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Major Histocompatibility Complex (MHC) Definition
The major histocompatibility complex can be defined as a tightly linked cluster of genes whose products play an important role in intercellular recognition and in discrimination between self and non-self. The term ‘histo’ stands for tissue and ‘compatibility’ refers to ‘getting along or agreeable’. On the other hand, the term ‘complex’ refers to the ‘genes that are localized to a large genetic region containing multiple loci’. These genes code for antigens which involve in the determination of the compatibility of the transplanted tissue. The compatible tissues will be accepted by the immune system while the histo-incompatible ones are rejected. The rejection of foreign tissue leads to an immune response to cell surface molecules. The concept was first identified by Peter Gorer and George Snell. The main function of MHC molecules is to bring antigen to the cell surface for recognition by T cells. In humans, the genes coding for MHC molecules are found in the short arm of chromosome 6.
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Major Histocompatibility Complex (MHC) Types
In humans, the MHC molecules are divided into three types, Class I, Class II and Class III. Class I MHC molecules are coded from three different locations called A, B and C and these molecules are expressed in all nucleated cells. Class II MHC genes are located in the D region and there are several loci such as DR, DQ and DP and these molecules are expressed only in antigen-presenting cells. Class III MHC genes are coded in the region between Class I and Class II genes. Class III MHC genes codes for cytokines and complement proteins which play an important role during the immune response.
Class I MHC Molecule
- The structure of Class I MHC molecule consists of two polypeptide chains α and β. These two chains are connected together by non-covalent bonds. The α chain is characterized as an internal membrane glycoprotein with a molecular weight of 45000 Da (in humans). Β chain, on the other hand, is an extracellular microglobulin with a molecular mass of 12kDa.
- The α chain is made up of approximately 350 amino acids and also divided into three globular domains α1, α2 and α3. Each of these domains contains roughly 90 amino acids. The N terminal of α chain is the place of α1 domain, while α2 and α3 are present after α1 The α2 domain is characterized by the formation of a loop of 63 amino acids; the loop is formed due to intrachain disulfide bond. α3 also contains a disulfide bond enclosing 86 amino acids. The α1 and α2 domains interact to form peptide-binding units of class I MHC molecule.
- Moreover, α chain also consists of a stretch of 26 hydrophobic amino acids which holds the α chain on the plasma membrane. This transmembrane segment is present as a form of α helix at the hydrophobic region of the plasma membrane. An intracellular domain or the carboxyl-terminal of α chain is located inside the cell and it contains around 30-40 amino acids.
- In humans the β chain is non-polymorphic and it is dimorphic in mice. α3 and β chain are structurally similar to the immunoglobulin C domain and also characterized as a disulfide loop. A peptide binding platform is formed by β plated sheets of α1 and α2
- Tcyt Cell (cytotoxic T cell) has specificity towards cells containing peptides associated with Class I MHC due to the presence of CD8 antigen on the surface of Tcyt Cell. CD8 antigen has an affinity towards the α3 domain of Class I MHC molecules.
Class II MHC Molecule
- Class II MHC molecules are heterodimers and characterized by two non covalently connected polypeptide chains. The chains are termed as a heavy chain (α, 30kDa) and light chain (β, 26kDa).
- Similar to class I MHC molecules, class II MHC molecules are also characterized by an extracellular amino terminal domain, a transmembrane domain and an intracellular carboxy terminal tail.
- The class II MHC molecules are expressed on the surface of the antigen-presenting cells such as B cells, dendritic cells, and macrophages.
- The α chain is divided into two domains α1 and α2, while the β chain is also divided into two groups β1 and β2. The β2 domain is responsible for the binding of T cell co-receptor CD4. The α1 and β1 domain, on the other hand, involved in the formation of the antigen-binding sites. Peptides containing 13-20 amino acids can bind at the antigen-binding site of class II MHC.
- The presence of disulfide bonds in α2, β1, and β2 domains are also an important structural feature of the class II MHC molecules.
Class III MHC Molecule
- There are several serum proteases which involve in compliment system come under the group of class III MHC molecules.
- Class III MHC molecules do not have any involvement in antigen presentation.
- The complement components such as asC2, C4A, and C4B, and factor B are the most important compounds involve as class III MHC molecules. Apart from these tumor necrosis factors α and β and some heat shock proteins also come under this category.
Antigen Presentation and Processing
The T cells can recognize the foreign antigen when the antigen is attached to the MHC molecules as an MHC peptide complex. The formation of the MHC-peptide complex requires the degradation of protein antigen by several steps. The degradation process is known as antigen processing. These degraded proteins are then attached to the MHC molecules inside the cell and then the MHC molecules transported to the membrane to present the antigen with the T cell.
Antigen Presentation Pathway: Class I MHC molecules (Cytosolic pathway)
- Class I MHC molecules involve in presenting intracellular or endogenous pathogens or antigens. Intracellular pathogens refer to those organisms which live and replicates inside the host cell. An example of this type of pathogen is a virus.
- Under normal condition the MHC class I molecules forms a complex with the self-peptides or self-antigens. While, in case of any viral infection, the MHC class I molecules present the peptide derived from the virus which is then further recognized by T cells.
- Cell components such as a nucleus, endoplasmic reticulum and Golgi apparatus play an important role in antigen processing and presentation.
- When a virus infected a normal cell, the viral DNA moves inside the cell and produce viral proteins with the help of the host cell mechanisms. The viral proteins are synthesized in the cytosol.
- The cytoplasm also contains a cylindrical protein complex called the proteasome. The main function of the proteosome is to degrade the unwanted or damaged protein into smaller peptides. At the time of viral infection, the viral proteins interacted with the proteosomes present in the cytoplasm. The processing took place in the cytosol and as a result, the proteins are degraded into smaller peptides (8-15 amino acid long).
- In the next step, these fragmented peptides are transported into the endoplasmic reticulum. The transport took place due to a peptide delivery system called the transporter associated with antigen processing (TAP). TAP is made up of two domains or subunits called TAP 1 and TAP 2.
- Inside the endoplasmic reticulum the α and β chains of MHC class I molecules are synthesized and by the help of a group of chaperone proteins, the MHC class I molecule is formed and moves towards the TAP. As a result, the peptides bind at the peptide-binding site of the class I MHC molecule inside the endoplasmic reticulum and forms the MHC class I-peptide complex.
- In the next step, the MHC class I- peptide complex moves to the surface of the Golgi apparatus and by the help of secretory vesicle, it moves towards the surface of the plasma membrane.
- Once the MHC class I-peptide complex reaches the cell surface, the T cell receptors recognize the antigen peptide complex. Moreover, the co-receptor CD8 of the T cell attaches with the α3 domain of the MHC class I molecule. Hence, the antigen is presented to the T cell.
Antigen Presentation Pathway: Class II MHC molecules (Endocytic Pathway)
- MHC class II molecules are responsible for presenting exogenous or extracellular pathogen or antigen. The extracellular pathogen refers to the organisms which can grow and reproduce outside of the host cell. Bacteria, exotoxins, parasites are examples of extracellular antigens. These antigens are taken up by the cell by endocytosis or phagocytosis.
- Only the antigen-presenting cells involved in antigen processing and presentation by MHC class II molecules. These cells include B cells, macrophages, and dendritic cells. The pathway took place only after the engulfment of the antigen by the antigen-presenting cells.
- Inside the cell, the antigen carries a covering called an endosome. The endosome is fused with the lysosome present in the cytoplasm and forms endolysosomes. As a result, the foreign protein is degraded by the proteolytic enzyme present inside the lysosome and small peptides are formed.
- The class II MHC molecules are synthesized and formed in the endoplasmic reticulum. The α and β chain of the molecule is also associated with the invariant chain. This association helps to restrict the binding of self-antigen with the class II MHC molecule. The invariant chain- MHC complex is then transported from the endoplasmic reticulum to the Golgi apparatus and from the Golgi apparatus to another vesicle. Inside the vesicle, the invariant chain is digested and only a small fragment (Class II-associated invariant chain polypeptide: CLIP) is attached with the molecule.
- In the next step, the vesicle containing the MHC class II molecule is then fused with the vesicle containing fragmented peptides. The fragmented peptide is then bound with the MHC class II molecule by displacing the CLIP. This newly formed MHC class II-peptide complex is then transported to the surface of the cell.
- Once at the cell surface, the antigen is presented to the T cells. The T cell recognizes the peptide bound with the MHC class II molecule by the help of the T cell receptor and the CD4 co-receptor binds with the β2 domain of the class II MHC molecule.
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Major Histocompatibility Complex (MHC)- Types and Pathways