MAJOR HISTOCOMPATIBILITY COMPLEX by Pranzly.ppt
- 2. DEFINITION • Major histocompatibility complex (MHC) is the cluster of gene arranged within a long continuous stretch of DNA on chromosome number 6 in Human which encodes MHC molecules. • MHC molecule is a cell surface glycoprotein receptor present in APCs and acts as antigen presenting structure • The main function of MHC molecules is to bind to peptide antigens and display them on the cell surface for recognition by appropriate T-cells. • In Human MHC is known as Human Leucocyte antigen (HLA) complex.
- 3. THE GENES OF MHC ARE RECOGNIZED IN THREE CLASSES, CONSEQUENTLY THERE ARE THREE TYPES OF MHC MOLECULES. Types CLASS MHC 1 CLASS MHC 2 CLASS MHC 3
- 5. CLASS MHC 1 • Class-I MHC gene encodes glycoprotein molecule which expressed on the surface of all nucleated cells and platelets. • Association of α-chain and β2 microglobulin is required for expression of class-I MHC molecule on cell membrane. MHC-I molecule contains α-chain 45KDa β2- microglobulin molecule 12KDa
- 6. α-CHAIN OF CLASS MHC 1 • The α-chain is a transmembrane glycoprotein encoded by polymorphic gene within A, B and C region of Human HLA complex • The α-chain is anchored in the plasma membrane by its hydrophobic trans- membrane segment and hydrophilic cytoplasmic tail. • A transmembrane domain of about 25 hydrophobic AA followed by short stretch of charged (hydrophilic) amino acids(AA) of cytoplasmic tails of 30 AA. • α1 and α2 domains interacts to form a deep groove on the top which is a peptide binding cleft. It can binds antigen of 8-10 AA long α-chain is made up of 3 domains α1 90 amino acids α2 90 amino acids α3 90 amino acids
- 7. β2-microglobulin OF CLASS MHC 1 • β2 microglobulin is a protein encoded by a highly conserved gene located on different chromosome • β2 microglobulin is similar in size and organization to α3 domain. • β2 microglobulin does not contain transmembrane region and is non-covalently linked with α-chain.
- 8. peptide binding cleft CLASS MHC 1 Membrane distal domain Membrane proximal Domain (Ig fold structure) transmembrane region Cytoplasmic tail
- 9. MECHANISM OF CLASS MHC 1 MHC class I glycoproteins present antigens of endogenous origin to TCRs of CD8+ T cells Endogenous peptides derive from degradation of intracellular proteins, including viral or tumor antigens through the PROTEOSOME. Degradation products translocate from the cytoplasm to the endoplasmatic reticulum (ER) where they are loaded on MHC class I molecules via the peptide loading complex Cellular components involved in the presentation of endogenous antigens, from proteasome subunits to the peptide-loading complex, are collectively referred to as antigen-processing machinery (APM). CD8+ T lymphocytes express CD8 receptors, the TCR fits the epitope within the MHC class I molecule, thus CD8+ T lymphocytes triggers the cell to undergo programmed cell death by APOPTOSIS.
- 10. FUNCTION OF CLASS MHC 1 1. ANTIGEN PROCESSING AND PRESENTATION • bind endogenous peptide antigens and present to CD8+ T cells. • CD8 T cells are specific for MHC-I antigen 2. TRANSPLANT REJECTION During transplant of an organ or stem cells, MHC molecules themselves act as antigens and can provoke immune response in the recipient causing transplant rejection.
- 11. CLASS MHC 2 • Class-II MHC is the glycoprotein molecule expressed primarily on antigen presenting cells such as macrophages, dendritic cells and B- cells. • Structure of class MHC 2 resemble class MHC 1 the only difference is that peptide binding cleft is formed by both α-chain and β-chain. MHC-II molecules contains two different polypeptide chains which are associated by non- covalent interactions. α-chain 33 KDa β-chain 28KDa
- 12. α-CHAIN OF CLASS MHC 2 • α-chain of MHC-II is a membrane bound glycoprotein that contains external domains, a transmembrane segment and a cytoplasmic tail. • α-chain are made up of two domains (α1 and α2) • The peptide biding cleft is a open ended groove formed between α- chain and β-chain at proximal end. • The cleft can bind antigenic peptide of 13-18 amino acids long
- 13. β-CHAIN OF CLASS MHC 1 • β-chain of MHC-II is a membrane bound glycoprotein that contains external domains • β-chain are made up of two domains (β1 and β2) • β-gene of some MHC class 2 can get tandemly duplicated instead of one gene per homologues chromosome a cell can have more genes. • Because of this one cell can simultaneously express more than two allelic products because of this one cell can express as many as 20 MHC molecules.
- 14. peptide binding cleft CLASS MHC 2 Membrane distal domain Membrane proximal Domain (Ig fold structure) transmembrane region Cytoplasmic tail
- 15. MECHANISM OF CLASS MHC 2 They present exogenous antigen to CD4+ T cell. Phagocytes such as (macrophage, dendritic cell) take up entities by phagocytosis into phagosome which fuse with lysosome to form endosome. Class MHC 2 synthesise by endoplasmic reticulum is transported to endosome compartment via Golgi apparatus.(α-chain and β-chain are complexed with a polypeptide chain called invariant chain-which prevent them to bind to endogenous peptide ) Due to acidic nature of endosome the INVARIANT CHAIN is removed where it binds to exogenous peptide and then it is transferred to membrane surface. Where T helper cell with the help of CD4+ recognise it and elicit a immune response
- 16. FUNCTION OF CLASS MHC 2 • MHC-II is to bind peptide antigen and present to CD4+ T (HELPER)cells. • MHC-II are found on surface of Antigen presenting cells (APCs). • CD4+ T-cells are specific for MHC-II. • Activates B cells for antibody production • Plays a significant role in graft versus host response and in mixed lymphocyte reaction (MLR)