The Major Histocompatibility Complex (MHC) is the system present in human is known as the Human Leukocyte Antigen (HLA) system. The MHC system consists of some small group of genes present on human chromosome 6. The same defense system present in mice is known as H-2 system. The arrangement of genes is different in human and mice. These groups of genes can divide into three groups.
Those genes which encodes for the glycopeptides from the surface of nucleated cells is Class I MHC. This class is more active against the antigenic peptides and presents it to cytotoxic T-cells.
The group of gene that encodes the glycopeptides from only three cells like B-cells, Macrophages and Dendritic cells is known as the Class MHC II. The Class MHC II present antigenic peptides to Helper T-cells.
The third group of genes known as the Class III MHC genes. The product of this group is inflammatory cytokines and complement protein. These proteins are required for the inflammatory response of cells.
The genes related to Class I MHC are located near the telomeric end, Class II MHC genes are present on the centromeric end and the Class III genes can be found between the Class 1 MHC and Class II MHC.
The Class I MHC in human is known as Classical class I genes and are highly expressed among the human cells. These genes are present on A, B and C regions. In the same class some other genes are present this group of genes are known as the nonclassical class I genes. The Class II MHC genes are present on the DP, DR and DQ regions. The first two MHC classes encodes the molecule which have same structure and involve in the presentation and dispensation of antigen. The Class III MHC is different as it encodes for some complement factors C2, C4, BF, inflammatory cytokines, Heat shock protein and tumor necrosis factors.
The Class I and II have bit similar structure and are membrane bounded glycoprotein. These groups form the stable complex with antigen derived peptides on T-cell surface for recognition of antigen. The molecules of Class I MHC consist of α chain associated with β2 microglobulin molecule noncovalently. The α chain is encoded by A, B and C region of genes and it is a transmembrane protein where as β2 is encoded by the genes present on the conserved region of another chromosome. In detail α chain is consist of α1, α2 and α3 and each part have the approximately 90 amino acids. The other β2 unit has not transmembrane protein and is associated with similar to α3 unit. This association shapes the peptide binding cleft which is specific against specific antigen. Without the β2 the antigen will not presented on surface of cell. The Class I MHC is thought as the immunoglobuline family because of the sequence similarities with immunoglobuline. The α3 domain of Class I MHC is active against the CD8 cells and is responsible for its attachment.
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Figure1. Class I MHC molecules. 1) Intracellular proteins are degraded in proteasomes. 2) This degradation synthesis antigenic peptides. 3) Antigenic peptides are transported into RER.4) Class I MHC molecules attach antigenic peptides in RER and for complex.5) these complexes are transported from the Golgi to the surface of cell for presentation of peptide to CD8+ T cells.
The Class II MHC consist of nonidentical glycoprotein domains, α and β. These two chains has non covalent bond between each other. These each domain have two units, α1 and α2 and on the other side β1 and β2. The Class II is categorized in immunoglobuline superfamily because the sequence of α2 and β2 domains is similar to immunoglobuline. These domains also have antigen binding cleft for antigen dispensation.
The T-cells have the ability to recognize the antigen especially if the antigen peptides attach to the MHC cleft on the surface of cell. The complete process is known as the Antigen Processing and Presentation. This process works by shaping the MHC-peptide complex and precede when the antigenic peptide degraded and attachment of this degraded peptides with MHC molecules on T-cell surface for recognition. The peptide attachment with MHC I and MHCII occur in different chambers of cells.
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Figure2. Class II MHC molecules 1) Extracellular proteins are get enter into endosomes. 2) Lysozomes fuse with endosomes. 3) Degradation of endocytosed proteins in the vesicle, to form antigenic peptides. 4) Class II MHC molecules, DM and invariant chain fuses with the endolysozomal vesicle and degradation of invariant chain to CLIP, deletion of clip, and Class II MHC molecules attach antigenic peptides. 5) Class II MHC-antigenic peptide complexes transportes to the surface of cell, for presentation to CD4+ T cells.
In the process of antigen elimination the immune system undergoes through two discrete pathways.
Cytosolic Pathway
Endocytic Pathway
In the Cytosolic pathway the endogenous derived antigenic peptides attach to Class I MHC molecule. These proteins can be normal or foreign particle derived protein. In the endocytic pathway the Class II MHC attach to exogenous antigen derived peptides. These antigens enter in the endosome by the process of phagocytosis and endocytosis.
Cytosolic Pathway
The proteasomes produce the peptides for presentation. The proteolytic system degrades the intracellular protein into small peptides. The protein which go through the proteolysis have short protein ubiquitin bind to it on lysine residue to form ubiquitin protein complex. This complex actually degraded into short peptides by proteasome and transferred to rough endoplasmic reticulum (RER) lumen. This proteasome sense the complex in a condition when ubiquitin is bind to protein. The Class I MHC is synthesized in the RER with TAP proteins. This TAP protein plays its role in transportation of peptides into the RER. This mechanism of MHC molecule complex involve many steps like calrecticulin, tapasin , calnexin and cheperones. The molecule binds to α unit first is the calnexin and cause it folding.
Endocytic pathway
The antigen is phagocyte or endocyte by the macrophage. The antigen is degraded into the peptides by the action of lysosome or endosome. The antigen travel from early to late endosome and then to lysosome which run into the hydrolytic enzymes in combination with low pH. Within the endocytic compartment the MHC II attaches the peptides on the cleft.
The endocytic compartment returns to the cell surface and fuse with plasma membrane. In response to a mechanism the peptides present in the RER lumen which is specific to Class MHC I inhibit its binding with Class MHC II. This mechanism is carried out by Ii CD74 invariant chain. The Ii CD74 attaches to peptide binding cleft of MHC I and inhibit its attachment with MHC II. After this attachment the MHC molecules are transported to Golgi from RER where proteolytic activities degrade the invariant chain (Ii CD74) and form the CLIP to bind MHC II. Later on the CLIP is removed by the proteolytic activity of HLA-DM. in this way the binding of peptide make the molecule stable and move to the cell surface for detection of TH cells.
