Major Histocompatibility Complex
(MHC)
Prof. Dr. Ahmed Mohammed Salih
Ph.D. (MM), M.Sc. (Immuno.) M.Sc. (MMM)

Major Histocompatibility Complex
• Major Histocompatibility Complex :
• The MHC is a collection (complex) of genes
arrayed within a long continuous stretch of
DNA on chromosome 6 in humans
MHC
Cell nucleus

These genes encode
Class I and class II
MHC molecules,
they are membrane
bound glycoproteins
that are closely
related in structure
and function.
Cell
membrane
MHC – I MHC- II

• Since the MHC was first defined in mice by
Gorer and Snell in 1937, the World Health
Organization (WHO) Nomenclature
Committee has named HLA (Human Leukocyte
Antigen) to the human MHC

Why the name
(Histocompatibility Antigen) ??
• Histocompatibility: (tissue compatibility in
transplantation)
• Antigens: Proteins on tissues and cells that
determine their rejection when grafted between two
genetically different individuals that cause a very
strong immune response and are most important in
rejection

• Expression of MHC antigens on cells:
MHC antigens are expressed on the cell
surface in a co-dominant manner: products of
both parental genes are found on the same
cells.

In all nucleated cell:
Muscles
Epithelial cells
Nerve cells
Blood cells
In Antigen presenting cells
(APC)
Monocytes, macrophages
Dendritic cells, B cells
Expression of MHC antigens on cells:

Antigen Processing in MHC I

Antigen Processing in MHC II

There are Three Classes of MHC:
• Class I genes
• encode glycoproteins expressed on the
surface of nearly all nucleated cells, where
they present antigens of altered self cells
necessary for the activation of Tc cells.

• Class II genes
• encode glycoproteins expressed primarily on
APCs (dendritic, MO, B cells) where they
present processed Ag peptides to Th cells.

• Class III genes
• encode somewhat different products, some of
which are also associated with the immune
process. These include a number of soluble
serum proteins such as some of the C'
components, TNF, and steroid enzymes.

Major Histocompatibility Complex
(MHC) in response to infections
• The major histocompatibility complex plays a
central role in the development of both:
• humoral
• and cell mediated immune responses
• and are the principal determinants of graft
rejection.

Major Histocompatibility Complex
(MHC) in response to infections

How can the MHC be involved in
Immune response??
• T cells only recognize antigen when it is
associated with an MHC molecule thus MHC
molecules play a critical role in Ag recognition
by T cells.

MHC or HLA in Organ Transplantation
• The clinical significance of the MHC is realized
in organ transplantation.
• Cells and tissues are routinely transplanted as
a treatment for a number of diseases.

• The transplant of organs is one of the greatest
therapeutic achievements of the twentieth
century. In organ transplantation, the adaptive
immunity is considered the main response
exerted to the transplanted tissue.

In transplantation, the principal target of the
immune response in recipient (patient) is the
MHC (major histocompatibility complex)or the
HLA (Human Leukocyte Antigen) molecules
expressed on the surface of donor cells, because
they vary between individuals.

Tissue cells
MHC or HLA molecules

• Types of grafts
• 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)

• Because we get different HLA molecules, they
are regarded as foreign antigens on the
surface of the donor cells
• The process by which the immune system
recognizes pathogens, tumors, and
transplantation antigens involves the same
HLA antigen recognition molecules by the
immune system of the recipient.

• The rejection response to grafted tissue is
caused by cell surface molecules (MHC or
HLA) that induce an antigenic stimulus.

Why we Don’t have the same HLA?

Before Starting the Organ Transplantation :
• HLA Testing for compatibility
• To support the transplant programs, several
clinical laboratories perform various HLA tests,
including HLA typing of the recipient and the
donor, screening of HLA antibodies in the
recipient, and detection of antibodies in the
recipient that are reactive with lymphocytes
of a prospective donor (cross-matching)

• Historically, HLA typing was conducted by
serologic testing by using antiserum in
complement-dependent cytotoxic assays.
• Recently, more precise DNA-based HLA typing
methods using molecular techniques, such as
sequence-specific oligonucleotide probe
hybridization, sequence-specific primer
amplification, sequencing-based typing, and
reference strand-based conformation analysis,
have been developed and are frequently used

Survival rate of grafts
• There is a clear relationship between the
degree of HLA matching (compatibility) and
graft survival in transplants from living-related
donors.
• Simultaneous analysis of matched living-
related allografts HLA allografts showed 10-
year projected survival rates

• To avoid hyperacute rejection, it is very
important to identify recipient anti-HLA
antibodies to antigens expressed on donor
with blood cells.

ALLOGRAFT REJECTION
• However, reaction of the host immune system
against allo-antigens of the graft (HVG) results
in its rejection and is the major obstacle in
organ transplantation.
• The rejection time of a graft may vary with the
antigenic nature of the graft and the immune
status of the host and is determined by the
immune mechanisms involved

Types of Graft Rejection
• Hyper - acute rejection:
This occurs in instances when the recipient
has preformed high titer antibodies.
• A graft may show signs of rejection within
minutes to hours due to immediate reaction
of antibodies and complement system
activation that leads to lysis of the grafted
cells.

• Accelerated (2nd set; secondary) rejection
Transplantation of a second graft, which shares a
significant number of antigenic determinants
with the first one, results in a rapid (2 - 5 days)
rejection.
• It is due to presence of T-lymphocytes sensitized
during the first graft rejection.
• Accelerated rejection is mediated by immediate
production of lymphokines, activation of
monocytes and macrophages, and induction of
cytotoxic lymphocytes.

• Acute (1st set; primary) rejection
The normal reaction that follows the first grafting
of a foreign transplant takes 1 - 3 weeks.
• This is known as acute rejection and is mediated
by T lymphocytes sensitized to class I and class II
antigens of the allograft, elicitation of
lymphokines and activation of monocytes and
macrophages.

• Chronic rejection
Some grafts may survive for months or even
years, but suddenly exhibit symptoms of
rejection.
• This is referred to as chronic rejection, the
mechanism of which is not entirely clear.
• The hypotheses are that this may be due to:
- infection causes,
- loss of tolerance induced by the graft, etc.

Graft Versus Host Disease (Rejection)
(GVHD)
• Graft versus host disease (GVHD) is an
immune-mediated disease resulting from a
complex reaction of the donor adaptive
immunity against the recipient tissues.

• Most severely occurs with allogeneic
hematopoietic-cell transplantation (HCT)(Bone
marrow transplant).

• The acute GVHD develops within 100 days of
transplantation, describes a distinctive syndrome
of:
- Dermatitis (Pruritic painful rash (median onset,
day 19 post-transplantation; range, 5-47 days)
- Hepatitis (liver involvement, anorexia, weight
loss, followed rarely by hepatic coma
- Enteritis (Diarrhea, intestinal bleeding, cramping
abdominal pain)

Dermatitis associated with GVHD

• Chronic GVHD describes a more diverse
syndrome developing after day 100.
• In addition to allogeneic HCT, procedures
associated with high risk of GVHD include
transplantation of solid organs rich of
lymphoid tissue.

Immunologically privileged sites and
tissues
• There are certain locations in the body in which
allografts are not readily rejected. These include:
- the brain,
- anterior chamber of the eye,
- testis,
- renal tubule,
- uterus, etc.
• This stems from the fact that such sites may lack
of good lymphatic drainage.

• Similarly, corneal graft is an excellent example
that enjoys the highest success rate of any
form of organ transplantation.

PROCEDURES TO ENHANCE GRAFT SURVIVAL
• 1- Donor selection
Based on extensive experiences with renal
transplants, certain guidelines can be followed
in donor selection and recipient preparation
for most organ transplants. The most
important in donor selection is the MHC
identity with the recipient; an identical twin is
the ideal donor. Grafts from an HLA-matched
sibling have 95-100% chance of success.

• 2- Recipient preparation
The recipient must be infection-free and must
not be hypertensive. One to five transfusions
of 100-200 ml whole blood from the donor at
1-2 week intervals improves the graft survival
and is practiced when possible.

• 3- Immunosuppression
Immunosuppressive therapy is most essential
part of allo-transplantation.

• Q- Why the fetus isn't rejected by the
maternal immune system during
pregnancy?????

• The researchers discovered that embryo
implantation sets off a process that ultimately
turns off a key pathway required for the
immune system to attack foreign bodies. As a
result, immune cells are never recruited to the
site of implantation and therefore cannot
harm the developing fetus.

- The research team has discovered that the onset of
pregnancy causes the genes that are responsible for
recruiting immune cells to sites of inflammation to be
turned off within the decidua.
- As a result of these
changes, T cells are not
able to accumulate
inside the decidua and
therefore do not attack
the fetus and placenta.

Questions ???