MHC ( multihistocompatibility complex)

1. MAJOR HISTOCOMPATIBILITY
COMPLEX (MHC)
BOND KING
SWU

2. THE MHC
• Is the gene region located on chromosomes 6 in
humans and it encodes the antigen presenting
cells molecules designated class I MHC and class II
MHC.
• In between the two region MHC I and MHC II are
the class III MHC genes that encodes some of the
complement proteins.
• Both classes of MHC molecules consists of two
polypeptide chains non covalently associated.

3. MHC
• each class of MHC has three distinct forms:-
Class I MHC- HLA-A, HLA-B and HLA-C
Class II MHC – HLA-DP, HLA-DQ, HLA-DR
Class II MHC genes Class I MHC genes
HLA-DP,HLA-DQ,HLA-DR HLA-B,HLA-C,HLA-A
00 00 00 0 0 0

4. MHC
• The total set of MHC alleles class I and II inherited
from one parent is haplotypes (seen genotype)
• Each form MHC has several alleles(variants) in the
population.
• Each allelic variants can potentially bind a
number of antigen peptides.
• When a peptide binds to MHC molecules, the
complex formed subsequently displayed in the
cell surface, where it can be recognized by T cell

5. MHC
• In effect ,these complex alert T cell that a foreign
substance (micro-organism) is present.
• Recognization of these complexes is required for
T cells activation, which is a requirement for most
adaptive immune responses.
• The genes that determined the out come of the
graft were referred as the histocompatibility
genes and the proteins encoded to the genes
histocompatibility antigen.

6. CLASS I MHC IN HUMAN
• Three forms of class I MHC proteins can be
identified in all human nuclear cells.
• There molecule form a complex with antigen
fragments within the cells and the complex is
displayed on a cell surface.

7. DISCOVERY OF CLASS I MHC
• Mouse was used in experiments (skin grafts)
• Human blood transfusion was used ( graft)
because cells are transfused from one
individual to another.
• Therefore ,individual who had received a
foreign graft (blood transfusion) or mother
who had several pregnancies (multiparous)
were identified as graft recipients ( serum
tested for anti-MHC antibodies).

8. • Individual who have received blood transfusions
would have generated antibodies specific for the
MHC antigens present on transfused blood cells.
• For mothers who had several pregnancies is that
lymphocytes from the fetus enter the maternal
circulation during delivery.
• Since fetal lymphocytes expresses paternal MHC
antigens (as well as the mother MHC antigens)the
fetal cells are foreign grafts.

9. • the mother’s immune system would be activated
in response to the foreign MHC and would lead to
the production of anti-MHC (paternal antibodies).
• Because MHC molecules to which antibodies
were generated were present in the human
leukocytes these MHC molecules were called
human leukocytes antigen and the gene locus
that encoded them the HLA locus.
• The HLA locus is synonym with MHC locus the
genetic term for this region.

10. Description of class I MHC
Two polypeptides
• Polymorphic heavy chain MHC locus
chromosome 6.
• Non polymorphic light chain (B2
microglobulin)- chromosome 15

11. Class I MHC polymorphism and
Nomenclature
• Each HLA (A,B,C) gene has many allelic variant
forms in the population (polymorphic)
• HLA-A1 HLA-A2 HLA-A3 and so on.

12. Expression of class I MHC
• Each of three forms of class I MHC are
co-dominantly expressed.
• The three class I alleles (variants)inherited from
each parents are expressed on the cell.
examples
the child inherits the following alleles from one
parent (HLA-A ,HLA-B8 and HLA-Cw4) and the
following alleles from the parent( HLA- A2,HLA-
B37 and HLA-Cw7) all six different molecules will
be present on the child nucleated cells.

13. EXPRESSION
PATERNAL ALLELES MATERNAL ALLELES
HLA-A1 HLA-A2
HLA-B8 NUCLEATED HLA-B37
CELLS
HLA-CW4 HLA-CW7

14. Class I MHC

15. CLASS II MHC
• Three forms of class II MHC can be identified
on antigen presenting cells.
• These molecules bind antigen fragments
within a cystolic vacuole and the complex is
then displayed on the surface of the antigen
presenting.

16. Discovery of class II MHC
• The human class II MHC gene region known as
the HLA-D region was identified using the mixed
leukocyte reaction (MLR)
• MLR is a laboratory technique used as a
predictive test for graft rejection.
• This assay is used to determine whether T cells
forms one individual will be activated when they
interact with class II MHC protein present on
another individual cells(allogenic MHC).

17. • HLA-D region consisted of three gene loci
HLA-DP ,HLA-DQ, HLA-DR
Examples
In individual who are genetically identical
(monozygotic twins)T cells will not be activated in
MLR on the other hand. If two individuals are
genetically desperate the CD4+ T cells recognizing
the class MHC proteins as foreign and respond by
proliferation.

18. Description of class II MHC
• They are comprised of two poly peptide chains
( alpha and beta).each chain is polymorphic and
the genes that encodes them are located within
the MHC locus
• For the most part, class II MHC molecules are
normally Expressed on antigen presenting cells (B
cells, monocytes, macrophases and dendrite
cells)
• Exposure to some cytokins can enhance the
number of class II MHC molecules expressed on
an antigen presenting cells.

19. Class II MHC polymorphism and
Nomenclature
• Each HLA-D (DP,DQ,DR) gene has many allelic
variants or forms in a population and so the
HLA-D genes are said to be polymorphic.
• Each gene variant (allele) is given a number
example
HLA-DR alleles are numbered
HLA-DR1 , HLA-DR2

20. Expression of class II MHC
• Class II molecules are co-dominantly expressed.
• Each class is different various combination of
polypeptide are possible
• When a child inherits two entirely different sets
of alleles at least 12 different combination.
(four for each HLA-DR,DP,DQ) are possible,
however not all combinations will be represented
equally because some combinations are more
stable than others.

21. Examples
if a child inherits HLA-DR1 which is comprised
of sigma(1) and beta(1) from the one parent
and HLA-DR4 comprised of alpha(4) and
beta(4) from the other parent, the number of
possible combinations of HLA-DR on the cell
surface would be (HLA-DR (1)/ (1) ,HLA-DR
(4)/ (4) ,HLA-DR (1)/ (4) and HLA-DR (4)/ (1)

22. • The expression of so many different class II
MHC molecules on an antigen presenting cells
greatly increase the liklihood that an antigen
peptide will form a complex with an MHC
protein and be presented on the cell surface
of the T cells to recognize.

23. • Parental alleles maternal alleles
HLA- A1 HLA-A2
HLA-B8 HLA-B37
HLA-CW4 ANTIGEN HLA-CW7
PRESENTING
HLA-DPW1 CELLS HLA- DPW7
HLA- DQ5 HLA-DQ9
HLA-DR3 HLA-DR4

24. Class II MHC

25. Role of MHC in immune response
• Based on the studies the MHC gene loci were
aimed to identify those molecule that were
involved in graft rejection.
• Important molecules in host defense
• In normal host immune response, antigenic
peptides are displayed on cell surfaces
complexed with MHC molecules.

26. • Cytotoxic T cells (CD8+ T cell) recognize
antigen peptide complexed with a class I MHC
molecules on the cell surface.
• In contrast helper T cells ( CD4+ T cell) will
recognize antigen peptide displayed with a
class II MHC molecules

27. Importance
• A sucessful immune response, demands that
helper T cells (CD4+) are activated, and this
can only occur if antigenic displayed on the
cells surface in association with class II MHC
• In turn, experiment of that complex requires
that one of the inherited MHC alleles is
capable of binding one of antigen peptides
generated in the phagocytosis vacoule.

28. Transplantation immunology
Transplantation
• Is there process where by an individual
(recepient) receives cells or tissues from a 2nd
individual (donar)

29. classification
• Isograft :-graft in which there is no genetic
different between donar and receipent
(genetically identical individual)
• Allograft:- graft between the member of same
species
• Xenograft:-graft across a species
• Autograft:-self tissue transferred from one
body site to another in the same individual.

30. • For some part ,transplants are allografts are so
there is a genetic disparity betwn the donar
and receipent (MHC loci)
• To some extent the MHC genetic disparity
determine whether a graft will be accepted or
rejected becoz the proteins( antigens) that
they encode have been shower to induce the
most vigrous rejection episodes.

31. Graft rejection
• Immunologic response of a transplant
receipent to the cells of the graft from a non-
histocompatible donor.

32. classification
1.Hyperacute rejection
• Occurs minutes to 1 hour following the
engraftment.
• Antibody mediated phenomenon and is
associated with complement activator, blood
clot formation and rapid graft failure.
• Indicates that the recipient has been
previously exposed to the donor MHC antigen
• Graft removal

33. Acute rejection
• Occurs week after tissue transplant and is
caused by helper and cytotoxic T-cell
activation (cell mediated)

34. Chronic Rejection
• May occur weeks, months or years Post
transplant.
• Associated with a notable increase in the
levels of non T cell derived non specific
growth factors.
• No treatment, graft must be removed
• Humoral and cell mediated.

35. Rejection in bone marrow
transplantation
• Used to treat leukemias and lymphocytes
• These types of transplants are unique in that
the donor cells attack the receipent tissues.
• Referred to as graft versus host disease(GVHD)
• T cells present in the graft are stimulated
becoz the recipient is recognized as foreign.
• Recipients are seriously immunocompromised
and so their immune system cannot attack the
graft with the same intensity.

36. Immunosupressive therapies
• Because acute rejection a T- cell mediated event,
many of the therapies target the T-cells
• Treatment for acute rejection consists of
increasing dose of immunosuppressive drugs.
• Commonly used drugs are cyclopshorin A and
FK506 which block the production of a T cell
growth factor
• Prednisone is used as non specific anti-
inflammatory agent, targets macrophages and
reduced antigen presentation of T cells.

37. Screening to ensure compatibility
• Recipients and potential donor, are pre-
screened to ensure the best possible genetic
match at MHC loci to minimize rejection.
• The pre-transplantation screening test are
based on serological cellular and molecular
typing techniques
• Pre-transplantation testing is more commonly
referred as histocompatibility testing and
includes tissue matching and tissue typing.

38. Histocompatibility testing
A. TISSUE MATCHING
• Also referred as cross-matching
• To as certain donor-recipient compatibility.

39. serologic approach
• Donor and recipient tissues are reacted
separately with panels of antibodies for
various MHC alleles and their relation are
compared.
• The problem with this approach is that allelic
difference can be detected only if an antibody
is available for the allele.

40. Cellular approach
• Used mixed leukocyte reaction (MLR)
• Donor and recipient cells are cultured together
for several classes to allow T cells to be activated
and proliferate in response to disparate MHC
proteins.
• The amount of proliferation can be measured and
used to predict the magnitude of rejection.
• Bone marrow transplant and cases of related
donor.

41. Molecular approach
• Used restriction fragment length
polymorphism(RFLP) and the polymerase
chain reaction (PCR)
• RFLP- enzymes are used to cleave genomic
DNA to obtain a pattern of fragmentation
• The genetic disparity between the donor and
recipient can be assessed by comparing
pattern of fragmentation.

42. PCR
• Directs amplification of a particular DNA
sequence selected by use of primers (short
nucleic acid sequence)that border the genes
of interest.
• The degree of disparity betwn the recipients
and the donor for the selected sequences can
be determined.

43. Tissue testing
• Individuals HLA genotype
• PCR is the method of choice.
• Serologic approach- incubation of the
individuals blood with panel of antibody of
known specificity

44. Paternity and histocompatibility
testing
• Histocompatibility testing may also be used to
determine paternity.
• In this situation, paternity is not confirmed.
• The test is based on exclusion.
• If the child does not express any/ the same
HLA alleles as the male being tested, paternity
can be excluded.

45. • Organs – tissue that can be transplanted from
human
• Kidney liver
heart skin
lungs cornea
pancreas blood
bone marrow cord blood