunologically competent graft is transplanted into an
immunologically suppressed recipient (host).
The grafted cells survive and react against the host cells
i.e instead of reaction of host against the graft, the reverse occurs.
* GVH reaction is characterized by fever, pancytopenia, weight loss, rash ,
diarrhea, hepatsplenomegaly and death
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