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Major Histocompatibility Complex(MHC)

Major Histocompatibility Complex(MHC)

What is MHC?– HLA– H-2 (in the mouse)– Minor histocompatibility antigens

What is MHC?– HLA– H-2 (in the mouse)– Minor histocompatibility antigens

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There may be polymorphic antigens other than MHC that differ between the donor and the recipient.

These antigens induce weak or slower ( more gradual) rejection reactions than do MHC molecules and are called Minor histocompatibility antigens.

There may be polymorphic antigens other than MHC that differ between the donor and the recipient.

These antigens induce weak or slower ( more gradual) rejection reactions than do MHC molecules and are called Minor histocompatibility antigens.

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Minor histocompatibility antigens are proteins that are processed an presented to host T cells association with self MHC molecules on host APCs (by indirect pathway).

Minor histocompatibility antigens are proteins that are processed an presented to host T cells association with self MHC molecules on host APCs (by indirect pathway).

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Significance of the MHCSignificance of the MHC

role in immune response role in organ transplantation role in predisposition to disease

role in immune response role in organ transplantation role in predisposition to disease

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Genetic barriers to transplantationGenetic barriers to transplantation

• autologous: in the same individual (autograft)

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

• homologous: between individuals of the same species (allograft)

• heterologous: between individuals different species (xenograft)

• autologous: in the same individual (autograft)

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

• homologous: between individuals of the same species (allograft)

• heterologous: between individuals different species (xenograft)

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Principles of transplantationPrinciples of transplantation

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Minor histocompatibility antigensand graft survival

Minor histocompatibility antigensand graft survival

minor histocompatibility antigens also cause rejection

The rejection time is variable but longer than that for major histocompatibility antigen

They have additive effects

minor histocompatibility antigens also cause rejection

The rejection time is variable but longer than that for major histocompatibility antigen

They have additive effects

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Graft versus host (GVH) diseaseGraft versus host (GVH) disease

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GVH disease in humansGVH disease in humans

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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

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The mouse MHC genesThe mouse MHC genes

I

DK

A E

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

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Polymorphism of MHC antigens (based on phenotype)

Polymorphism of MHC antigens (based on phenotype)

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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

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Polymorphism of MHC genes(based on DNA sequence/ PCR)

Polymorphism of MHC genes(based on DNA sequence/ PCR)

2096

22 481

360460

110220

0100200300400500

2096

22 481

360460

110220

0100200300400500

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MHC products expressed on cellsMHC products expressed on cells

If Jack and Jill have four children; Bo, Kim, Mo and Lee

They’ll all inherit antigens of the parental MHC

Oft their haplotypes will be of the father or mother

Unless during meiosis, a crossover should occur

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The inheritance of MHC genesThe inheritance of MHC genes

Jack Jill

D P

D Q

D R

B

C

A

1 2 3 4

Bo Kim M o Lee

1 3 41 2 3 42

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MHC products expressed on cellsMHC products expressed on cells

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Crossing overresults in new haplotypes

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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, etc.)

Differential expression of MHC antigens

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Alloreactivity of T cells:MLR and CTL generationAlloreactivity of T cells:

MLR and CTL generation

CD4+TH1

CD8+CTL

CD8+preCTL

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Alloreactivity of T cellsAlloreactivity of T cells

T CELLT CELL

DRW 11DRW 17

PositiveSelection

ThymusAlloreaction

(MLR)

Proliferation and

Differentiation

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Inflammation

lysis

ADCC

lysis

IL2, IFN

TNF, NO2

IL2, IL4, IL5

IL2, TNF, IFN

rejection

Mechanisms of graft rejectionMechanisms of graft rejection

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Tempo of rejection reactionTempo of rejection reaction

type of rejection

time taken cause

chronic months-years unclear causes: cross reactive Ab, immune complexes, slow cellular reaction, tolerance breakdown, disease recurrence

accelerated days reactivation of sensitized T cells (secondary response)

acute days-weeks

primary activation of T cells

hyperacute minutes- hours preformed anti-donor antibodies and complement

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Immunosuppressive agentsImmunosuppressive agents

application(s)mode of actionagent

corticosteroids, prednisone

anti-inflammatory, altering T-cell and PMN traffic

organ transplant, hypersensitivity, autoimmunity

rapamycin Inhibition of T cell activation by IL-2

organ transplant

cyclosporine, ticrolimus

inhibition of IL-2 production by T cells

organ transplant,

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Immunosuppressive agentsImmunosuppressive agents

application(s)mode of actionagent

azathioprine, 6-MP purine metabolism

organ transplant

methotrexate folate metabolism organ transplant

cyclophosphamide, melphalan

alkylation of DNA, RNA and proteins

autoimmune diseases, organ transplant

x-irradiation Lymphopenia malignancy/marrow transplantation

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Removal of T cells from marrow graftRemoval of T cells from marrow graft

Magnet

Magnetic antibodies

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HLA and disease associationHLA and disease association

Disease Associated alleles Frequency in

Relative riskpatients control

Ankylsoing spondylitis

Reiter’s disease

Acute anterior uveitis

Psoriasis vulgaris

Dermatitis herpetiformis

B27

B27

B27

CW6

DR3

9

79

52

87

85

9

9

9

33

26

87.4

37.0

10.4

13.3

15.4