Immunology Lecture HLA, Transplantation and Complement delivered to BDS

1. HLA Transplantation and
Complement
Dr. Muhammad Yahya Noori
Based upon Warren Levinson 1

2. Human Leukocyte Antigen
• The success of tissue and organ transplants
depends on the donor's and recipient's human
leukocyte antigens (HLA) encoded by the HLA
genes.
• These proteins are alloantigens
(They differ among members of the same species)
• If the HLA proteins on the donor's cells differ
from those on the recipient's cells, an immune
response occurs in the recipient.
Based upon Warren Levinson 2

3. Major Histocompatibility Complex
• The genes for the HLA proteins are
clustered in the major
histocompatibility complex (MHC),
located on the short arm of
chromosome 6
– Three of these genes (HLA-A, HLA-B,
and HLA-C) code for the class I MHC
proteins.
– Several HLA-D loci determine the
class II MHC proteins, i.e., DP, DQ,
and DR
– Class I MHC proteins are found on
the surface of all nucleated cells,
including those that have class II
MHC proteins.
Based upon Warren Levinson 3

4. MHC Proteins
Class I MHC Proteins
• These are glycoproteins found on the surface of virtually all nucleated
cells.
• The complete class I protein is composed of a 45,000-molecular weight
heavy chain non-covalently bound to a Beta 2-microglobulin.
• The polymorphism of these molecules is important in the recognition of
self and non-self.
CLASS II MHC PROTEINS
• These are glycoproteins found on the surface of certain cells, including
macrophages, B cells, dendritic cells of the spleen, and Langerhans' cells of
the skin.
• They are highly polymorphic glycoproteins composed of two polypeptides
(MW 33,000 and 28,000) that are non-covalently bound.
• Like class I proteins, they have hypervariable regions that provide much of
the polymorphism. Based upon Warren Levinson 4

5. A comparison between MHC I and II
Based upon Warren Levinson 5

6. Mode of HLA Expression
• Each person has two haplotypes
– one on the paternal chromosome
– Other on the maternal chromosome
• These genes are polymorphic
– For example, there are at least 47 HLA-A genes, 88 HLA-B genes, 29 HLA-C genes, and
more than 300 HLA-D genes, but any individual inherits only a single allele at each locus
from each parent and thus can make no more than 2 class I and II proteins
at each gene locus.
– Expression of these genes is codominant
– Each person can make as many as 12 different HLA proteins
– 3 at class I loci and 3 at class II loci, from both chromosomes.
– There are an unknown number of minor antigens encoded by genes at sites other than
the HLA locus that can lead to slow graft rejection.
Based upon Warren Levinson 6

7. Biological Importance of MHC
• The ability of T cells to recognize antigen is dependent
on association of the antigen with either class I or class
II proteins.
• For example, cytotoxic T cells respond to antigen in
association with class I MHC proteins.
• Helper cell activity depends on both the recognition of
the antigen on antigen-presenting cells and the
presence on these cells of "self" class II MHC proteins.
• This requirement to recognize antigen in association
with a "self" MHC protein is called MHC restriction.
Based upon Warren Levinson 7

8. Transplant
Terminology
Autograft:
Transfer of an individual's own tissue to another site in the
body is always permanently accepted
Syngeneic graft:
A transfer of tissue between genetically identical individuals
Xenograft
A transfer of tissue between different species, is always
rejected by an immunocompetent recipient.
Allograft
A graft between genetically different members of the same
species
Based upon Warren Levinson 8

9. Transplant Rejection
• Unless immunosuppressive measures are taken, allografts
are rejected by a process called the allograft reaction.
• In an acute allograft reaction, vascularization of the graft is
normal initially, but in 11 to 14 days, marked reduction in
circulation and mononuclear cell infiltration occurs, with
eventual necrosis.
• This is called a primary (first-set) reaction.
• A T-cell–mediated reaction is the main cause of rejection
of many types of grafts, e.g., skin
• Antibodies contribute to the rejection of certain
transplants, especially bone marrow
Based upon Warren Levinson 9

10. Graft Versus Host Reaction
• Well-matched transplants of bone marrow may establish themselves
initially in 85% of recipients, but subsequently a graft versus-host (GVH)
reaction develops in about two-thirds of them.
• This reaction occurs because grafted immunocompetent T cells proliferate
in the irradiated, immunocompromised host and reject cells with "foreign"
proteins, resulting in severe organ dysfunction.
• The donor's cytotoxic T cells play a major role in destroying the recipient's
cells. Among the main symptoms are maculopapular rash, jaundice,
hepatosplenomegaly, and diarrhea .
• Many GVH reactions end in overwhelming infections and death.
• There are three requirements for a GVH reaction to occur:
– The graft must contain immunocompetent T cells
– The host must be immunocompromised
– The recipient must express antigens (e.g., MHC proteins) foreign to the donor
Based upon Warren Levinson 10

11. Complement
• The complement system consists of approximately 20 proteins that
are present in normal human (and other animal) serum.
• The term "complement" refers to the ability of these proteins to
complement, i.e., augment, the effects of other components of
the immune system, e.g., antibody.
• Complement is an important component of our innate host
defenses.
• There are three main effects of complement:
– Lysis of cells such a s bacteria , allografts, and tumor cells
– Generation of mediators that participate in inflammation and attract
neutrophils
– Opsonization, i.e., enha ncement of pha gocytosis.
Complement proteins a re synthesized ma inly by the liver.
Based upon Warren Levinson 11

12. Complement Activation
Based upon Warren Levinson 12

13. Regulation of Complement
Opsonization
Microbes are phagocytized much better in the presence of C3b.
Chemotaxis
5a and the C5,6,7 complex attract neutrophils.
Anaphylatoxin
C3a , C4a , and C5a cause degranulation of mast cells. Ana phyla toxins can also bind directly to smooth
muscle cells of the bronchioles
Cytolysis
Insertion of the C5b,6,7,8,9 complex into the cell membrane leads to killing or lysis of many types of
cells
Enhancement of Antibody ProductioN
The binding of C3b to its receptors on the surface of activated B cells greatly enhances antibody
production
Based upon Warren Levinson 13