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* Only MHC class I that is associated with peptide will be expressed at the surface.
 
* 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.
 
** The immune system is therefore able to see antigen from intracleeular pathogens.
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==Structure and Function Of MHC Class II==
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===Structure===
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* MHC class II is expressed mainly on macrophages, dendritic cells and B-lymphocytes.
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* MHC class II consists of membrane-associated α and β chains.
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**  Each chain is a transmembrane glycoprotein.
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** The extracellular parts of each chain have two Ig-like domains.
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*** α1 and 7alpha;2, β1 and β2.
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**** The outer domains (α1 and β1) are variable-like.
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**** The inner domains (α2 and β2) are constant-like.
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* The 3-dimensional structure of MHC class II is similar to MHC class I.
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** The outer domains of the α and β chains fold in a similar way to the α1 and α2 domains of class I.
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*** Produce the antigen-binding groove.
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===Function===
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* MHC class II molecules bind antigenic peptides and present them to TcR on CD4+ T-cells.
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* The antigen-binding groove is larger and more open than that of MHC class I.
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** MHC II can therefore interact with larger peptides.
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* MHC class II are present on those cells that have antigen-processing ability.
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** Interact with antigenic peptides originating from an extracellular source.
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* After synthesis, MHC class II molecules are transported into special endosomes.
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** These endosomes fuse with lysosomes that contain the digested remnants of phagocytosed microorganisms.
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*** The peptides from the lysosome interact with the MHC class II molecules.
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**** The peptide-MHC class II complex gets transported to the cell surface.
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==Interaction of MHC With Antigen==
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* The MHC molecules do not recognise specific amino acid sequences of antigens.
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** Instead, they recognise particular motifs of amino acids.
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* The association of any MHC allele with a peptide may be determined by the presence of as few as two amino acids.
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** However, these determinants must be present within a particular array.
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* The actual identity of the amino acids in not important for MHC binding.
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** Instead, the physical and chemical characteristics of the amino acid are vital.
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* Interactions of individual amino acids at the head and tail of the peptide-binding groove control the binding of peptides.
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** Are mainly positioned at the floor of the antigen-binding groove, or within the helices facing into the groove.
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** These MHC amino acids associate with amino acids near the ends of the peptides.
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*** The intervening stretch of peptide folds into a helix within the groove.
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*** Is the target for T cell receptor recognition.
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===TcR-MHC Interaction===
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* Only peptide associated with self-MHC will interact with and activate T-cells.
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** T-cells cannot be activated by a peptide on a foreign cell.
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** T-cells will react against foreign MHC molecules.
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*** This is the basis of graft rejection.
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===The Genetics of the MHC===
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* Different individuals have different critical amino acids within the MHC.
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** I.e. different amino acids that determine peptide binding.
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** This variation is termed '''MHC polymorphism'''.
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* There are millions of variations in antibodies and TcR.
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** However, with MHC there is very limited variation between molecules.
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* MHC polymorphism has been best studied in the human.
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===In the Human===
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* Humans express:
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** Three types (loci) of MHC class I molecules.
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*** HLA (Human Leukocyte Antigen)- A, B, and C.
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** Three loci of MHC class II molecules.
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*** HLA-DP, DQ and DR.
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* In the entire human population there are only approximately 50 different variants (alleles) at each MHC class I and class II locus.
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**  The variation within MHC class I is entirely on the class I heavy chain.
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*** The β2m is invariant.
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** The variation within MHC class II is mainly within the β chains.
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* Every individual has two alleles at each MHC locus.
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** One inherited from each parent.
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** Any individual will therfore express two variants at most at each locus.
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*** This gives a maximum variability for an individual of:
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**** 6 different variants of MHC class I.
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***** 2 each of HLA- A, B and C.
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**** 6 different variants of MHC class II.
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***** 2 each of HLA- DP, DQ and DR.
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* Many animal species have fewer loci than the human.
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** E.g. ruminants have no MHC class II DP.
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===MHC and Disease===
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* Antigen from a pathogen has to be seen by the host MHC before an efficient immune response can occur.
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** There is therefore a constant evolutionary battle between the host and the pathogen.
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*** There is selective pressure on the pathogen to evolve proteins that do not interact with the host MHC.
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*** There is selective pressure on the host to continue to recognize the pathogen.
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* The consequence of this parallel evolution is that host-pathogen relationships can lead to the selection of particular MHC variants, for example:
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** MHC class II alleles DR13/DR1*1301 are prevalent in Central and Western Africa .
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*** Impart resistance to malaria.
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** MHC-DRB1 is prevalent in Western Europe, but rare in the Inuit populations of North America.
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*** Associated with the clearance of hepatitis B infection in Western Europe.
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*** Inuits have the highest incidence of hepatitis B in the world.
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** In humans there are also strong associations between certain alleles and some autoimmune diseases, for example:
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*** Diabetes mellitus.
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*** Ankylosing spondylitis.
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*** Rheumatoid arthritis.
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