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[[Image:MHC.jpg|thumb|right|250px|Major Histocompatibility Complexes - B. Catchpole, RVC 2008]]

[[Image:MHC.jpg|thumb|right|250px|Major Histocompatibility Complexes - B. Catchpole, RVC 2008]]

==Introduction==

==Introduction==

T-cells rely on Major Histocompatability Complexes (MHC), which are molecules manufactured within cells for the purpose of presenting antigen fragments so that they can be detected by the immune system. MHC has evolved to form two classes for antigen presentation: '''MHC I''' presents digested fragments from antigen in '''cellular cytoplasm''', and '''MHC II''' presents digested fragments from antigen in the '''tissue fluid'''. MHC I tends to bind slightly smaller peptides (~9 amino acids) than MHC II (~15 amino acids).

T-cells rely on Major Histocompatability Complexes (MHC), which are molecules manufactured within cells for the purpose of presenting antigen fragments so that they can be detected by the immune system. MHC has evolved to form two classes for antigen presentation: '''MHC I''' presents digested fragments from antigen in '''cellular cytoplasm''', and '''MHC II''' presents digested fragments from antigen in the '''tissue fluid''' (extracellular). MHC I tends to bind slightly smaller peptides (~9 amino acids) than MHC II (~15 amino acids).

==MHC I==

==MHC I==

[[Image:MHC I Structure.jpg|thumb|right|200px| Structure of MHC I molecule - Copyright Prof Dirk Werling DrMedVet PhD MRCVS]]

[[Image:MHC I Structure.jpg|thumb|right|200px| Structure of MHC I molecule - Copyright Prof Dirk Werling DrMedVet PhD MRCVS]]

MHC class I is expressed on virtually all nucleated cells and consists of a membrane-associated heavy chain bound non-covalently with a secreted light chain. The heavy chain is made up of three distinct extracellular protein domains - α1, α2 and α3. The heavy chain C - terminus is cytoplasmic.

MHC class I is expressed on virtually all nucleated cells (so, for example, it is not expressed on erythrocytes), although quantity varies betweeen cell types, and consists of a membrane-associated heavy chain bound non-covalently with a secreted light chain. The heavy chain is made up of three distinct extracellular protein domains - α1, α2 and α3. The heavy chain C - terminus is cytoplasmic.

The light chain is known as β2-microglobulin and is similar in structure to one of the heavy chain domains. It is not membrane associated but binds to the α3-domain of the heavy chain.  

The light chain is known as β2-microglobulin and is similar in structure to one of the heavy chain domains. It is not membrane associated but binds to the α3-domain of the heavy chain.  

===Presentation Pathway===

===Presentation Pathway===

[[Image:MHC I processing.jpg|thumb|200px|left|'''MHC I presentation pathway, courtesy of B. Catchpole, 2008''']]

[[Image:MHC I processing.jpg|thumb|200px|left|'''MHC I presentation pathway, courtesy of B. Catchpole, 2008''']]

MHC I presents '''endogenous''' (intracellular) peptides. Viral proteins are broken down to peptides by the proteasome and transferred to the endoplasmic reticulum (ER) via transporters associated with antigen processing (TAP) molecules. In the ER peptides are processed with empty MHC I molecules and exported to the cell surface for presentation to the T-cell receptors of [[T_cells#Cytotoxic_CD8.2B|CD8⁺ T-cells]]

MHC I presents '''endogenous''' (intracellular) peptides. Viral proteins are broken down to peptides by the proteasome and transferred to the endoplasmic reticulum (ER) via transporters associated with antigen processing (TAP) molecules. In the ER peptides are processed with empty MHC I molecules and exported to the cell surface for presentation to the T-cell receptors of [[T_cells#Cytotoxic_CD8.2B|CD8⁺ T-cells]]. The purpose of presentation in this manner is to kill the cell to prevent viral replication. Activation of the cell with '''Interferon''' enhances expression of MHC class I molecules as part of the [[Innate Immunity to Viruses|innate immunity]] to viruses.

==MHC II==

==MHC II==

===Presentation Pathway===

===Presentation Pathway===

[[File:MHC Class II Presentation.png|thumb|left|200px|MHC Class II Presentation pathway - RJ Francis, RVC, 2012]]

[[File:MHC Class II Presentation.png|thumb|left|200px|MHC Class II Presentation pathway - RJ Francis, RVC, 2012]]

MHC II presents '''exogenous''' (ECF) peptides. Endocytosed antigen interacts with MHC II in the cytoplasm to form a complex:

MHC II presents '''exogenous''' (Extracellular fluid - ECF) peptides. Endocytosed antigen interacts with MHC II in the cytoplasm to form a complex:

*Antigen is endoycotsed from the ECF

*Antigen is endoycotsed from the ECF

*Lysosomes fuse with primary endosomes to digest the antigen to peptides

*Lysosomes fuse with primary endosomes to digest the antigen to peptides

==Antigen/MHC Interaction==

==Antigen/MHC Interaction==

MHC molecules do not recognise specific amino acid sequences of antigens, rather they recognise particular motifs of amino acids. The association of any MHC allele with a peptide may be determined by the presence of as few as two amino acids, however these determinants must be present in a particular array. The actual identity of the amino acids in not important for MHC binding but the physical and chemical characteristics of the amino acid are vitally important.

MHC molecules do not recognise specific amino acid sequences of antigens, rather they recognise particular motifs of amino acids. The association of any MHC allele with a peptide may be determined by the presence of as few as two amino acids, however these determinants must be present in a particular array. The actual identity of the amino acids is not important for MHC binding, but the physical and chemical characteristics of the amino acid are vitally important.

Interactions of individual amino acids at the head and tail of the peptide-binding groove control the binding of peptides. The amino acids are mainly positioned at the floor of the antigen-binding groove, or within the helices facing into the groove. MHC amino acids associate with the amino acids near the ends of the peptides and the intervening stretch of peptide folds into a helix within the groove.

Interactions of individual amino acids at the head and tail of the peptide-binding groove control the binding of peptides. The amino acids are mainly positioned at the floor of the antigen-binding groove, or within the helices facing into the groove. MHC amino acids associate with the amino acids near the ends of the peptides and the intervening stretch of peptide folds into a helix within the groove.

MHC molecules have the capacity to bind to trillions of different peptides. They adopt a flexible, floppy conformation until peptide binding when the molecules fold around the peptide to increase the stability of the complex. A small number of anchor residues then tether the peptide allowing different sequences between anchors and different lengths of peptides to bind.

MHC molecules have the capacity to bind to trillions of different peptides. They adopt a flexible, floppy conformation until peptide binding when the molecules fold around the peptide to increase the stability of the complex. A small number of anchor residues then tether the peptide. This configuration allows different sequences between anchors, and also allows peptides of different lengths to bind.

==TCR-MHC Interaction==

==TCR-MHC Interaction==

[[Image:MHC T cell Interaction.jpg|thumb|right|200px|Molecules of T lymphocyte recognition - Copyright Prof Dirk Werling DrMedVet PhD MRCVS]]

[[Image:MHC T cell Interaction.jpg|thumb|right|200px|Molecules of T lymphocyte recognition - Copyright Prof Dirk Werling DrMedVet PhD MRCVS]]

Only peptide associated with self-MHC will interact with and activate [[T cells]], which cannot be activated by a peptide on a foreign cell.

Only peptide associated with MHC will interact with and activate [[T cells]]. T cells therefore cannot be directly activated by a peptide on a foreign organism.

T cells will react against foreign MHC molecules and this is the basis of graft rejection

T cells will react against foreign MHC molecules (e.g. from a different person) and this is the basis of graft rejection, for example in Heart transplants.

==MHC Genetics (Polymorphism)==

==MHC Genetics (Polymorphism)==

===MHC Polymorphism In People===

===MHC Polymorphism In People===

* There are three types (loci) of MHC class I molecules known as human leukocyte antigen (HLA)- A, B, and C

* There are three types (loci) of MHC class I molecules known as human leukocyte antigen (HLA) - A, B, and C

* Equally there are three loci of MHC class II molecules - HLAs DP, DQ and DR

* Equally there are three loci of MHC class II molecules - HLAs DP, DQ and DR

In the entire human population there are only approximately 50 different variants (alleles) at each MHC class I and class II locus.

In the entire human population there are only approximately 50 different variants (alleles) at each MHC class I and class II locus.

The variation within MHC class I is entirely based on the class I heavy chain (the β2m is invariant). The variation within MHC class II is mainly within the β chains. Every individual has two alleles at each MHC locus inherited one from each parent. Any individual will therefore express two variants at most at each locus.

The variation within MHC class I is entirely based on the class I heavy chain (the β2m is invariant). The variation within MHC class II is mainly within the β chains. Every individual has two alleles at each MHC locus inherited one from each parent. Any individual will therefore express two variants at most at each locus.

This gives a maximum variability for an individual of:

This gives a maximum variability for an individual of:

* 6 different variants of MHC class I (2 each of HLA- A, B and C)

* 6 different variants of MHC class I (2 each of HLA - A, B and C)

* 6 different variants of MHC class II (2 each of HLA- DP, DQ and DR)

* 6 different variants of MHC class II (2 each of HLA - DP, DQ and DR)

Many animal species have fewer loci than the human e.g. ruminants have no MHC class II DP.

Many animal species have fewer loci than the human e.g. ruminants have no MHC class II DP.

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{{Jim Bee 2007}}

{{Jim Bee 2007}}

[[Category:Adaptive Immune System]]

[[Category:Adaptive Immune System]]

[[Category:Lymphocytes]]

[[Category:Lymphocytes]]

[[Category:Image Review]]

[[Category:Image Review]]