major histocompatibility complex

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Major Histocompatibility complex

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What is MHC? Early attempts to transplant tissues failed Rejection of transplanted tissue was associated with inflammation and lymphocyte infiltration IMMUNE GRAFT REJECTION

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Skin from an inbred mouse grafted onto the same strain of mouse Skin from an inbred mouse grafted onto a different strain of mouse ACCEPTED REJECTED Genetic basis of transplant rejection Inbred mouse strains - all genes are identical Transplantation of skin between strains showed that rejection or acceptance was dependent upon the genetics of each strain

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Important terms: 1. self molecules 2. non-self molecules 3.MHC molecules 4.T cells

Types of HLA genes:

Types of HLA genes MHC class 1 HLA-A HLA-B HLA-C MHC class 2 HLA-DPA1 HLA-DPB1 HLA-DQA1 HLA-DQB1 HLA-DRA1 HLA-DRB1

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Chains Peptide a -chain MHC I

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Present in all nucleated cells. MHC class I proteins contain an α chain & β2-micro-globulin (not part of the MHC encoded by chromosome 15). They present antigen fragments to cytotoxic T-cells via the CD8 receptor on the cytotoxic T-cells and also bind inhibitory receptors on NK cells .

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a -chain Peptide b -chain MHC II

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On most immune system cells, specifically on antigen-presenting cells . MHC class II proteins contain α & β chains. They present antigen fragments to T-helper cells by binding to the CD4 receptor on the T-helper cells

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Antigen Presentation

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Characteristic MHC-I pathway MHC-II pathway Composition of the stable peptide-MHC complex Polymorphic chain α and β2 microglobulin, peptide bound to α chain Polymorphic chains α and β, peptide binds to both Types of antigen presenting cells (APC) All nucleated cells Dendritic cells , mononuclear phagocytes, B lymphocytes , some endothelial cells, epithelium of thymus T lymphocytes able to respond Cytotoxic T lymphocytes (CD8+) Helper T lymphocytes (CD4+) Origin of antigenic proteins cytosolic proteins (mostly synthetized by the cell; may also enter from the extracellular medium via phagosomes ) Proteins present in endosomes or lysosomes (mostly internalized from extracellular medium) Enzymes responsible for peptide generation Cytosolic proteasome Proteases from endosomes and lysosomes (for instance, cathepsin ) Location of loading the peptide on the MHC molecule Endoplasmic reticulum Specialized vesicular compartment Molecules implicated in transporting the peptides and loading them on mhc TAP (transporter associated with antigen processing) DM, invariant chain

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Cell surface peptides of Ag Antigen recognition by T cells requires peptide antigens and presenting cells that express MHC molecules T cell r esponse No T cell response No T cell response No T cell response No T cell response Soluble native Ag Cell surface native Ag Soluble peptides of Ag Cell surface peptides of Ag presented by cells that express MHC antigens T

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MHC-binding peptides Each human usually expresses: 3 types of MHC class I (A, B, C) and 3 types of MHC class II (DR, DP,DQ) of different T cell antigen The number receptors is estimated to be 1,000,000,000,000,000 Each of which may potentially recognise a different peptide antigen How can 6 invariant molecules have the capacity to bind to 1,000,000,000,000,000 different peptides?

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A flexible binding site? NO because: at the cell surface, such a binding site would be unable to • allow a high enough binding affinity to form a trimolecular complex with the T cell antigen receptor • prevent exchange of the peptide with others in the extracellular milieu A binding site that is flexible enough to bind any peptide?

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A flexible binding site? A binding site that is flexible at an early, intracellular stage of maturation Formed by folding the MHC molecules around the peptide. Floppy Compact Allows a single type of MHC molecule to • bind many different peptides • b ind peptides with high affinity • f orm stable complexes at the cell surface • Export only molecules that have captured a peptide to the cell surface

The genetic mechanisms::

The genetic mechanisms: Polygenecity Polymorphism Co-dominance

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     B C A DP DQ DR  1 Polygeny      B C A DP DQ DR  1 Variant alleles polymorphism Genes in the MHC are tightly LINKED and usually inherited in a unit called an MHC HAPLOTYPE      B C A DP DQ DR  1 Additional set of variant alleles on second chromosome MHC molecules are CODOMINANTLY expressed Two of each of the six types of MHC molecule are expressed Diversity of MHC molecules in the individual HAPLOTYPE 1 HAPLOTYPE 2

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The loci which specify MHC’s are polymorphic. Many alleles may exist at a locus: HLA A locus has ~60 alleles HLA B locus ~110 alleles HLA C locus ~40 alleles The high level of allelism creates diversity within a species (thus restricting allografting) but does not produce diversity within an individual .

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Thank You