MHC

Histocompatibility Ags

1-Minor Histocompatibility Complex

HLA

2-Major Histocompatiblity Complex H-2

Major Histocompatibility Complex(MHC)

Major Histocompatibility Complex(MHC)

What is MHC?– HLA– H-2– Minor histocompatibility antigens

What is MHC?– HLA– H-2– Minor histocompatibility antigens

Significance of the MHCSignificance of the MHC

role in immune responserole in organ transplantationrole in predisposition to disease

role in immune responserole in organ transplantationrole in predisposition to disease

Major Histocompatibility Complex: History

• Transplantation: autograft or autologus(syngraft) no regection allograft or allogenic graft rejection

Genetic barriers to transplantationGenetic barriers to transplantation

• autologous: in the same individual

• isologous: between genetically Identical individuals, i.e., identical twins (inbred animals)

• homologous: between individuals of the same species

• heterologous: between individuals different species

• autologous: in the same individual

• isologous: between genetically Identical individuals, i.e., identical twins (inbred animals)

• homologous: between individuals of the same species

• heterologous: between individuals different species

The laws of transplantationThe laws of transplantation

The mouse MHC genesThe mouse MHC genes

I

DK

A E

class II c lass Iclass I class III(C4, factor-B ,TNF, etc.)

Mouse MHC

• H-2K H-2 I-A= DP II human

• H-2D H-2 I-E = DR human

• H-2L

HLA Detection

• 1-by serologicaly

• 2-by mixed leukocyte reaction(MLR)

Cytotoxic T lymphocyte (CTL) generation

Cytotoxic T lymphocyte (CTL) generation

CD4+TH1

CD8+CTL

CD8+preCTL

The human MHC genesThe human MHC genes

class II c lass ID P D Q D R B C A

B C A

D P D Q D R

1 2 2 2 1 1 9 3 1 2 2 1 3

Polymorphism of MHC genesPolymorphism of MHC genes

10

76

18 32

221188

4285

0

50

100

150

200

250

DPA DPB DQA DQB DRB B C A

10

76

18 32

221188

4285

0

50

100

150

200

250

DPA DPB DQA DQB DRB B C A

Class-I expressed on all nucleated cells in man, and also on erythrocytes in mice.

Class-II expressed primarily on antigen presenting cells (dendritic cells, macrophages and B cells)

Differential expression of MHC antigens

PROPERTIES MHC

• Immune responses: antibody formation

• Highly polymorphic

• Bind peptide: recognized by T cells: Th__MHCII

• Tc__MHCI

• Co_dominant

• Three-dimensional structure determined by X-ray crystallography

Structure of Class I MHC

NH2

Alloantigenicsites

CHO

NH2

COOH

COOH

P

α1

α2

α3

β2

OH

Plasma membrane

Disulfide bridge

Papain cleavage

Cytoplasm

NH2

Structure of Class I MHC• Two polypeptide chains, a long α chain and a

short β chain, called β2 microglobulin • Four regions:1. Peptide-binding region - a groove formed from

α1 and α2 domains of the α chain : 8-10 residue,greatest variability,anchor site 2. Immunoglobulin-like region = highly conserved

α3 domain that homologus to Ig domain and non-covalently bound to beta2 Mic- site to which CD8 on T cell binds

Structure of Class I MHC(continued)

3. Transmembrane region – stretch of hydrophobic amino acids spanning membrane

4. Cytoplasmic region – contains sites for phosphorylation and binding to cytoskeletal elements

Structure of Class I MHC

NH2

Alloantigenicsites

CHO

NH2

COOH

COOH

P

α1

α2

α3

β2

OH

Plasma membrane

Disulfide bridge

Papain cleavage

Cytoplasm

NH2

Structure of Class I MHC Peptide-binding Region

• a “groove” composed of an α-helix on two opposite walls and eight β-pleated sheets forming the floor

• residues lining groove most polymorphic

• peptide in groove 8-10 amino acids long

• specific amino acid on peptide required for “anchor site” in groove

Variability For Polymorphism

Structure of Class II MHC

Plasma membrane

Cytoplasm

CHO

CHO

CHO

NH2 NH2

COOH COOH

α1

α2 β2

β1

Structure of Class II MHC• Two polypeptide chains, α and β, of

roughly equal length. • Four regions:1. Peptide-binding region – a groove

formed from the α1 and β1 domains of the α and β chains – site of polymorphism

2. Immunoglobulin-like region – conserved α2 and β2 domains – β2 is site to which CD4 on T cell binds