3 MHC

Major Histocompatibility
Complex (MHC)
1
• Is a set of cell surface molecules encoded by a large family
gene which controls a major part of the immune system
• In humans, the MHC is also called the Human Leukocytes
Ag (HLA). HLA (Human Leukocyte Antigen)
• The proteins encoded by the MHC are expressed on the surface of

cells, and display both self-antigens (peptide fragments from the
cell itself) and non-self-antigens. (e.g. fragments of an invading
bacterium)
2
Importance of MHC molecules
1- Ag presentation:-
bind peptide fragments derived from pathogens (Ag) and
display them on the cell surface for recognition by the
appropriate T-cells.
2-The MHC determines compatibility of donors for organ
transplant.
3 -The MHC determines susceptibility to an autoimmune
disease.
4- in forensic medicine
Structure of HLA
• Glycoproteins, heterodimers (two chains)
• Structure of HLA molecules of both classes enables

antigen binding and contact with T cell receptors.
• Extracellulary located peptide binding cleft
• Polymorphic (predominantly in the cleft).
• Nonpolymorphic part of the molecule contains binding

sites for the T cell molecules CD4 and CD8
• MHC gene family is divided into three subgroups: class I,
Class I molecule (HLA-A, B, C)
• expressed on all nucleated cells
• Presents endogenous Ag to T-lymphocyte (CD8+)
Class II molecule (HLA-DR, DQ, DP)

• expressed on B lymphocyte, activated T lymphocyte,
monocyte, macrophage, dendritic cells, etc.
• Presents exogenous Ag to helper T-lymphocyte (CD4+)
Class III encodes for immune components such as

complement (C2, C4, factor B), as well as cytokines (e.g.
tumour necrosis factor (TNF).
MHC molecules structure
-MHC class I occurs as an α chain

composed of three domains—α1, α2, and α3.
- The α1 binds to unit of the non-MHC

molecule β2 microgloulin (encoded on
human chromosome 15).
- the peptide binding groove ,where the Ag
binds , in the central region of the α1/α2.
-The amino acid sequences in this groove
determines which particular peptide binds to
it .
Structure of HLA class II. molecules
1. α chain
α1: polymorphic sites
α2: binding of CD4
2. b chain
b1: polymorphic sites
b2: binding of CD4
Structure of HLA class I, class II
Class I Class II
cleft by α1 and α2 : Ag-binding cleft by α1 and β1 : Ag-binding
pocket, α3 domain : interact with pocket ,α2, 2: interact with
CD8 on T cells CD4 on T cells
Class I Class II
peptide
peptide
binding
binding
area
area
cell
cell
membrane
membrane
Cytoplasmic Cytoplasmic tails
9
10
Biological functions of MHC
— T differentiation
— Antigen presentation
Recognition of antigen by T cells is necessary
for induction of the immune response
11
12
Explain:
 It is very difficult to find same MHC among

the un-related population within each species.
 Different individuals have different ability of

immune response to a particular antigen.
13
MHC genes
Polymorphism of MHC genes
Encoded in Chromosome 6
The number of gene loci for MHC class I and
class II molecules varies between species and
between different haplotypes within each species.
HLA class III. are soluble molecules as complement,TNF,
HSP .Many other proteins involved in antigen presentation

14
Features of MHC genes
1. Multiple alleles
2. Co-dominant
3. Haplotype heredity
} Polymorphism of
MHC genes
Cause graft rejection due to variable HLA
molecules in each persons
15
Co-dominant expression
Medical Immunology 吉林大学基础医学院免疫学教研室 16
MHC in transplantation
 Histocompatibility antigens are the targets

for rejections.
 MHC molecules are expressed on
transplanted tissues and induce the immune
response of recipient.
17
18
MHCa MHCa
MHCb
MHCx
19
Immunodeficiences-MHC defect
• Bare lymphocyte syndrome:
mutation in genes regulating class II
MHC transcription
- reduced number of CD4+ T cells in
periphery ,defective activation of
CD4+ T cells , fatal, treatment: BM
transplantation
• Class I MHC deficiencies:
- decreased number of CD4+ T cells in
periphery, patients suffer from
respiratory tract bacterial infection
20
HLA-associated diseases
Ankylosing spondylitis B27
Type 1 diabetes DR3 .DR4 ,
Multiple sclerosis DR2
Rheumatoid arthritis DR4

Explain:
 It is very difficult to find same MHC among

the un-related population within each species.
 Different individuals have different ability of

immune response to a particular antigen.
22
Immune –tolerance
The inability to invoke an immune response to an
antigen, occurs principally because of:
Clonal deletion of self-reactive T- and B-cells during
development this called (central tolerance)
Clonal anergy (peripheral tolerance): occurs in the
peripheral tissues when immature B-cells encounter
soluble antigens that cross-link B-cell receptors, or
when T-cells encounter unprocessed antigen or
processed antigen in the absence of co-stimulatory
signals. 23
Central and peripheral tolerance to self
The principal fate
of lymphocytes that
recognize self antigens
in the generative
organs
is death (deletion
Some T cells may
differentiate into
regulatory (suppressor)
T lymphocytes
24
The immunological equilibrium: balancing
lymphocyte activation and control
Activation Tolerance
Effector T cells Regulatory T cells
Normal: reactions Controlled response to

against pathogens pathogens
Inflammatory No response to self Ag
disease, e.g.
reactions against self
Autoimmunity
• Autoimmunity is a problem of self/non-self
discrimination
• 5 % to 7% adult affected.
• Two third women.
• More than 40 human diseases autoimmune
in origin.
Effects of autoimmunity
• 1) Tissue destruction
• Diabetes: CTLs destroy insulin-producing b-cells in
pancreas
• 2) Antibodies block normal function
• Myasthenia gravis: Ab binds acetylcholine receptors
• 3) Antibodies stimulate inappropriate function
• Graves’ disease: Ab binds TSH receptor
• Mimics thyroid-stimulating hormone
• Activates unregulated thyroid hormone production
• 4) Antigen-antibody complexes affect function
• Rheumatoid arthritis:
Causes of autoimmunity
1) Release of sequestered Ag
• Smoking damages alveoli, exposes collagen
• Anti-collagen Ag damages lung and kidney
• Anti-sperm Ab produced in some men after vasectomy
• May be triggered by injury or infection
2) Immune stimulation
• Microbial infection stimulates APCs carrying self Ag
• High level of APCs with “second signal” breaks anergy

Mechanisms of autoimmunity
• Ag released from hidden location.
• Antigen generated by molecular changes.
• Molecular mimicry.
• Alteration in Ag processing.
• Infection.
• Genetic factors.
• Lymphocytes abnormalities.
• Failure of central tolerance.
• Overcome of peripheral tolerance.
• Polyclonal lymphocytes activation.
GENETIC FACTORS
• The important genes that regulate the development
of autoimmunity are located within MHC.
• MHC have got critical role in maturation of T cell &

induction of IR .
• MHC ll genes are directly responsible for auto

antigen processing and presentation.
• The structure of Ag binding groove will determine ,
if specific Ag will trigger an AU response.
• Eg. SLE: DLA- A7 , POLYARTHRITIS: DLA- A7
Treatment for autoimmunity
• Immunosuppression ( prednisone, cyclosporin A)
• Removal of thymus (some MG patients)
• Plasmapheresis (remove Ab-Ag complexes)
• T-cell vaccination (activate suppressing T cells??)
• Block MHC with similar peptide
• Anti-CD4 monoclonal Ab
• Anti-IL2R monoclonal Ab

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Major Histocompatibility

• The proteins encoded by the MHC are expressed on the surface of

• Structure of HLA molecules of both classes enables

• Polymorphic (predominantly in the cleft).

• Nonpolymorphic part of the molecule contains binding

Class II molecule (HLA-DR, DQ, DP)

Class III encodes for immune components such as

-MHC class I occurs as an α chain

- The α1 binds to unit of the non-MHC

Cytoplasmic Cytoplasmic tails

 It is very difficult to find same MHC among

 Different individuals have different ability of

The number of gene loci for MHC class I and

class II molecules varies between species and

between different haplotypes within each species.

HLA class III. are soluble molecules as complement,TNF,

HSP .Many other proteins involved in antigen presentation

Cause graft rejection due to variable HLA

molecules in each persons

 Histocompatibility antigens are the targets

Type 1 diabetes DR3 .DR4 ,

Multiple sclerosis DR2

Rheumatoid arthritis DR4

 It is very difficult to find same MHC among

 Different individuals have different ability of

Normal: reactions Controlled response to

• Anti-collagen Ag damages lung and kidney

• Anti-sperm Ab produced in some men after vasectomy

• May be triggered by injury or infection

• High level of APCs with “second signal” breaks anergy

• MHC have got critical role in maturation of T cell &

• MHC ll genes are directly responsible for auto

• Removal of thymus (some MG patients)

• Plasmapheresis (remove Ab-Ag complexes)

• T-cell vaccination (activate suppressing T cells??)

• Block MHC with similar peptide

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