Major Histocompatibility Complex

(MHC)

Major Histocompatibility Complex (MHC)

* The MHC is a closely linked complex of genes that
govern production of the major histocompatibility
* In humans, MHC resides on the short arm of
chromosome 6
* Three genes (HLA-A, HLA-B, 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
* HLA genes are very diverse (polymorphic)
i.e. there are many alleles of the class I and II genes

The Human Leukocyte Antigen

(HLA) System

Essential to immune function: HLA

molecules present peptide antigens to the
immune system (T-cells)
Important for self versus non-self distinction

Major Histocompatibility Complex (MHC)

* Between the class I and class II gene loci, there is a
third locus (Class III)
* This locus contains genes encoding tumor necrosis
factor, lymphotoxin and two complement components
(C2 and C4)
* Class III antigens do not participate in MHC restriction
or graft rejection

MHC Class I Antigens

* Class I MHC antigens are : HLA-A, HLA-B and HLA-C
* These antigens are glycoproteins found on surfaces
of all nucleated human cells and on platelets
* HLA-A contains 24 different antigenic specificities,
HLA-B contains 52 and HLA-C contains 11
* Class I MHC antigens are involved of MHC restriction
of cell mediated cytotoxicity

HLA Class I Monitors Inside of the Cell

Tapasin
CR
CN

Dr. Brian Freed

MHC Restriction
* Endogenously processed cytosolic peptides in virus
infected cells or tumor cells are transported to the
surface of the cells
* They bind to MHC I molecules to be recognized by
cytotoxic T-cells which then kill these cells
* In other words;
T-cells are only activated when they recognize both
antigen and class I MHC molecules in association

MHC Class II Antigens

Class II antigens are: HLA-DP, HLA-DQ, HLA-DR
antigens
These antigens are glycoproteins found on the
surface of macrophages, B-cells, Dentritic cells,
langerhans cells of skin and activated T cells
HLA-DP contain 6 different antigenic specificities,
HLA-DQ contains 9 and HLA-DR contains 20

HLA Class II Monitors Outside of Cell

Peptides
Extracellular
Proteins

DM
monitors
peptide
specificity
for DR

DM
Dr. Brian Freed

MHC Class II Antigens

* Helper T-cells recognize antigens on antigenpresenting cells only when the antigens are
presented on the surface of cells in association
with class II MHC
* Class II antigens react with the CD4 molecule
on the helper T-cells which secrete cytokines

Class I MHC and Class II MHC

MHC Class I

MHC Class II

HLA-A, HLA-B, HLA-C

HLA-DP, HLA-DQ,
HLA-DR

Found on

All nucleated somatic

cells

Macrophages, B-cells,
Dendritic cells,
langerhans cells of skin
and activated T cells

Recognized by

CD8 TC cells

CD4 TH cells

Functions

Presentation of Ag to
TC cells leading to
elimination of tumor or
infected host cell

Presentation of Ag to
TH cells which secrete
cytokines

Nomenclature

Class I (1.1
Mb)
Complement
& cytokines

Class III (0.7 Mb)

Class II (2.2
Mb)

Gene

low high resolution typing

subtype=01

Allele:
Haplotype:
Genotype:

HLADRB1*0401

HLADRB1*0401

HLADQB1*0302

HLADRB1*0301

HLADQB1*0201
DRB1*02

HLADRB1*04

HLADQB1*0302

J. Noble

HLA Class I and II Molecules Have a Distinct Structure and Function

Binds 8-10mers
Expressed on most
Nucleated cells
Presents Cytosolic
Proteins to CD8+ T cells

Binds 13-25mers
Expressed on APCs,
Macs, B cells, activated
T cells
Presents Vesicular
Proteins to CD4+ T cells

2 3

Class I

Class II

BDC

T cell Recognition of Antigen on an APC

Antigen

Endocytosis
+
CD4
CD4+

TT cell
cell
APC

TCell
Receptor

Peptide
MHCII

Antigenpresenting cells (APCs):

monocytes, macrophages, dendritic cells, B cells
Teaching slides: www.barbaradaviscenter.com

Humoral
Versus
Cellular
Immune
Response

Transplantation
and
Graft Rejection

Types of grafts
1) Autografts :
The transfer of an individuals own tissues
from place to place
e.g. Skin grafts
(regularly accepted)

2) Isografts :
Transfer of tissues between genetically
identical persons
e.g. Identical twins ( accepted permanently)

Types of grafts
3) Allografts (homograft):
- Transfer of a graft between genetically different
members of same species
e.g from one human to another
- Rejection occur if donor and recipient are not matched
4) Xenograft (heterograft):
- Transfer of tissues between different species
- Always rejected

Mechanism Of Graft Rejection

1) Both TH and TC are activated
- TC cells destroy graft cells by direct contact
TH cells secrete cytokines that attract and activate
macrophages, NK cells and polymorphs leading to
cellular infiltration and destruction of graft (Type IV)
- B cells recognize foreign antigens on the graft and
produce antibodies which bind to graft cells and
. Activate complement causing cell lysis
. Enhance phagocytosis, i.e. opsonization (Type II)
. Lead to ADCC by macrophages, NK,PML
- Immune complex deposition on the vessel walls
induce platelets aggregation and microthrombi
leading to ischemia and necrosis of graft (Type II)

Types Of Graft Rejection

!) Hyperacute rejection:
- It occurs hours after transplantation
- In individual with preformed antibodies either due to blood groups incompatibility or previous sensitization
by blood transfusion, previous transplantation
2) Acute Rejection:
- It occurs 10 to 30 days after transplantation
- It is mainly T-cell mediated
3) Chronic or late rejection:
- It occurs over a period of months or years
- It may be cell mediated, antibody mediated or both

Graft Versus Host (GVH) Reaction

* An immunologically competent graft is transplanted into
an immunologically suppressed recipient (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 , diarrhea, hepatsplenomegaly and
death