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FUNCTION OF MHC MOLECULES

FUNCTION OF MHC MOLECULES. THE STRUCTURE OF MHC GENE PRODUCTS. 2. 1. 1. 1. 3. 2. 2. 2m. 1 2 3. 1 2. 1 2. 3 and 2m Ig supergene family 2 and 2.  2.  1.  2 m.  3. THREE DIMENSIONAL STRUCTURE OF THE MHC CLASS I MOLECULE. PEPTIDE.

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FUNCTION OF MHC MOLECULES

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  1. FUNCTION OF MHC MOLECULES

  2. THE STRUCTURE OF MHC GENE PRODUCTS 2 1 1 1 3 2 2 2m 1 23 1 2 1 2 3 and 2m Ig supergene family 2 and 2

  3. 2 1 2m 3 THREE DIMENSIONAL STRUCTURE OF THE MHC CLASS I MOLECULE PEPTIDE PEPTIDE EXPRESSED IN ALL NUCLEATED CELLS

  4. 1 1 2 2 THE THREE DIMENSIONAL STRUCTURE OF MHC CLASS II MOLECULES PEPTIDE PEPTIDE EXPRESSED ON PROFESSIONAL ANTIGEN PRESENTING CELLS

  5. THE PEPTIDE BINDING SITE OF MHC CLASS I MOLECULES

  6. THE PEPTIDE BINDING SITE OF MHC CLASS II MOLECULES PEPTIDE

  7. a-chain a-chain Peptide b-chain Peptide b2-M Cleft geometry MHC class I accommodate peptides of 8-10 amino acids MHC class II accommodate peptides of >13 amino acids

  8. Acid elute peptides Peptides can be eluted from MHC molecules

  9. MHC MOLECULES ARE EXPRESSED WITH BOUND PEPTIDES DERIVED FROM SELF OR NON-SELF PROTEINS Kidney epithelial cell B-cell, macrophage, dendritic cell Present intra- and extracellular environment Liver cell Class II MHC Overlapping peptides of various sizes, which derive from membrane/exogeneous proteins 70% derives from MHC molecules Present intracellular environment Class I MHC – code of 6 Immunological ID Peptides of restricted size, which derive from cytosolic or nuclear proteins

  10. Eluted peptides from MHC molecules have different sequences but contain motifs N C T Y Q R T R L V I S Y F P E I H L K Y Q A V T T I S Y I P S A K R G Y V Y Q Q L S I I N F E K L A P G N Y P A L Peptides bound to a particular type of MHC class I molecule have conserved patterns of amino acids A common sequence in a peptide antigen that binds to an MHC molecule is called a MOTIF Amino acids common to many peptides tether the peptide to structural features of the MHC molecule ANCHOR RESIDUES Tethering amino acids need not be identical but must be related Y & F are aromatic V, L & I are hydrophobic Side chains of anchor residues bind into POCKETS in the MHC molecule Different types of MHC molecule bind peptides with different patterns of conserved amino acids

  11. Class I Class II (HLA-DR) 1 1 2 1 2m 2 2 3 Allelic polymorphism is concentrated in the peptide antigen binding site Polymorphism in the MHC affects peptide antigen binding Allelic variants may differ by 20 amino acids

  12. 30 HLA-DPb allele sequences between Nucleotides 204 and 290 (amino acids 35-68) E-A Y-F A-E A-D Silent I-L A-V DPB1*01011 TAC GCG CGC TTC GAC AGC GAC GTG GGG GAG TTC CGG GCG GTG ACG GAG CTG GGG CGG CCT GCT GCG GAG TAC TGG AAC AGC CAG AAG GAC ATC CTG GAG GAG DPB1*01012 --- --- --- --- --- --- --- --- --A --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*02012 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*02013 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -AC -A- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*0202 CT- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -AG --- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*0301 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --C --- --- --- --- --- --- --- C-- --- --- --- DPB1*0401 -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*0402 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*0501 CT- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -AG --- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*0601 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --C --- --- --- --- --- --- --- C-- --- --- --- DPB1*0801 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*0901 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --C --- --- --- --- --- --- --- --- --- --- --- DPB1*1001 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*11011 --- --- --- --- --- --- --- --- --A --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- C-- --- --- --- DPB1*11012 --- --- --- --- --- --- --- --- --A --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- C-- --- --- --- DPB1*1301 --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*1401 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --C --- --- --- --- --- --- --- C-- --- --- --- DPB1*1501 --- --- --- --- --- --- --- --- --A --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- C-- --- --- --- DPB1*1601 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*1701 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --C --- --- --- --- --- --- --- --- --- --- --- DPB1*1801 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*1901 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -AG --- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*20011 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --C --- --- --- --- --- --- --- C-- --- --- --- DPB1*20012 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --C --- --- --- --- --- --- --- C-- --- --- --- DPB1*2101 CT- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -AG --- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*2201 CT- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -AG --- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*2301 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*2401 -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -AG --- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*2501 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --- --- --- --- --- --- --- --- C-- --- --- --- DPB1*26011 --- --- --- --- --- --- --- --- --A --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- DPB1*26012 --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- Most polymorphisms are point mutations Polymorphic nucleotides encode amino acids associated with the peptide binding site

  13. COMBINATION OF MHC ALLOTYPES IN INDIVIDUALS AND IN THE POPULATION * * * * * *

  14. Molecular basis of MHC types and variants POLYGENISM Several MHC class I and class II genes encoding different types of MHC molecule with a range of peptide-binding specificities. POLYMORPHISM Variation >1% at a single genetic locus in a population of individuals MHC genes are the most polymorphic known The type and variant MHC molecules do not vary in the lifetime of the individual The diversity in MHC molecules exists at the population level This sharply contrast diversity in T and B cell antigen receptors which exists within the individual

  15. Populations need to express variants of each type of MHC molecule • The rate of replication by pathogenic microorganisms is faster than human reproduction • In a given time a pathogen can mutate genes more frequently than humans and can easily evade changes in MHC molecules • The number of types of MHC molecules are limited To counteract the flexibility of pathogens • The MHC has developed many variants of each type of MHC molecule • These variants may not necessarily protect all individuals from every pathogen, but will protect the population from extinction

  16. THE OUTCOME OF INFECTION IN A POPULATION WITH POLYMORPHIC MHC GENES MHC-Gen MHC XX v v v v v Pathogen that evades MHC X v v v v v v v v v v v v v v v v v v v v Example: If MHC X was the only type of MHC molecule Population threatened with extinction Population is protected

  17. FUNCTIONS OF MHC • CLASSICAL MHC GENE PRODUCTS • Presentation of peptides derived from self proteins – continuos presentation of self for the immune system • Determination of immunological self • Self MHC + self peptides • Presentation of peptides derived from foreign (antigenic) proteins • Determination of non-self • Self MHC + non-self peptides • Allogeneic immune response against non-self MHC (transplantation) • Recognition of non-self MHC + peptide combinations – consequence of MHC-restricted T-cell recognition • NK cell recognition • T-lymphocyte differentiation and selection in the thymus • T-lymphocyte survival in the periphery • NON CLASSICAL MHC GENES • Specialized functions • PROTEINS STRUCTURALLY RELATED TO CLASSICAL MHC MOLECULES

  18. LOCALIZATION OF MHC GENES Chromosome 6 short arm MHC Chromosome 15 2m Non- classical MHC genes E, G, F Classical MHC genes POLYMORPHIC HLA – Human Leukocyte Antigen HLA –A, B, C class I EXPRESSED IN ALL NUCLEATED CELLS HLA – DR, DP, DQ class II EXPRESSED IN PROFESSIONAL APC Class III genes

  19. OTHER GENES IN THE MHC – not polymorphic MHC Class 1b genes EncodingMHC class I-like proteins that associate with -2 microglobulin Restricted tissue expression HLA-Gtrophoblast, interacts CD94 (NK-cell receptor). Inhibits NK cell attack of foetus/ tumours HLA-E in the membrane of certain cells, binds conserved leader peptides from HLA-A, B, C. Interacts with CD94 HLA-F fetal liver, eosinophil surface, function unknown MHC Class II genes Encoding several antigen processing genes HLA-DMand in professional APC, proteasome components (LMP-2 & 7), peptide transporters(TAP-1 & 2), HLA-DO and DO Many pseudogenes MHC Class III genes Encoding complement proteins C4A and C4B, C2 and FACTOR B TUMOUR NECROSIS FACTORS-/ Immunologically irrelevant genes Genes encoding 21-hydroxylase, RNA Helicase, Caesin kinase Heat shock protein 70, Sialidase

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