MHC proteins and

Transplantation
BY DR. SAMIA BESHIR
HLA or MHC proteins
Two types
1- MHC class I proteins:
➢ Glycoproteins found on surface of all nucleated cells and platelets.
➢ Encoded by the allelic genes on chromosome 6 at the A locus, the B locus
and the C locus.
➢ Structure:
MHC class I molecule consists of a heavy polypeptide chain (α) which is
non-covalently bound to a light β chain called β2 microglobulin. The
heavy chain is highly polymorphic and is similar to an immunoglobulin
molecule; it has hypervariable regions in its N-terminal, which contains the
antigen binding groove.
They have a constant region where the CD8 proteins of the T cytotoxic cells bind.
2- MHC class II proteins:
➢ Are glycoproteins found on surface of certain cells, mainly antigen
presenting cells (macrophages, B lymphocytes, dendritic cells ,
Langerhans's cells of the skin) and activated T cells.
➢ Encoded for by genes on chromosome 6 loci DP,DQ,DR
➢ They have a constant region where the CD4 proteins of T helper cells
bind.
➢ Structure:
MHC class II molecules consist of 2 polypeptide chains (α and β) that
are non-covalently bound. They have a hypervariable region that
provides the polymorphism and contains the peptide antigen binding
groove
MHC proteins
MHC proteins
Biologic importance of MHC
1-Role in immune response
Antigen presentation and recognition of antigen by T-cells
The ability of T cells to recognize antigens is dependent on association
of the antigen with either class I or class II MHC proteins. T cytotoxic
cells (CD8) respond to antigen in association with class I MHC proteins.
T helper cells (CD4) recognize antigen in association with class II MHC
proteins.
This requirement to recognize antigen with a self MHC protein is called
MHC restriction and is required by T cells only. B cells are not MHC
restricted and they recognize antigens in plasma with their surface IgM
acting as the antigen receptor
2- Role in predisposition to diseases
In autoimmune diseases
Many autoimmune are associated with certain MHC genes.
3- Role in organ transplantation and graft rejection
Success of organ transplant is determined by the compatibility of the
MHC genes of the donor and recipient.
4- Role in : Paternity testing and forensic investigations
MHC genes and MHC proteins
MHC genes and MHC proteins
Inheritance of MHC genes
➢ Each person has two haplotypes i.e. two sets of these genes, one on
the paternal and the other on the maternal chromosome 6.
➢ HLA genes are very diverse or polymorphic i.e. there are many alleles
of the class I and class II genes.
➢ For example there are at least 147 HLA-A genes, 200HLA-B genes,
90 HLA-C genes and more than 500 HLA-D genes, but any
heterozygous individual inherits only a single allele at each locus from
each parent and thus can make no more than two class I and class II
proteins at each gene locus.
Inheritance of MHC genes
Mendelian law
➢Expression of these genes is codominant i.e. the proteins encoded by
both the paternal and maternal genes are produced.
➢Each person can make as many as 12 HLA proteins, three at class I loci
and three at class II loci, from both paternal and maternal
chromosomes.
➢In addition to the MHC proteins encoded by the MHC genes, there are
an unknown number of minor antigens encoded by genes at sites other
than the MHC locus, these minor antigens ,known as Minor
histocompatibility antigens, can induce a weak immune response that
results in slow rejection of a graft.
Minor Histocompatibility
antigens
These are antigens that differ between the donor and recipient. They
induce weak or slower rejection reactions than do major
histocompatibility antigens.
Most of these antigens are proteins that are presented to host T cells in
association with self MHC molecules on host APCs.
Transplantation
➢ Transplantation : is grafting tissues or organs from one individual to
another or from one place to another in the same individual.
➢It enables the replacement of a diseased organ by another healthy
one.
➢ The main obstacle in organ transplantation is graft rejection, which is
due to the presence of tissue antigens that differ from one individual to
another, thus stimulating an immune response that causes the
rejection.
➢ These antigens are the human leucocyte antigens(HLA) or
histocompatibility antigens ( MHC ) and are genetically determined by a
set of genes called the major histocompatibiliy gene complex(MHC).
MHC and Transplantation
➢Success of tissue and organ transplant depends on the
donor´s and recipient´s human leukocyte antigens(HLA or
MHC antigens) encoded by HLA genes.
➢HLA or MHC antigens are proteins that are alloantigens i.e.
differ among members of the same species.
➢If HLA proteins on the donor´s cells differ from those on
the recipient’s cells an immune response occurs in the
recipient.
➢There are two types of HLA or MHC proteins,MHC- class I
and MHC-class II proteins
Transplantation(Grafting)
Types of grafts:
1- Autograft: graft of tissue within the same person e. g. skin graft.. This
is permanently accepted and no immunosuppressive is needed.
2- Syngenic or isograft graft : graft between genetically identical
persons(identical twins), permanently accepted and no
immunosuppressive needed
3- Xenograft: graft between different species. Always rejected
4-Allograft: graft between genetically different members of the same
species. Rejection may occur if the donor and recipient are not properly
matched. Need immunosuppressive drugs.
Mechanism of graft rejection
The acceptance or rejection of a transplant is determined, in large part,
by the MHC I especially those from locus B, and MHC II proteins on the
donor cells especially those from locus DR, with MHC II playing the
major role.
Mechanisms of graft rejection
Allograft(donor) MHC molecules are presented for recognition by the T
cells of the recipient in two ways :
1-Direct pathway: donor MHC may be presented on donor APCs to
recipient T cells or
2-Indirect pathway : Donor MHC may be picked up by host APCs that
enter the graft and be processed and presented to T cells as peptides
associated with self MHC molecules
Role of T cells (cellular immune response)
Both TH and Tc cells are activated
Tc cells destroy graft cells by direct contact(cytotoxicity)
TH cells secrete cytokines that attract and activate macrophages, NK
cells and polymorphs leading to cellular infiltration and destruction of
the graft( DHR). i.e. type IV hypersensitivity reaction.
Role of B cells (humoral immune response)
1-B cells recognize foreign antigens on the graft and produce antibodies
which bind to graft cells and :
• activate complement causing cell lysis
• enhance phagocytosis by opsonization
• leads to ADCC
all these mechanisms are type II hypersensitivity reaction
2- Immune complexes deposition on the blood vessel walls(e.g. in renal
graft) induce platelet aggregation and micro -thrombi formation leading
to ischaemia and necrosis of the graft,i.e. type III hypersensitivity
reactions
Allograft rejection
Types of rejection: clinically 3 types, according to
speed of rejection
1-Hyperacute rejection:
• occurs within a few minutes to a few hours after
transplant.
• It is a rare type of rejection that occurs in individuals
with preformed antibodies either due to blood groups
incompatibility or previous sensitization by blood
transfusion, pregnancy or previous transplantation
2- Acute rejection :
• occurs within days or weeks after transplantation.
• It is mainly T cell mediated.
3- Chronic or late rejection :
• occurs slowly over a period of months or years after transplant.
• It may be cell-mediated, antibody mediated or both.
Incompatibility of minor MHC proteins and side effects of
immunosuppressive drugs are likely to play a role. Main
pathological finding is atherosclerosis of the vascular
endothelium.
Graft versus host
rejection(GVH)
• This condition occurs when an immunologically competent
graft e.g. bone marrow, is transplanted into an
immunologically suppressed recipient or host.
• The grafted cells survive and react against the host cells
i.e. instead of reaction of host against the graft, the reverse
occurs
• GVH reaction is characterized by
fever,pancytopenia,weight loss,rash,hepatosplenomegally
and death
Prevention of graft rejection
1. Proper choice of donors : through
➢ ABO blood group compatibility tests
➢ Tissue typing tests for HLA antigens(HLA typing)
➢ Cross-matching tests, used to test the recipient´s serum
for the presence of preformed antibodies against the
donor´s HLA antigens.
➢ Screening for diseases e.g.HIV,Hepatitis,cancer
2. Postoperative immunosuppressive therapy
This is used to prevent graft rejection, by non-
specifically interfering with the induction or
expression if the immune response.
However such immunologically suppressed
individuals are susceptible to infections and cancer.
HLA typing tests
HLA-typing or tissue typing tests: ( Specimen is blood)
Are laboratory tests performed to determine the closest match
between the donor and recipient.
Methods:
1-Molecular HLA typing or DNA sequencing by PCR to determine
the haplotype (i.e. class I and classII alleles on both
chromosomes of both the donor and recipient). Method of choice.
2-Serological typing: to determine the MHC proteins class I and II on
cells of both donor and recipient.
3-Blood cross-matching test: to detect preformed ABO antibody.
Immune-privileged sites
❖ Eye ( cornea)
❖ Testicular tubules
❖ Brain
❖ Placenta
 Privileged sites
Eye: the aqueous humor of the anterior chamber allows
cells and molecules to exist without close contact with the
vasculature, thus hiding them from the immune
system.(cornea transplant)
Testicles: these are developed and closed prior to the
development of the immune system, thus never recognized
as self. But if breached by infection, injury or surgery then
the immune system can react against them once being
exposed.
Brain: blood-brain barrier can limit the exchange of
cells and large molecules between the vasculature
and the immune system
Placenta: the fetus is an allograft(expressing many
histocompatibility antigens foreign to the mother)
that is not rejected by the mother immune system.
A lot of theories have been postulated.
Fetus not rejected????
Theories
1-Placenta trophoblast cells do not express polymorphic
MHC I or MHC II molecules but expresses only the non-
polymorhic MHC I molecule(HLA-G).
2-The major function of HLA-G is to provide a ligand for the
killer cell inhibiting receptors(KIRs) on maternal NK cells,
thus preventing them from killing the fetal cells.
3-Presence of proteins inhibitory to cytokines and
complement.
4- The α fetoprotein, synthesized in the fetal liver, have
immunosuppressive properties.