MHC ( Major histocompatibility complex ) molecule.
- MHC is a tightly linked cluster of genes, which products can play crucial role in intercellular recognition and in discrimination between self and nonself.
Occurence: Present in every vertebrate species.
Location: It is located on chromosome no 6 in human called HLA ( Human leucocyte antigen) , and on chromosome 17 in mice known as H-2 ( Histocompatibility-2) complex.
Features: 1) MHC is highly polymorphic. Many alternatives form of gene or allele exist in at each locus. The phenomenon of having multiple stable forms of one gene in the population is known as genetic polymorphism.
2) MHC molecule codominantly expressed, protein transcribed from both maternal (mother) and paternal ( father) chromosome.
Classification of MHC genes.
MHC genes are divided into three classes:
I) class I MHC gene.
I) Class II MHC gene.
III) Class III MHC gene.
Class I and class I MHC gene encode the antigen presenting MHC molecule. The peptide antigen- presenting MHC molecules are generally called classical MHC molecule. These both classes also encode proteins that do not function in the presentation of peptide antigens to T- cells.
Class I MHC gene:
Class I MHC genes expressed glycoproteins called MHC molecule, sometimes reffered to as MHC antigens on nearly all nucleated cells.
Components:
Class I genes consists of
I) An alpha or heavy chain.
II) and a beta 2 microglobin.
Alpha or heavy chain:
Alpha chain comprises with three extracellular domain such as alpha1, alpha2,and alpha3 domain.
Each domain contains around 90 amino acids longs.
Alpha1 and alpha 2 domains form a antigen binding pocket where the peptides are bind to MHC class I gene.
Alpha 3 domain:
The alpha 3 domain is highly conserved and interacts with CD8 membrane molecule which is present on cytooxic - T cells. It is attached with plasma membrane and it is invariant.
Transmembrane domain:
There is a transmembrane domain around 25 hydrophobic amino acid which is inserted in to cell membrane
Cytoplasomic tail:
Beta 2 microglobin:
Every MHC class molecule are expressed on the surface of a cell in noncovalent association with a small invariant polypeptide called beta 2 microglobin.
Molecular weight: 12 k dal.
It is coded from chromosome ( human chromosome number 15 ) . The polypeptide similar size with Alpha 3 domain.
Microglobin chain bound with Alpha chain non covalently. It is essential for proper folding of Alpha chain. It has no transmembrane region meaning that does not penetrate to cell membrane. Beta microglobin chain is identical in all cells and it is present intracellular or endogenous antigen cell surface.In the absence of beta 2 microglobulin chain the class 1 MHC chain is not expressed on the cell membrane. Class 1 MHC molecules are expressed on most nucleated cells but the the level of expression differs among different cell types. The highest level of class 1 molecules are expressed by lymphocytes whereas fibroblasts, liver hepatocytes, and neural cells express very low levels of class 1 MSc molecules. A few cell types ( e.g neurons, and sperm cells at certain stages of differentiation ) appear to lak class 1 MHC molecules altogether.
Class II MHC gene:
It is IgG like extracellular domain. Member of IgG super family. It is generally found in professional antigen presenting cells at dendritic cells, mononuclear phagocytes, some endothelial cells and B- cells which can play a role in immune system.
Occurrence: only on antigen presenting cell.
Domain: Alpha chain, ( molecular weight 35 K dal ) Beta chain. ( 28 K dal )
Sub domain: Alpha chain: Alpha 1, alpha 2 Beta chain: beta 1, beta 2.
Alpha and beta chain both anchor in plasma membrane.
Alpha1 and Beta 1 domain form the antigen binding pocket. Bind peptides upto 13 to 18 amino acids.
Bind longer peptides as compared to MHC class 1 molecule.
Binding site:
Beta 2 subdomain is binding site for CD4 molecule present in the T-
helper cells.
Class two genes express MHC molecule constitutive only on antigen presenting cells. Antigen presenting cells are classified as professional and non professional antigen presenting cell. Professional antigen presenting cells are are dendritic cells, macrophages, and B- lymphocytes. Non professional antigen presenting cells like fibroblast, thymic epithelial cells, glial cells can be induced to express class 2 MHC molecules or co- stimulatory signal.
Function:
The major function of MHC gene II is to present processed antigens, which are derived primary from exogenous sources to CD4+ T- lymphocytes. MHC-II thereby are critical for the initiation of the antigen specific immune response.
Difference between MHC I and MHC II molecule.
Sub: Class I class II
Occurence: Nucleated cells APCs.
Binding site: CD8 CD4
Domain: Alpha( 1,2,3) , Alpha ( 1,2 )
Beta 2 microglobin. Beta ( 1,2 )
Cytoplasmic tail: 1 2
Important aspects of MHC:
1) Although there is a high degree of polymorphism for a species,an individual has maximum of 6 different class I MHC products and only slightly more class 2 MHC products.
2) MHC molecule has only one binding site.
The different peptides can bind to a given MSc molecule to the same site, but only one at a time.
3) MHC polymorphism is determined only in the germline. There are no Recombinational mechanisms for generating diversity.
4) MHC molecules (class 1 and class 2) are membrane bound, recognition by T- cells requires cell- cell contact.
5) Alleles for MHC genes are co-dominant.Each MHC gene product is expressed on the cell surface of an individual nucleated cell.
6) Endogenous peptides associated with class I MHC and are recognised by T- cytotoxic cells . Exogenous peptides associated with class II MHC and are recognised by T- helper cells.
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Class I MHC gene:
Class I MHC genes expressed glycoproteins called MHC molecule, sometimes reffered to as MHC antigens on nearly all nucleated cells.
Components:
Class I genes consists of
I) An alpha or heavy chain.
II) and a beta 2 microglobin.
Alpha or heavy chain:
Alpha chain comprises with three extracellular domain such as alpha1, alpha2,and alpha3 domain.
Each domain contains around 90 amino acids longs.
Alpha1 and alpha 2 domains form a antigen binding pocket where the peptides are bind to MHC class I gene.
Alpha 3 domain:
The alpha 3 domain is highly conserved and interacts with CD8 membrane molecule which is present on cytooxic - T cells. It is attached with plasma membrane and it is invariant.
Transmembrane domain:
There is a transmembrane domain around 25 hydrophobic amino acid which is inserted in to cell membrane
Cytoplasomic tail:
Beta 2 microglobin:
Every MHC class molecule are expressed on the surface of a cell in noncovalent association with a small invariant polypeptide called beta 2 microglobin.
Molecular weight: 12 k dal.
It is coded from chromosome ( human chromosome number 15 ) . The polypeptide similar size with Alpha 3 domain.
Microglobin chain bound with Alpha chain non covalently. It is essential for proper folding of Alpha chain. It has no transmembrane region meaning that does not penetrate to cell membrane. Beta microglobin chain is identical in all cells and it is present intracellular or endogenous antigen cell surface.In the absence of beta 2 microglobulin chain the class 1 MHC chain is not expressed on the cell membrane. Class 1 MHC molecules are expressed on most nucleated cells but the the level of expression differs among different cell types. The highest level of class 1 molecules are expressed by lymphocytes whereas fibroblasts, liver hepatocytes, and neural cells express very low levels of class 1 MSc molecules. A few cell types ( e.g neurons, and sperm cells at certain stages of differentiation ) appear to lak class 1 MHC molecules altogether.
Class II MHC gene:
It is IgG like extracellular domain. Member of IgG super family. It is generally found in professional antigen presenting cells at dendritic cells, mononuclear phagocytes, some endothelial cells and B- cells which can play a role in immune system.
Occurrence: only on antigen presenting cell.
Domain: Alpha chain, ( molecular weight 35 K dal ) Beta chain. ( 28 K dal )
Sub domain: Alpha chain: Alpha 1, alpha 2 Beta chain: beta 1, beta 2.
Alpha and beta chain both anchor in plasma membrane.
Alpha1 and Beta 1 domain form the antigen binding pocket. Bind peptides upto 13 to 18 amino acids.
Bind longer peptides as compared to MHC class 1 molecule.
Binding site:
Beta 2 subdomain is binding site for CD4 molecule present in the T-
helper cells.
Class two genes express MHC molecule constitutive only on antigen presenting cells. Antigen presenting cells are classified as professional and non professional antigen presenting cell. Professional antigen presenting cells are are dendritic cells, macrophages, and B- lymphocytes. Non professional antigen presenting cells like fibroblast, thymic epithelial cells, glial cells can be induced to express class 2 MHC molecules or co- stimulatory signal.
Function:
The major function of MHC gene II is to present processed antigens, which are derived primary from exogenous sources to CD4+ T- lymphocytes. MHC-II thereby are critical for the initiation of the antigen specific immune response.
Difference between MHC I and MHC II molecule.
Sub: Class I class II
Occurence: Nucleated cells APCs.
Binding site: CD8 CD4
Domain: Alpha( 1,2,3) , Alpha ( 1,2 )
Beta 2 microglobin. Beta ( 1,2 )
Cytoplasmic tail: 1 2
Important aspects of MHC:
1) Although there is a high degree of polymorphism for a species,an individual has maximum of 6 different class I MHC products and only slightly more class 2 MHC products.
2) MHC molecule has only one binding site.
The different peptides can bind to a given MSc molecule to the same site, but only one at a time.
3) MHC polymorphism is determined only in the germline. There are no Recombinational mechanisms for generating diversity.
4) MHC molecules (class 1 and class 2) are membrane bound, recognition by T- cells requires cell- cell contact.
5) Alleles for MHC genes are co-dominant.Each MHC gene product is expressed on the cell surface of an individual nucleated cell.
6) Endogenous peptides associated with class I MHC and are recognised by T- cytotoxic cells . Exogenous peptides associated with class II MHC and are recognised by T- helper cells.
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