3. • Difficulty during transplantation…rejection
• Immune responses: antibody formation, TH, CTL
• Highly polymorphic √
• Bind peptide…….. recognized by T cells
4. • Are self antigen (autoantigen)
• Found on all cells of nucleated humans and all
• Discovered during transplantation experiment in mice
– Transplanted organ is accepted sometimes (genetically the
same) and rejected some other time (genetically different)
– The answer was given by George Snell: the tissue of donor and
recipient are incompatible
– Closely related gene: Major histocompatibility complex (MHC)
5. MHC Genes
The human MHC genome is called HLA (Human
Leukocyte Antigen-HLA)….tightly linked cluster of genes
The mouse MHC genome is H-2.
• MHC class I = HLA-A, HLA-B & HLA-C
• MHC class II = HLA-DP, HLA-DQ, &HLA-DR (D region)
• MHC class III = Complement factors C2, C4,&
• Genes encoding in this MHC III do not play any
role in antigen presentation.
6. MHC is Polygenic and Polymorphic
It is polygenic because it has several genes for each
class (3 for class-I, 6 for class-II).
It is polymorphic due to the relatively large number
of alleles within each MHC class within the species.
9. Importance of MHC polymorphism
• Polymorphism and polygeny
– is the generation of a highly diverse repertoire of
MHC molecules capable of presenting a large variety
of Ag peptides to T cells
10. MHC gene inheritance to offspring
• Most individuals are heterozygous in terms of MHC
• For each MHC genes every individual inherits one
MHC allele from each parent, maternal and paternal.
• The MHC molecules are expressed co-dominantly
• In any mating, four possible combinations of
haplotypes can be found in the progenies, for each
11. Classification and structure of MHC
• 2 types of polymorphic genes, the class I and II
encodes two groups of structurally distinct but
• MHC class-I is made up of two polypeptide
chains: One large called and one small called
2 microglobulin, it is not polymorphic.
• The chain has 3 extracellular domains (1, 2
& 3), a transmembrane and a cytoplasmic
12. The 1 and 2 domains form a cleft where the
Ag fragment of antigen binds.
The 2 microglobulin has only one
No transmembrane portion
No cytoplasmic tail
Immunoglobulin-like region: highly
conserved α3 domain - site to which CD8 on T
cell binds 12
15. MHC Class-II molecules
o Composed of two polypeptide chains and .
o Each chain has two extracellular domains 1 2
and 1 and 2
o A transmembrane segment
o A cytoplasmic tail
o The 1 and 1 domains form the cleft for the Ag
oImmunoglobulin-like region – conserved α2 and β2
domains – β2 is site to which CD4 on T cell binds 15
19. Class I or II MHC: Interaction with Peptides
• Has a broad specificity
• Has a single peptide binding cleft
• The peptide sequences that bind to MHC molecules are
distinct from those recognized by T cells
• The affinity of peptide-MHC interactions is much lower
than that of antigen-antibody binding
• Peptide-MHC complexes persist long due to low rate of
• MHC molecules don’t discriminate between self and non
20. Genomic of MHC molecules
In Humans, MHC is located on the short arm of
chromosome 6 and -2 Microglobulin is encoded by a gene
on chromosome 15
MHC of human occupies ~3500kb
• MHC-I are in the most telomeric region and MHC-II
are in the most centromeric region of HLA locus
• Other genes in the class II locus
-TAP 1 and 2
- subunits of a cytosolic protease complex (Proteasome)
22. •MHC class III = Between class I and II gene
• Complement factors C2, C4,& Factor B
• Genes encoding in this MHC III do not play
any role in antigen presentation
23. Expression of MHC molecules
• MHC-I expressed on all nucleated cells
• MHC-II expressed on APCs: Macrophages, B cells and Dendritic cells
• Expression of MHC molecules is increased by cytokines!!
produced during innate and adaptive immune responses
Interferon , , , Tumor necrosis factor (TNF) and
lymphotoxin increases expression of class I molecules
Interferon : stimulates expression of class II molecules??
26. Both of them have a peptide-binding groove with a
wall of 2 α helices and a floor of 8 β-pleated sheets
Close-ended groove for class I MHC requires an 8-10
amino acid-length peptide to bind
Open-ended groove for Class II MHC lets it bind a
peptide 13-25 amino acids long
Peptide-binding site for MHC-I and MHC-II are
28. Properties of MHC
o are membrane-bound, recognition by T cells
requires cell-cell contact.
o Peptide/antigen from cytosol attach to class
I MHC and is recognized by CD8+ cells.
o Peptide from vesicles associates with class
II MHC and is recognized by CD4 cells.
29. o Though there is a high degree of polymorphism
(MCH) for a species, an individual has maximum
of six different class I MHC products and maybe
more class II MHC products (12).
o Antigen must associate with a given MHC of that
individual, otherwise no immune response can
30. o Mature T cells must have a T cell receptor that
recognizes the peptide associated with self MHC
o Each MHC molecule has only one binding site
o Different peptide/antigen can bind a given MHC
o All bind to the same site, but only one at a time.
31. o MHC polymorphism is determined at germline.
There is no recombinational mechanism for
o Cytokines increase level of expression of MHC.
o `controlled by transcription factors
o Alleles for MHC genes are co-dominant. Each
MHC gene product is expressed on the cell
surface of an individual nucleated cell.
32. MHC & Immune responsiveness
• The MHC polymorphism within a species will generate a
diversity of binding specificities, and thus different
patterns of responsiveness to antigens.
• The absence of an MHC molecule that can bind and
present a given peptide, or the absence of T-cell
receptors that can recognize a given peptide–MHC
molecule complex, could result in the absence of
• Some HLA alleles occur at a much higher frequency in
those suffering from certain diseases than in the general
population: autoimmune disorders, certain viral diseases,
disorders of the complement system, some neurologic
disorders, and several different allergies.