Difference between revisions of "Major Histocompatability Complexes"

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{{OpenPagesTop}}
 
 
[[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''' (extracellular). 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) to present antigen fragments for their recognition. MHC has evolved to form two classes for antigen presentation: '''MHC I''' presents digestion fragments from antigen in '''cellular cytoplasm''', and '''MHC II''' presents digestion fragments from antigen in the '''tissue fluid'''. As such, MHC I tends to bind slightly smaller peptides (~9 amino acids) than MHC II (~15 amino acids).
 +
 
 +
=Classes=
  
 
==MHC I==
 
==MHC I==
 +
[[Image:MHC I processing.jpg|thumb|200px|right|'''MHC I presentation pathway, courtesy of B. Catchpole, 2008''']]
 
===Structure===
 
===Structure===
−
[[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
−
 
+
* MHC class I consists of a membrane-associated heavy chain bound non-covalently with a secreted light chain
−
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.
+
** Heavy chain:
−
 
+
*** Made up of three distinct extracellular protein domains
−
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.  
+
**** α1, α2 and α3
−
The MHC class I domains are structurally and genetically related to immunoglobulin and TcR domains; the outer domains (α1 and α2) are like the variable domains and the α3 domain and β2m are like the constant domains.
+
*** The C- terminus is cytoplasmic
−
 
+
** Light chain:
−
MHC class I molecules are folded to form specific 3-dimensional structures. The α1 and α2 domains are folded to produce an antigen-binding groove which can bind molecules of a limited size only (8-10 amino acids). This limits the size of epitope seen by the T-cell receptors.
+
*** Known as β2-microglobulin
 +
*** Similar in structure to one of the heavy chain domains
 +
*** Not membrane associated
 +
**** But binds to the α3-domain of the heavy chain
 +
[[Image:MHC I Structure.jpg|thumb|right|150px| Structure of MHC I molecule - Copyright Prof Dirk Werling DrMedVet PhD MRCVS]]
 +
* The MHC class I domains are structurally and genetically related to immunoglobulin and TcR domains
 +
** The outer domains (α1 and α2) are like the variable domains
 +
** The α3 domain and β2m are like thrconstant domains
 +
* MHC class I molecules are folded to form specific 3-dimensional structures
 +
** The α1 and α2 domains are folded to produce an antigen-binding groove
 +
*** This groove can bind molecules of a limited size only (8-10 amino acids)
 +
**** This limits the size of epitope seen by the T-cell receptors
  
 
===Presentation Pathway===
 
===Presentation Pathway===
−
[[Image:MHC I processing.jpg|thumb|200px|left|'''MHC I presentation pathway, courtesy of B. Catchpole, 2008''']]
+
*MHC I presents '''endogenous''' (that is, intracellular) peptides
−
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<sup>+</sup> 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.
+
*Viral proteins are broken down to peptides by the proteasome and transferred to the endoplasmic reticulum via TAP (Transporters associated with Antigen Processing) molecules
 +
*In the ER peptides are processed with empty MHC I molecules and exported to the cell surface for presentation
 +
* MHC class I molecules present these to the T-cell receptors of [[Lymphocytes#Cytotoxic CD8+|'''CD8+ T-cells''']]
  
 
==MHC II==
 
==MHC II==
−
[[Image:MHC II Structure.jpg|thumb|right|200px| Structure of MHC II molecule - Copyright Prof Dirk Werling DrMedVet PhD MRCVS]]
+
[[Image:MHC II presentation.jpg|thumb|200px|right|'''MHC II presentation, courtesy of Janeway, et al. 2008''']]
  
 
===Structure===
 
===Structure===
−
MHC class II is expressed mainly on [[Macrophages|macrophages]], [[T cell differentiation#Antigen Presentation by Dendritic Cells|dendritic cells]] and [[B cells|B-lymphocytes]]. MHC class II consists of membrane-associated &alpha; and &beta; chains with each chain being a transmembrane glycoprotein. The extracellular parts of each chain have two Ig-like domains - &alpha;1 and &alpha;2, &beta;1 and &beta;2. The &beta;2 domain is responsible for the activation of [[T cells|T helper cells]] through the interaction with the CD4<sup>+</sup> on the cell surface of the T helper cells. The outer domains (&alpha;1 and &beta;1) are variable and the inner domains (&alpha;2 and &beta;2) are constant.
+
* MHC class II is expressed mainly on [[Macrophages|macrophages]], [[T cell differentiation#Antigen Presentation by Dendritic Cells|dendritic cells]] and [[Lymphocytes#B Cells|B-lymphocytes]]
−
 
+
* MHC class II consists of membrane-associated &alpha; and &beta; chains
−
The 3-dimensional structure of MHC class II is similar to MHC class I; the outer domains of the &alpha; and &beta; chains fold in a similar way to the α1 and α2 domains of class I to produce the antigen-binding groove.
+
**  Each chain is a transmembrane glycoprotein
−
 
+
** The extracellular parts of each chain have two Ig-like domains
 +
*** &alpha;1 and 7alpha;2, &beta;1 and &beta;2
 +
**** The outer domains (&alpha;1 and &beta;1) are variable-like
 +
**** The inner domains (&alpha;2 and &beta;2) are constant-like
 +
* The 3-dimensional structure of MHC class II is similar to MHC class I
 +
** The outer domains of the &alpha; and &beta; chains fold in a similar way to the α1 and α2 domains of class I
 +
*** Produce the antigen-binding groove
 +
[[Image:MHC II Structure.jpg|thumb|right|150px| Structure of MHC II molecule - Copyright Prof Dirk Werling DrMedVet PhD MRCVS]]
 
===Presentation Pathway===
 
===Presentation Pathway===
−
[[File:MHC Class II Presentation.png|thumb|left|200px|MHC Class II Presentation pathway - RJ Francis, RVC, 2012]]
+
*MHC II presents '''exogenous''' (that is, derived from the ECF) peptides
−
MHC II presents '''exogenous''' (Extracellular fluid - ECF) peptides. Endocytosed antigen interacts with MHC II in the cytoplasm to form a complex:
+
*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
−
*MHC II is meanwhile being produced by the endoplasmic reticulum, along with an invariant chain chaperone
+
**MHC II is meanwhile being produced by the endoplasmic reticulum, along with an invariant chain chaperone
−
*These pathways (endoytotic and secretory) merge to allow interaction between the antigen and MHC II and the invariant chain is digested, leaving a CLIP peptide in the binding groove.
+
**These pathways (endoytotic and secretory) merge to allow interaction between the antigen and MHC II:
−
*Foreign antigen then replaces the CLIP peptide
+
***The invariant chain is digested, leaving a CLIP peptide in the binding groove
−
*The MHC II-antigen complex is then secreted to the cell surface for presentation to [[T_cells#Helper_CD4.2B|CD4<sup>+</sup> T-cells]]
+
***Foreign antigen then replaces the CLIP peptide
−
 
+
*The MHC II-antigen complex is then secreted to the cell surface for presentation to [[Lymphocytes#Helper CD4+|CD4+ T-cells]]
−
==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 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.
 
  
−
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.
+
=Interaction of MHC With Antigen=
 +
* The MHC molecules do not recognise specific amino acid sequences of antigens
 +
** Instead, 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 within a particular array
 +
* The actual identity of the amino acids in not important for MHC binding
 +
** Instead, the physical and chemical characteristics of the amino acid are vital
 +
* Interactions of individual amino acids at the head and tail of the peptide-binding groove control the binding of peptides
 +
** Are mainly positioned at the floor of the antigen-binding groove, or within the helices facing into the groove
 +
** These MHC amino acids associate with amino acids near the ends of the peptides
 +
*** The intervening stretch of peptide folds into a helix within the groove
 +
*** Is the target for [[Lymphocytes#T Cells|T cell]] receptor recognition
 +
*MHC molecules have the capacity to bind to trillions of different peptides
 +
**Adopt a flexible '''floppy''' conformation until a peptide binds
 +
**Folds around the peptide to increase stability of the complex
 +
**Uses a small number of anchor residues to tether the peptide allowing different sequences between anchors and different lengths of peptides 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|150px|Molecules of T lymphocyte recognition - Copyright Prof Dirk Werling DrMedVet PhD MRCVS]]
−
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.
+
* Only peptide associated with self-MHC will interact with and activate [[Lymphocytes#T Cells|T cells]]
−
 
+
** [[Lymphocytes#T Cells|T cells]] cannot be activated by a peptide on a foreign cell
−
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.
+
** [[Lymphocytes#T Cells|T cells]] will react against foreign MHC molecules
−
 
+
*** This is the basis of graft rejection
−
==MHC Genetics (Polymorphism)==
 
−
[[Image:Location of Polymorphic Residues 1.jpg|thumb|right|200px|Location of Polymorphic Residues - Copyright Prof Dirk Werling DrMedVet PhD MRCVS]]
 
−
Each individual has 6 types of MHC; MHC molecules are co-dominantly expressed. The combination of alleles in a chromosome is called an '''MHC Haplotype'''.
 
  
−
Different individuals have different critical amino acids within the MHC i.e. different amino acids that determine peptide binding. This variation is termed '''MHC polymorphism'''.
+
[[Image:Location of Polymorphic Residues 1.jpg|thumb|right|150px|Location of Polymorphic Residues - Copyright Prof Dirk Werling DrMedVet PhD MRCVS]]
−
*Each polymorphic variant is called an '''allele'''
 
−
Both type I and type II MHC molecules are highly polymorphic - the most polymorphic regions of class I are in the alpha 1 and alpha 2 domains. The most polymorphic regions of class II are in the alpha 1 and beta 1 domains.
 
  
−
Most polymorphisms are point mutations and there are millions of variations in [[Immunoglobulins|antibodies]] and TCRs; however, with MHC there is very limited variation between molecules. Allelic variation within the MHC molecule occurs at the peptide binding site and on the top or sides of the binding cleft. Polymorphisms and polygenism in the MHC provides protection from pathogens evading the immune system.
+
=The Genetics of the MHC (Polymorphism)=
 +
*Each individual has 6 types of MHC
 +
*MHC molecules are co-dominantly expressed
 +
*The combination of alleles in a chromosome is called an '''MHC Haplotype'''
 +
* Different individuals have different critical amino acids within the MHC
 +
** I.e. different amino acids that determine peptide binding
 +
** This variation is termed '''MHC polymorphism'''
 +
**Each polymorphic variant is called an '''allele'''
 +
*Both type I and type II MHC molecules are highly polymorphic
 +
**Most polymorphic regions of class I are in the alpha 1 and alpha 2 domains
 +
**Most polymorphic regions of class II are in the alpha 1 and beta 1 domains
 +
*Most polymorphisms are point mutations
 +
* There are millions of variations in [[Immunoglobulins|antibodies]] and TCR
 +
** However, with MHC there is very limited variation between molecules
 +
*Allelic variation within the MHC molecule occurs at the peptide binding site and on the top or sides of the binding cleft
 +
*Polymorphisms and polygenism in the MHC protects the population from pathogens evading the immune system
 
* MHC polymorphism has been best studied in the human
 
* MHC polymorphism has been best studied in the human
−
[[Image:Location of Polymorphic Residues 2.jpg|thumb|right|200px|Location of Polymorphic Residues - Copyright Prof Dirk Werling DrMedVet PhD MRCVS]]
+
[[Image:Location of Polymorphic Residues 2.jpg|thumb|right|150px|Location of Polymorphic Residues - Copyright Prof Dirk Werling DrMedVet PhD MRCVS]]
−
 
 
−
===MHC Polymorphism In People===
 
−
* 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
 
−
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 &beta; 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:
 
−
* 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)
 
−
Many animal species have fewer loci than the human e.g. ruminants have no MHC class II DP.
 
−
 
 
−
==MHC and the Disease Process==
 
−
Antigen from a pathogen has to be seen by the host MHC before an efficient immune response can occur so inevitably there is a constant evolutionary battle between the host and potential pathogens. Specifically, there is selective pressure on the pathogen to evolve proteins that do not interact with the host MHC and equally a selective pressure on the host to continue to be able to recognize the pathogen.
 
−
 
 
−
One consequence of this parallel evolution is that host-pathogen relationships can lead to the selection of particular MHC variants, for example:
 
−
* MHC class II alleles DR13/DR1*1301 are prevalent in Central and Western Africa and impart resistance to malaria.
 
−
* MHC-DRB1 is prevalent in Western Europe, but rare in the Inuit populations of North America, and is associated with the clearance of hepatitis B infection in Western Europe, and so, perhaps unsuprisingly, Inuits have the highest incidence of hepatitis B in the world.
 
  
−
In humans there are also strong associations between certain alleles and some autoimmune diseases, for example:
+
==In the Human==
−
* [[Diabetes Mellitus|Diabetes mellitus]]
+
* Humans express:
−
* Ankylosing spondylitis
+
** Three types (loci) of MHC class I molecules
−
* Rheumatoid arthritis
+
*** HLA (Human Leukocyte Antigen)- A, B, and C
−
<br><br>
+
** Three loci of MHC class II molecules
−
{{Jim Bee 2007}}
+
*** HLA-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
 +
**  The variation within MHC class I is entirely on the class I heavy chain
 +
*** The β2m is invariant
 +
** The variation within MHC class II is mainly within the &beta; chains
 +
* Every individual has two alleles at each MHC locus
 +
** One inherited from each parent
 +
** Any individual will therfore express two variants at most at each locus
 +
*** 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 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
  
 +
=MHC and Disease=
 +
* Antigen from a pathogen has to be seen by the host MHC before an efficient immune response can occur
 +
** There is therefore a constant evolutionary battle between the host and the pathogen
 +
*** There is selective pressure on the pathogen to evolve proteins that do not interact with the host MHC
 +
*** There is selective pressure on the host to continue to recognize the pathogen
 +
* The consequence of this parallel evolution is that host-pathogen relationships can lead to the selection of particular MHC variants, for example:
 +
** MHC class II alleles DR13/DR1*1301 are prevalent in Central and Western Africa
 +
*** Impart resistance to malaria
 +
** MHC-DRB1 is prevalent in Western Europe, but rare in the Inuit populations of North America
 +
*** Associated with the clearance of hepatitis B infection in Western Europe
 +
*** Inuits have the highest incidence of hepatitis B in the world
 +
** In humans there are also strong associations between certain alleles and some autoimmune diseases, for example:
 +
*** Diabetes mellitus
 +
*** Ankylosing spondylitis
 +
*** Rheumatoid arthritis
  
−
{{OpenPages}}
 
 
[[Category:Adaptive Immune System]]
 
[[Category:Adaptive Immune System]]
 
[[Category:Lymphocytes]]
 
[[Category:Lymphocytes]]
 
[[Category:Image Review]]
 
[[Category:Image Review]]

Revision as of 12:34, 18 August 2010

Major Histocompatibility Complexes - B. Catchpole, RVC 2008

Introduction

T-cells rely on Major Histocompatability Complexes (MHC) to present antigen fragments for their recognition. MHC has evolved to form two classes for antigen presentation: MHC I presents digestion fragments from antigen in cellular cytoplasm, and MHC II presents digestion fragments from antigen in the tissue fluid. As such, MHC I tends to bind slightly smaller peptides (~9 amino acids) than MHC II (~15 amino acids).

Classes

MHC I

MHC I presentation pathway, courtesy of B. Catchpole, 2008

Structure

  • MHC class I is expressed on virtually all nucleated cells
  • MHC class I consists of a membrane-associated heavy chain bound non-covalently with a secreted light chain
    • Heavy chain:
      • Made up of three distinct extracellular protein domains
        • α1, α2 and α3
      • The C- terminus is cytoplasmic
    • Light chain:
      • Known as β2-microglobulin
      • Similar in structure to one of the heavy chain domains
      • Not membrane associated
        • But binds to the α3-domain of the heavy chain
Structure of MHC I molecule - Copyright Prof Dirk Werling DrMedVet PhD MRCVS
  • The MHC class I domains are structurally and genetically related to immunoglobulin and TcR domains
    • The outer domains (α1 and α2) are like the variable domains
    • The α3 domain and β2m are like thrconstant domains
  • MHC class I molecules are folded to form specific 3-dimensional structures
    • The α1 and α2 domains are folded to produce an antigen-binding groove
      • This groove can bind molecules of a limited size only (8-10 amino acids)
        • This limits the size of epitope seen by the T-cell receptors

Presentation Pathway

  • MHC I presents endogenous (that is, intracellular) peptides
  • Viral proteins are broken down to peptides by the proteasome and transferred to the endoplasmic reticulum via TAP (Transporters associated with Antigen Processing) molecules
  • In the ER peptides are processed with empty MHC I molecules and exported to the cell surface for presentation
  • MHC class I molecules present these to the T-cell receptors of CD8+ T-cells

MHC II

MHC II presentation, courtesy of Janeway, et al. 2008

Structure

  • MHC class II is expressed mainly on macrophages, dendritic cells and B-lymphocytes
  • MHC class II consists of membrane-associated α and β chains
    • Each chain is a transmembrane glycoprotein
    • The extracellular parts of each chain have two Ig-like domains
      • α1 and 7alpha;2, β1 and β2
        • The outer domains (α1 and β1) are variable-like
        • The inner domains (α2 and β2) are constant-like
  • The 3-dimensional structure of MHC class II is similar to MHC class I
    • The outer domains of the α and β chains fold in a similar way to the α1 and α2 domains of class I
      • Produce the antigen-binding groove
Structure of MHC II molecule - Copyright Prof Dirk Werling DrMedVet PhD MRCVS

Presentation Pathway

  • MHC II presents exogenous (that is, derived from the ECF) peptides
  • Endocytosed antigen interacts with MHC II in the cytoplasm to form a complex:
    • Antigen is endoycotsed from the ECF
    • Lysosomes fuse with primary endosomes to digest the antigen to peptides
    • MHC II is meanwhile being produced by the endoplasmic reticulum, along with an invariant chain chaperone
    • These pathways (endoytotic and secretory) merge to allow interaction between the antigen and MHC II:
      • The invariant chain is digested, leaving a CLIP peptide in the binding groove
      • Foreign antigen then replaces the CLIP peptide
  • The MHC II-antigen complex is then secreted to the cell surface for presentation to CD4+ T-cells

Interaction of MHC With Antigen

  • The MHC molecules do not recognise specific amino acid sequences of antigens
    • Instead, 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 within a particular array
  • The actual identity of the amino acids in not important for MHC binding
    • Instead, the physical and chemical characteristics of the amino acid are vital
  • Interactions of individual amino acids at the head and tail of the peptide-binding groove control the binding of peptides
    • Are mainly positioned at the floor of the antigen-binding groove, or within the helices facing into the groove
    • These MHC amino acids associate with amino acids near the ends of the peptides
      • The intervening stretch of peptide folds into a helix within the groove
      • Is the target for T cell receptor recognition
  • MHC molecules have the capacity to bind to trillions of different peptides
    • Adopt a flexible floppy conformation until a peptide binds
    • Folds around the peptide to increase stability of the complex
    • Uses a small number of anchor residues to tether the peptide allowing different sequences between anchors and different lengths of peptides to bind

TCR-MHC Interaction

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
    • T cells cannot be activated by a peptide on a foreign cell
    • T cells will react against foreign MHC molecules
      • This is the basis of graft rejection
Location of Polymorphic Residues - Copyright Prof Dirk Werling DrMedVet PhD MRCVS

The Genetics of the MHC (Polymorphism)

  • Each individual has 6 types of MHC
  • MHC molecules are co-dominantly expressed
  • The combination of alleles in a chromosome is called an MHC Haplotype
  • Different individuals have different critical amino acids within the MHC
    • I.e. different amino acids that determine peptide binding
    • This variation is termed MHC polymorphism
    • Each polymorphic variant is called an allele
  • Both type I and type II MHC molecules are highly polymorphic
    • Most polymorphic regions of class I are in the alpha 1 and alpha 2 domains
    • Most polymorphic regions of class II are in the alpha 1 and beta 1 domains
  • Most polymorphisms are point mutations
  • There are millions of variations in antibodies and TCR
    • However, with MHC there is very limited variation between molecules
  • Allelic variation within the MHC molecule occurs at the peptide binding site and on the top or sides of the binding cleft
  • Polymorphisms and polygenism in the MHC protects the population from pathogens evading the immune system
  • MHC polymorphism has been best studied in the human
Location of Polymorphic Residues - Copyright Prof Dirk Werling DrMedVet PhD MRCVS

In the Human

  • Humans express:
    • Three types (loci) of MHC class I molecules
      • HLA (Human Leukocyte Antigen)- A, B, and C
    • Three loci of MHC class II molecules
      • HLA-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
    • The variation within MHC class I is entirely 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
    • One inherited from each parent
    • Any individual will therfore express two variants at most at each locus
      • 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 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

MHC and Disease

  • Antigen from a pathogen has to be seen by the host MHC before an efficient immune response can occur
    • There is therefore a constant evolutionary battle between the host and the pathogen
      • There is selective pressure on the pathogen to evolve proteins that do not interact with the host MHC
      • There is selective pressure on the host to continue to recognize the pathogen
  • The consequence of this parallel evolution is that host-pathogen relationships can lead to the selection of particular MHC variants, for example:
    • MHC class II alleles DR13/DR1*1301 are prevalent in Central and Western Africa
      • Impart resistance to malaria
    • MHC-DRB1 is prevalent in Western Europe, but rare in the Inuit populations of North America
      • Associated with the clearance of hepatitis B infection in Western Europe
      • Inuits have the highest incidence of hepatitis B in the world
    • In humans there are also strong associations between certain alleles and some autoimmune diseases, for example:
      • Diabetes mellitus
      • Ankylosing spondylitis
      • Rheumatoid arthritis
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