Download Major Histocompatibility Complex (MHC)

Major Histocompatibility
Complex (MHC)
Department of Microbiology
Major Histo-compatibility Complex (MHC)
• Major Histocompatibility complex (MHC) is a cluster of tightly
linked genes (crossing over frequency is very low i.e., 0.5%)
• They code for protein molecules playing role in presentation of
processed antigen fragments and in discrimination between self and
non-self.
• Two main products encoded by MHC genes are MHC I and MHC II
molecules present on the cell surface and playing role in
presentation of antigen fragments to immune cells.
– Cluster of genes found in all mammals
– Its products play role in discriminating self/non-self
– Participant in both humoral and cell-mediated immunity
MHC I Molecule
• In general, MHC I molecules are present on all
nucleated cells.
• MHC I receptors are made up of two polypeptide
chains called alpha chain and beta-macroglobulin.
• α- chain is of 45 kDa whereas β-macroglobulin is
of 12 kDa in size.
• The alpha chain is encoded by genes of MHC I
where as β- macroglobulin is coded by genes
other than MHC.
MHC I Molecule
• The alpha chain is made up of 3 extracellular
domains i.e., α 1, α 2 and α 3 domains.
• The peptide binding clefts are formed by two
distal domains of α chain i.e., α1 and α 2
domains.
• This peptide binding cleft is close ended and
can bind to a peptide of 8-9 amino acids.
MHC I Molecule
• The antigen fragments loaded on MHC I molecules
are derived from processing of endogenous antigens.
• Endogenous antigens are antigens
synthesized within the cell itself .
that
are
• Examples of Endogenous antigens are normal self
antigens, altered self antigens (tumour antigens),
viral antigens etc.
• Note that the viruses utilize the host cell machinery
to produce viral proteins. Thus, viral proteins are
also considered as endogenous antigen.
MHC I Molecule
• The endogenous antigens
are
processed
through
“cytosolic pathway” of
antigen processing.
• The antigenic peptides
loaded on MHC I molecules
are presented to T cells
having CD8+ receptors.
• (CD 8+ positive cells are T
cytotoxic cells).
Cytosolic pathway of antigen processing
MHC II molecule
• In general, MHC II molecules are present especially
on professional antigen presenting cells (APCs) i.e.,
Macrophages, Dendritic cells and B cells.
• MHC II receptors are made up of two polypeptide
chains called alpha and beta-chains.
• α-chain is of 31 -34 kDa in size.
• β-chain is of 25-29 kDa in size.
MHC II molecule
• The alpha chain is made up of 2 extracellular
domains i.e., α 1, and α 2 domains.
• The beta chain is made up of 2 extracellular
domains i.e., β 1, and β 2 domains.
• The peptide binding clefts are formed by two distal
domains of α and β chains i.e., α1 and β1 domains.
• This peptide binding cleft is open ended and can
bind to a peptide of 18-20 amino acids in size.
MHC II molecule
• The antigen fragments loaded on MHC II molecules are
derived from processing of exogenous antigens.
• Exogenous antigens are engulfed by the cells from outside
and they are taken into vacuoles.
• The exogenous term is used with respected to the APCs
which performs the processing and presentation of antigen.
• The term generally includes bacterial antigens, parasitic
antigens and proteins released from even other self cells.
MHC II molecule
The exogenous antigens are processed
through “endocytic pathway” of
antigen processing.
The antigenic peptides loaded on
MHC II molecules are presented to T
cells having CD4+ receptors.
(CD 4+ positive cells are T helper
cells).
Endocytic pathway of antigen presentation
Major Histocompatibility complex in different
Species
• All vertebrates have MHC
(Gene clusters)
• MHC of different species
are named as shown in
table.
Species
MHC molecule
Human
Human Leukocyte antigen (HLA)
Cattle
Bovine Leukocyte antigen (BoLA)
Horse
Equine Leukocyte antigen (ELA)
Pig
Swine Leukocyte antigen (SLA)
Poultry
B
Dog
Dog Leukocyte antigen (DLA)
Organization of MHC gene
• Genes of MHC are organized in 3 groups:
– Class I MHC genes
• Encode for glycoprotein molecules expressed on the surface
of all nucleated cells
• Major function to present processed Antigens to TC cells.
– Class II MHC genes
• Encode for glycoprotein molecules expressed on M, B-cells,
DCs (mainly on professional APCs)
• Major function to present processed Antigens to TH cells
– Class III MHC genes
• Encode for secreted proteins that have immune functions. Ex.
Complement proteins, inflammatory molecules
• Do not play role in presentation of antigenic peptides
Organization of MHC gene in Human
• Class I MHC Genes Found In Regions A, B and C
(codes for α-chain of MHC I molecule).
(It is important to note that β-macroglobulin component of MHC I is not coded by
MHC genes)
• Class II MHC Genes Found In Regions DR, DP and
DQ (codes for both α and β chains of MHC II
molecule).
• Class III MHC codes for a few complement
components (C2, C4, factor B) and cytokines for eg.,
TNF-α and β
Organization of human MHC gene
MHC genes are polymorphic
• MHC Products Are Highly Polymorphic
– Vary considerably from person to person
• Crossing over frequency (0.5%) between MHC genes is very less.
• Thus, MHC alleles present on one chromosome tends to remain as
such and inherited as set.
• This set of MHC alleles is generally termed as “Haplotype”.
• Thus, a person have two haplotypes transferred from mother and
father.
• MHC Alleles Are Co-dominantly Expressed
– Both mother and father alleles are expressed.
MHC-peptide binding
• Binding of processed peptide with the MHC does not show high level of
specificity (as shown in antigen-antibody interaction or antigen-T cell
receptor interactions).
• Peptide of suitable size with certain amino acid residues at specific positions
may bind to the MHC molecule.
• For eg: Peptides that bind to MHC molecule I is found to be of 8-10 amino
acid.
• And all these peptides have specific amino acid residues that is essential for
binding to a particular MHC molecule.
• Such binding specificity exhibited by MHC molecules for peptides is known
as “promiscus” binding.
• It is estimated that one type of MHC molecule (molecules from one allele)
can bind to 2500 different types of peptide.
All these peptides of 9 aa in length can bind to
H-2Dd (MHC I molecule of mice).
In this example binding specificity is decided
by amino acid present at position 2, 3 and 9.
So any peptide of this size with Glycine,
Proline at 2nd and 3rd position and Leucine or
Isoleucine at 9th position can bind to this MHC
molecule.
MHC haplotypes and disease resistance
• MHC plays very important role in giving protection by presenting
epitopes against which immune response is protective.
• Thus, MHC alleles are important factor which determines
susceptibility or resistance against any infectious agent.
• For this reason MHC exhibit high level of polymorphism and
each allele binds to a different set of polypeptides.
• In cattle, BoLA-A*6 allele is associated with resistance to
mastitis.
• BoLA-DRB3.2*23 allele is associated with incidence of severe
coliform mastitis.
• Poultry: Resistance against Mareks disease is associated with
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THANKS
Class I And II Specificity
• Several Hundred Allelic Variants Have Been Identified In
Humans
• However, up to 6 MHC I And 12 MHC II Molecules Are
Expressed In An Individual
• Enormous Number Of Peptides Needs To Be Presented
Using These MHC Molecules
• To Achieve This Task MHC Molecules Are Not Very
Specific For Peptides (Unlike TCR and BCR)
• Promiscuous Binding Occurs
– A peptide can bind a number of MHC
– An MHC molecule can bind numerous peptides
Class I And II Diversity And
Polymorphism
• MHC Is One Of The Most Polymorphic Complexes
Known
• Alleles Can Differ Up To 20 a/a
• Class I Alleles In Humans: 240 A, 470 B, 110 C
• Class II Alleles In Humans: HLA-DR 350 , 2 !
• HLA-DR
–  genes vary from 2-9 in different individuals!!!,
– 1  gene ( can combine with all  products
increasing number of APC molecules)
• DP (2 , 2 ) and DQ (2 , 3 )
Structure of T Cell Receptor
Alpha
chain
Beta
chain
CHO
CHO
CHO
CHO
Variable region “V”
Constant region “C”
Hinge “H”
Disulfide bridge
+
+
+
Transmembrane region
Cytoplasmic tail
Structure of Class I MHC
α1
NH2
NH2
Alloantigenic
sites
α2
β2
NH2
COOH
CHO
Disulfide bridge
α3
Papain cleavage
Plasma membrane
OH
P
Cytoplasm
COOH
Structure of Class II MHC
NH2
NH2
CHO
α1
β1
CHO
α2
β2
CHO
Plasma membrane
Cytoplasm
COOH
COOH
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Histocompatibility (transplantation) antigens
Antigens on tissues and cells that determine their rejection when grafted between two genetically different
individuals
Major histocompatibility (MHC) antigens
Histocompatibility antigens that cause a very strong immune response and are most important in rejection
MHC complex
Group of genes on a single chromosome encoding the MHC antigens
HLA (human leukocyte antigens)
MHC antigens of man (first detected on leukocytes)
H-2 antigens
MHC antigens of mouse
Types of graft (figure 1)
Xenograft
Grafts between members of different species (also known as heterologous, xenogeneic or heterografts)
Allograft
Grafts between two members of the same species (also known as allogeneic or homograft)
Isograft
Grafts between members of the same species with identical genetic makeup (identical twins or inbred animals)
Haplotype
A group of genes on a single chromosome
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PRINCIPLES OF TRANSPLANTATION (figure 2)
An immunocompetent host recognizes the foreign antigens on grafted tissues (or cells) and mounts an immune
response which results in rejection. On the other hand, if an immunocompromised host is grafted with foreign
immunocompetent lymphoid cells, the immunoreactive T-cells in the graft recognize the foreign antigens on the
host tissue, leading to damage of the host tissue.
Host-versus-graft-reaction
The duration of graft survival follows the order, xeno- < allo- < iso- = auto- graft. The time of rejection also
depends on the antigenic disparity between the donors and recipient. MHC antigens are the major contributors
in rejection, but the minor histocompatibility antigens also play a role. Rejection due to disparity in several
minor histocompatibility antigens may be as quick or quicker than rejection mediated by an MHC antigen. As in
other immune responses, there is immunological memory and secondary response in graft rejection. Thus, once
a graft is rejected by a recipient, a second graft from the same donor, or a donor with the same
histocompatibility antigens, will be rejected in a much shorter time.
Figure 3 Graft versus host disease
Graft-versus-host (GVH) Reaction
Histocompatible lymphoid cells, when injected into an immunocompromised host, are readily accepted.
However, the immunocompetent T lymphocytes among the grafted cells recognize the alloantigens and, in
response, they proliferate and progressively cause damage to the host tissues and cells. This condition is known
as graft-versus-host (GVH) disease (figure 3) and is often fatal.
Common manifestations (figure 4) of GVH reaction are diarrhea, erythema, weight loss, malaise, fever, joint
pains, etc. and ultimately death.