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Major Histocompatability Complexes (view source)
Revision as of 15:14, 28 August 2008
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==Structure and Function of MHC Class I==
=Classes=
==MHC I==
===Structure===
===Structure===
* MHC class I is expressed on virtually all nucleated cells
* 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 consists of a membrane-associated heavy chain bound non-covalently with a secreted light chain.
** Heavy chain:
** Heavy chain:
*** Made up of three distinct extracellular protein domains.
*** Made up of three distinct extracellular protein domains
**** α1, α2 and α3.
**** α1, α2 and α3
*** The C- terminus is cytoplasmic.
*** The C- terminus is cytoplasmic
** Light chain:
** Light chain:
*** Known as β2-microglobulin.
*** Known as β2-microglobulin
*** Similar in structure to one of the heavy chain domains.
*** Similar in structure to one of the heavy chain domains
*** Not membrane associated.
*** Not membrane associated
**** But binds to the α3-domain of the heavy chain.
**** But binds to the α3-domain of the heavy chain
* The MHC class I domains are structurally and genetically related to immunoglobulin and TcR domains.
* 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 outer domains (α1 and α2) are like the variable domains
** The α3 domain and β2m are like thrconstant domains.
** The α3 domain and β2m are like thrconstant domains
* MHC class I molecules are folded to form specific 3-dimensional structures.
* 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.
** The α1 and α2 domains are folded to produce an antigen-binding groove
*** This groove can bind molecules of a limited size only.
*** 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
**** This limits the size of epitope seen by the T-cell receptors.
===Function===
===Function===
* MHC class I molecules bind antigenic peptides derived from within the cell and present these to the T-cell receptors of '''CD8+ T-cells'''
** E.g. virus-encoded antigen
* Endogenously produced proteins are produced in the cell cytoplasm
** Intracellular pathogens utilise this cellular metabolic machinery for protein synthesis
** Many of the proteins synthesised are not used and are re-utilised by the cell
*** Peptides from these proteins are transported to the Golgi apparatus by specific transporter molecules
*** These peptides then interact with newly synthesized MHC class I molecules.
* Only MHC class I that is associated with peptide will be expressed at the surface
** The immune system is therefore able to see antigen from intracleeular pathogens
==MHC II==
===Structure===
===Structure===
* MHC class II is expressed mainly on '''macrophages''', '''dendritic cells''' and '''B-lymphocytes'''
* MHC class II is expressed mainly on macrophages, dendritic cells and B-lymphocytes.
* MHC class II consists of membrane-associated α and β chains
* MHC class II consists of membrane-associated α and β chains.
** Each chain is a transmembrane glycoprotein
** Each chain is a transmembrane glycoprotein.
** The extracellular parts of each chain have two Ig-like domains
** The extracellular parts of each chain have two Ig-like domains.
*** α1 and 7alpha;2, β1 and β2
*** α1 and 7alpha;2, β1 and β2.
**** The outer domains (α1 and β1) are variable-like
**** The outer domains (α1 and β1) are variable-like.
**** The inner domains (α2 and β2) are constant-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 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
** 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
*** Produce the antigen-binding groove.
===Function===
===Function===
* MHC class II molecules bind antigenic peptides and present them to TCR on CD4+ T-cells
* MHC class II molecules bind antigenic peptides and present them to TcR on CD4+ T-cells.
* The antigen-binding groove is larger and more open than that of MHC class I
* The antigen-binding groove is larger and more open than that of MHC class I.
** MHC II can therefore interact with larger peptides
** MHC II can therefore interact with larger peptides.
* MHC class II are present on those cells that have antigen-processing ability
* MHC class II are present on those cells that have antigen-processing ability.
** Interact with antigenic peptides originating from an extracellular source
** Interact with antigenic peptides originating from an extracellular source.
* After synthesis, MHC class II molecules are transported into special endosomes
* After synthesis, MHC class II molecules are transported into special endosomes.
** These endosomes fuse with lysosomes that contain the digested remnants of phagocytosed microorganisms
** These endosomes fuse with lysosomes that contain the digested remnants of phagocytosed microorganisms.
*** The peptides from the lysosome interact with the MHC class II molecules
*** The peptides from the lysosome interact with the MHC class II molecules.
**** The peptide-MHC class II complex gets transported to the cell surface
**** The peptide-MHC class II complex gets transported to the cell surface.
==Interaction of MHC With Antigen==
==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
===TCR-MHC Interaction===
* 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
===TcR-MHC Interaction===
* 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.
===The Genetics of the MHC===
===The Genetics of the MHC===
* Different individuals have different critical amino acids within the MHC
* Different individuals have different critical amino acids within the MHC.
** I.e. different amino acids that determine peptide binding
** I.e. different amino acids that determine peptide binding.
** This variation is termed '''MHC polymorphism'''
** This variation is termed '''MHC polymorphism'''.
* There are millions of variations in antibodies and TCR
* There are millions of variations in antibodies and TcR.
** However, with MHC there is very limited variation between molecules
** However, with MHC there is very limited variation between molecules.
* MHC polymorphism has been best studied in the human
* MHC polymorphism has been best studied in the human.
===In the Human===
===In the Human===
* Humans express:
* Humans express:
** Three types (loci) of MHC class I molecules.
** Three types (loci) of MHC class I molecules
*** HLA (Human Leukocyte Antigen)- A, B, and C.
*** HLA (Human Leukocyte Antigen)- A, B, and C
** Three loci of MHC class II molecules.
** Three loci of MHC class II molecules
*** HLA-DP, DQ and DR.
*** 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.
* 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 variation within MHC class I is entirely on the class I heavy chain
*** The β2m is invariant.
*** The β2m is invariant
** The variation within MHC class II is mainly within the β chains.
** The variation within MHC class II is mainly within the β chains
* Every individual has two alleles at each MHC locus.
* Every individual has two alleles at each MHC locus
** One inherited from each parent.
** One inherited from each parent
** Any individual will therfore express two variants at most at each locus.
** Any individual will therfore 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.
**** 6 different variants of MHC class I
***** 2 each of HLA- A, B and C.
***** 2 each of HLA- A, B and C
**** 6 different variants of MHC class II.
**** 6 different variants of MHC class II
***** 2 each of HLA- DP, DQ and DR.
***** 2 each of HLA- DP, DQ and DR
* Many animal species have fewer loci than the human.
* Many animal species have fewer loci than the human
** E.g. ruminants have no MHC class II DP.
** E.g. ruminants have no MHC class II DP
===MHC and Disease===
===MHC and Disease===
* Antigen from a pathogen has to be seen by the host MHC before an efficient immune response can occur
* 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 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 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
*** 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:
* 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 .
** MHC class II alleles DR13/DR1*1301 are prevalent in Central and Western Africa
*** Impart resistance to malaria.
*** Impart resistance to malaria
** MHC-DRB1 is prevalent in Western Europe, but rare in the Inuit populations of North America.
** 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.
*** Associated with the clearance of hepatitis B infection in Western Europe
*** Inuits have the highest incidence of hepatitis B in the world.
*** 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 humans there are also strong associations between certain alleles and some autoimmune diseases, for example:
*** Diabetes mellitus.
*** Diabetes mellitus
*** Ankylosing spondylitis.
*** Ankylosing spondylitis
*** Rheumatoid arthritis.
*** Rheumatoid arthritis