immunology ppt

1. 5. MHC molecules: Recognition of
antigens
1

2. 2
Major Histocompatibility Complex (MHC)

3. • Difficulty during transplantation…rejection
• Immune responses: antibody formation, TH, CTL
• Highly polymorphic √
• Bind peptide…….. recognized by T cells
3

4. • Are self antigen (autoantigen)
• Found on all cells of nucleated humans and all
vertebrates cells
• 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)
4

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,&
Factor B
• Genes encoding in this MHC III do not play any
role in antigen presentation.
5

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.
6

7. 7

8. Polymorphism of MHC Molecules
8

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
9

10. MHC gene inheritance to offspring
• Most individuals are heterozygous in terms of MHC
inheritance.
• 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
MHC gene.
10

11. Classification and structure of MHC
• 2 types of polymorphic genes, the class I and II
encodes two groups of structurally distinct but
homologous proteins.
• 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
segment. 11

12.  The 1 and 2 domains form a cleft where the
Ag fragment of antigen binds.
 The 2 microglobulin has only one
extracellular domain
No transmembrane portion
No cytoplasmic tail
Immunoglobulin-like region: highly
conserved α3 domain - site to which CD8 on T
cell binds 12

13. NH2
Alloantigenic
sites
CHO
NH2
COOH
P
α1
α2
α3
β2
OH
Plasma membrane
Disulfide bridge
Papain cleavage
Cytoplasm
NH2
13

14. 14

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
fragment
oImmunoglobulin-like region – conserved α2 and β2
domains – β2 is site to which CD4 on T cell binds 15

16. Plasma membrane
Cytoplasm
CHO
CHO
CHO
NH2 NH2
COOH COOH
α1
α2 β2
β1
16

17. 17

18. 18

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
Dissociation
• MHC molecules don’t discriminate between self and non
Self antigens
19

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)
- HLA-DM
20

21. 21

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
22

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??
23

24. 24

25. 25

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
structurally similar
26

27. 27

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.
28

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
occur.
29

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
molecule, degenerate
o All bind to the same site, but only one at a time.
30

31. o MHC polymorphism is determined at germline.
There is no recombinational mechanism for
generating diversity
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.
31

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
immune responsiveness.
• 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.
32

33. 33