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Major histocompatibility complex

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Major histocompatibility complex

  1. 1.  Major Histocompatibility Complex Cluster of genes found in all mammals Its products play role in discriminating self/non-self Participant in both humoral and cell-mediated immunity MHC Act As Antigen Presenting Structures In Human MHC Is Found On Chromosome 6 Referred to as HLA complex In Mice MHC Is Found On Chromosome 17 Referred to as H-2 complex
  2. 2. Gorer (1930s):1. Rejection of foreign tissue is the result of an immuneresponse to cell-surface molecules.2. Identification of I, II, III and IV groups of genes.Gorer and Snell (1940s & 1950s):1. Antigens encoded by the genes in the group II took part inthe rejection of transplanted tumors and other tissues.2. Snell called these genes “histocompatibility genes”(currently called H-2 genes)3. Snell was awarded the Nobel Prize in 1980.Earlier studies were done in inbred strain of mice.Pioneering studies were done by R.zinkernagel andP.Doherty,B. benacerraf etc
  3. 3. Aspects of MHC1. MHC molecules are membrane-bound. Recognition byT cells requires cell-cell contact.2. Peptide from cytosol associates with class I MHC and isrecognized by Tc cells. Peptide from vesiclesassociates with class II MHC and is recognized by Thcells.3. Although there is a high degree of polymorphism for aspecies, an individual has maximum of six differentclass I MHC products and only slightly more class IIMHC products.
  4. 4. 4. A peptide mustassociate with a givenMHC of thatindividual, otherwise noimmune response canoccur. That is one levelof control.Mature T cells musthave a T cell receptorthat recognizes thepeptide associated withMHC. This is thesecond level of control.
  5. 5. 5. Each MHC molecule has only one binding site.The different peptides a given MHC molecule canbind all bind to the same site, but only one at atime.6. MHC polymorphism is determined only in thegermline. There are no recombinationalmechanisms for generating diversity.7. Because each MHC molecule can bind manydifferent peptides, binding is termed degenerate.8 Cytokines (especially interferon-γ) increase levelof expression of MHC.
  6. 6. 9 Alleles for MHC genes are co-dominant. Each MHCgene product is expressed on the cell surface of anindividual nucleated cell.10 Why the high degree of polymorphism?Survival of species!11 The control of transplantation, autoimmunity, andthe other immune responses are the phenotypicconsequences of the function of molecules encoded inthe MHC.12. MHC fallows : 1. Polymorphism2. Polygenism3. linkage disequilibrium4. Co- Dominance
  7. 7.  Genes Of MHC Organized In 3 Classes Class I MHC genes Glycoproteins expressed on all nucleated cells Major function to present peptide Ags to TC Class II MHC genes Glycoproteins expressed on M , B-cells, DCs Major function to present processed Ags peptides to TH Class III MHC genesClass III molecules are not membrane proteins, are notrelated structurally to class I and class II molecules, and have norole in Ag presentation, although most play some role in immuneresponses. e.g., C2, C4a, C4b, factor B, 21-hydroxylase enzymes,TNFα, TNFβ, heat shock proteins (HSP)( include secreted proteins).MHC
  8. 8. Cell MembranePeptideMHC class I MHC class IIMHC moleculesPeptidebinding groove
  9. 9. Differential distribution of MHC moleculesTissue MHC class I MHC classT cells +++ +/-B cells +++ +++Macrophages +++ ++Other APC +++ +++Thymus epithelium + +++Neutrophils +++ -Hepatocytes + -Kidney + -Brain + -Erythrocytes - -The highest level ofclass I molecules areexpressed onlymphocytes: 1 % ofthe total plasmamembrane proteinsor 5 x 105 molecules/ cell.A few cell types(e.g., neurons andsperm cells at certainstages ofdifferentiation)appear to lack class IMHCmoleculesaltogether..Thymic epithelial cells and some other cell types can be induced to functionas APC and then express class II molecules under certain conditions.Cell activation affects the level of MHC expression.
  10. 10. 132MHC-encoded -chain of 43kDa ,Made Up Of3 Domains ( 1, 2 and 3)Overall structure of MHC class I molecules2m2-microglobulin, 12kDa, non-MHC encoded, non-transmembrane, non covalently bound to 3 domainThe a3 segment of the MHC I , is highlyconserved among MHC1 & serves as a bindingsite for CD8Peptide antigen in a groove formed from a pair of a-helicies on a floor of anti-parallel b strands-chain anchored to the cell membraneThe chain the HLA-A, -B, -C and 2m on different chromosome
  11. 11. Duadi tumours absence 2-m , cell is unable to express mhc 1 onthe memberane1, 2 and 3 contains 90amino acid , tm domain 25hypho AA, followed by shortstretch of hyphi AA andcytoplasm anchor of 30 aa3 domain & 2m havestructural & amino acidsequence homology with IgC domains Ig GENESUPERFAMILYAssociation Of Chain and 2Is Required For SurfaceExpression
  12. 12. 1 and 2 domains form two segmented -helices on eightanti-parallel -strands to form an antigen-binding cleft.Properties of the inner faces of the helices and floor of the cleftdetermine which peptides bind to the MHC moleculeThe formed cleft can bind peptides of 8 -10 amino acids in aflexible extended conformation.Chains Structures
  13. 13. 21and a -chain of 29kDa 1 and 2MHC-encoded, -chain of 34kDa , 1 and 221Overall structure of MHC class II moleculesand chains anchored to the cell membraneThese chains are non-covalently associatedpeptides2 & 2 domains have structural & amino acid sequencehomology with Ig C domains Ig GENE SUPERFAMILYNo -2 microglobulinPeptide antigen in a groove formed from a pairof -helicies on a floor of anti-parallelstrands
  14. 14. • CD4 Molecule Binds 2/ 2domains•The chains are the HLADRThe chains are the HLA DQand DPCleft is made of bothand chains
  15. 15.  Peptides Presented Through MHC I AreEndogenous Proteins As Few As 100 Peptide/MHC Complex CanActivate TC Peptide Features size 8-10 a/a, preferably 9 Peptides Bind MHC Due To Presence Of Specifica/a Found At The Ends Of Peptide. Ex. Glycine@ Position 2Class I MHC Peptides
  16. 16.  Peptides Presented Through MHC II AreExogenous Processed through endocytic pathway Peptides Are Presented To TH Peptides Are 13-18 a/a Long Binding Is Due To Central 13 a/a Longer Peptides Can Still Bind MHC II Like A long hot dog MHC I Peptides Fit Exactly, Not The Case WithMHC II PeptidesClass II MHC Peptides
  17. 17. MHC class IMHC class IICleft geometryPeptide is held in the cleft by non-covalent forces-chainPeptide-M-chain-chainPeptide
  18. 18. MHC-binding peptidesEach human usually expresses:3 types of MHC class I (A, B, C) and3 types of MHC class II (DR, DP,DQ)The number of different T cell antigen receptors isestimated to be 1,000,000,000,000,000Each of which may potentially recognise a differentpeptide antigen.How can 6 invariant molecules have the capacity tobind to 1,000,000,000,000,000 different peptides?
  19. 19. A flexible binding site?NO because: at the cell surface, such a binding site would beunable to allow a high enough binding affinity to form atrimolecular complex with the T cell antigen receptor & preventexchange of the peptide with others in the extracellular milieuA binding site that is flexible enough to bind any peptide?
  20. 20. So , here the answer lies …..A binding site that is flexible at an early, intracellular stage ofmaturation Formed by folding the MHC molecules around thepeptide.FloppyCompactAllows a single type of MHC molecule to• bind many different peptides• bind peptides with high affinity• form stable complexes at the cell surface• Export only molecules that have captured a peptide to the cellsurfaceVenus fly trap
  21. 21. Binding affinity of MHC to peptides- The association constant KD of the peptide-MHCmolecule complex is approximately 10-6.- The rate of association is low, but the rate ofdissociation is even lower.- Thus, the peptide-MHC molecule association is verystable under physiological conditions and most of theMHC molecules expressed on the membrane of a cellare associated with a peptide of self or nonself origin.
  22. 22. Peptides can be eluted from MHC moleculesPurify stable MHC-peptide complexesFractionate andmicrosequence peptidesAcid elutepeptides
  23. 23. E.g. for class 1 MHCBecause a single nucleated cell express about 105, copies ofeach class 1 molecule, many different peptides will beexpressed simultaneously on the surface of nucleated cell byclass 1 MHC molecule.It is also estimated that each of 2000 distinct peptide (foundafter elution & HPLC ) is presented with a frequency of 100 to4000 copies per cell.Evidence also suggest that even a single peptide- MHCcomplex may be sufficient to target a cell for recognization andlysis by a cytotoxic T lymphocyte with a receptor specific forthat target structure.Peptides after elution
  24. 24. Eluted peptides from MHC molecules have differentsequences but contain motifsPeptides bound to a particular type of MHC class I moleculehave conserved patterns of amino acidsA common sequence in a peptide antigen that binds to anMHC molecule is called a MOTIF
  25. 25. Amino acids common to many peptides tether the peptide tostructural features of the MHC molecule ANCHOR RESIDUESTethering amino acids need not be identical but must be relatedY & F are aromaticV, L & I are hydrophobicSide chains of anchor residues bind into POCKETS in the MHCmoleculeDifferent types of MHC molecule bind peptides with differentpatterns of conserved amino acidsR G Y YV Q Q LS I I FN E K LA P G YN P A L
  26. 26. In all peptides examined to date that bind to class 1 moleculecontains 2 anchors :1. carboxy terminal anchor. These anchors are generallyhydrophobic residue (eg leucine, isoleucine).2. anchor is reported at 2nd or 2nd or 3rd positions at the aminoterminal end end of the peptide .In general any , peptide of correct length that contains thesame or similar anchor residue will bind to same class 1 MHCmolecule.The main contacts between class 1 MHC molecule and peptideinvolves the anchors( residue 2 at the aminoterminal end andresidue 9 at the carboxyl terminus of the nanomeric peptide)
  27. 27. MHC molecules can bind peptides of differentlengthArchedpeptideB/w the anchors,the peptides arches away from the floor ofthe cleft in the middle allowing peptidesthat are slightly longer or shorter to accomodated Aminoacidthat are away from the MHC molecule are more exposed andpresumably can interact more directly with the T cellreceptor.
  28. 28. Slices throughMHC class Imolecules, whenviewed from abovereveal deep, wellconserved pocketsPeptide binding pockets in MHC class I molecules
  29. 29. Peptide antigen binding to MHC class II moleculesY F Q G G QR A SA S GIDT FD Y L NTR I KGSL F KNI P DD Y H KFN T KSLQ L TNI SY P I R TI VK S NKPA I RFG KD L Q N ALV N HHEN M TGT K YAY T L SSV P EKAL L LLV FY S W AF E LYY T SGYY T T DP YTR T SAG H GTY VR E PL NVN S PTT V LVEP P• Anchor residues are not localised at the N and C termini• Ends of the peptide are in extended conformation andare not conserved• Motifs are less clear than in class I-binding peptides• Pockets are more permissiveNegatively charged Hydrophobic
  30. 30. Slices through MHC class II molecules, when viewed from above revealshallow, poorly conserved pockets compared with those in MHC class ImoleculesPeptide binding pockets in MHC class II molecules
  31. 31. • MHC Adopt a flexible “floppy” conformation until a peptide binds• Fold around the peptide to increase stability of the complex• Tether the peptide using a small number of anchor residues• Allow different sequences between anchors and differentlengths of peptideSO, further explaination of the question…..
  32. 32. MHC molecules are targets for immune evasionby pathogens• Without T cells there is no effective immune response• Ag–specific T cells are activated by peptide/MHC complexes• There is therefore strong selective pressure for pathogens tomutate genes encoding antigens so that they can evade theformation of peptide/MHC complexes• The MHC has two strategies to prevent evasion by pathogens1. More than one type of MHC molecule in each individual2.Extensive differences in MHC molecules between individuals
  33. 33. Example: If MHC X was the only type of MHCmoleculePopulation threatened withextinctionSurvival ofindividualthreatenedPathogen thatevades MHC XMHCXX
  34. 34. Example: If each individual could make two MHCmolecules, MHC X and YImpact on theindividual dependsupon genotypePathogen thatevadesMHC XMHCXXMHCXYPopulation survivesMHCYYbut hassequencesthat bind toMHC Y
  35. 35. Example: If each individual could make two MHCmolecules, MHC X and Y……and the pathogen mutatesPopulation threatened withextinctionSurvival of individualthreatenedPathogen thatevadesMHC X but hassequences thatbind to MHC YMHCXXMHCXYMHCYYThe number of types of MHC molecule can not be increased ad infinitum….until itmutates toevade MHC Y
  36. 36. Populations need to express variants of eachtype of MHC molecule•Populations of microorganisms reproduce faster than humans•Mutations that change MHC-binding antigens or MHC moleculescan only be introduced to populations after reproduction•The ability of microorganisms to mutate in order to evade MHCmolecules will always outpace counter evasion measures thatinvolve mutations in the MHC•The number of types of MHC molecules are limited
  37. 37. To counteract the superior flexibility ofpathogens:Human populations possess many variants of each type of MHCmoleculeVariant MHC may not protect every individual from everypathogen.However, the existence of a large number of variants meansthat the population is prevented from extinction
  38. 38. YRYR XYXX XXR XYR YXR YYR YY XRXRXRYRFrom 2 MHC types and2 variants…….10 different genotypesVariants – alleles - of each type of MHC gene encode proteins that increasethe resistance of the population from rapidly mutating or newly encounteredpathogens without increasing the number of types of MHC moleculeVariant MHC molecules protect the populationPathogen thatevades MHC Xand YMHCXYMHCXXMHCYYMHCXXRMHCYYR…but binds to thevariant MHC XRand MHC YR
  39. 39. Molecular basis of MHC types and variantsPOLYMORPHISMThe presence of multiple alleles at a given genetic locus withinspeciesPOLYGENISMSeveral MHC class I and class II genes encoding different typesof MHC molecule with a range of peptide-binding specificities.MHC genes are the most polymorphic known.The type and variant MHC molecules do not vary in the lifetime of theindividual .This sharply contrasts diversity in T and B cell antigen receptorswhich are in a constant state of flux within the individualDiversity in MHC molecules exists at the population level.
  40. 40. Detailed Genomic Map of MHC genesThe MHC spans 4000 Kb of human DNA at chromosome no 6The human class 1 region span about 2000 kb at thetelomeric end of HLA comlex.1. MHC classical HLA- A, HLA-B & HLA C.2. MHC Class 1b genesEncoding MHC class I-like proteins that associate with -2 microglobulin:HLA –E,F,G,J & X (some are pseudogenes)HLA-G binds to CD94, an NK-cell receptor. Inhibits NK attack of foetus/tumoursHLA-E binds conserved leader peptides from HLA-A, B, C. Interacts withCD94HLA-F function unknown3. MIC region , which include MICA through MICE. MIC gene product areexpressed at low levels in epithelial cells and are inuced by heat or otherstimuli that influence heat shock protiens. MICA are highly polymorphic.
  41. 41. MHC Class II genes NON CLASSICAL GENESEncoding several antigen processing genes:HLA-DM and loading of antigenic peptide , proteasomecomponents LMP-2 & 7, peptide transportersTAP-1 & 2, HLA-DO and DO thymus & mature B cellsregulators of loading antigen peptideMany pseudogenesCLASS 2 MHC GENES are located at the centromericend of HLA1. HLA DR, DP&DQ multiple & chain DR= 3-4 functionalchain,1 chain.DP & DQ region each contains two of eachchain
  42. 42. MHC Class III genesCLASS 3 genes are between CLASS 1 & 2Encoding complement proteins C4A and C4B, C2 and FACTOR BTUMOUR NECROSIS FACTORS ANDImmunologically irrelevant genesGenes encoding 21-hydroxylase, RNA Helicase, Caesin kinaseHeat shock protein 70, SialidaseCongenital adrenal hyperplasia , mutation in gene encoding 21hydroxylase. The presence of linked class 3 genes is cluster isconseved in all species with MHC
  43. 43. Polymorphism in MHC Class I genesVariation >1% at a single genetic locus in a population ofindividualsIn the human population, over 1300 MHC class I alleles havebeen identified - some are null alleles, synonyms or differ inregions outside the coding region6993961981318 alleles(998 in October 2003)(657 in July 2000)8 215Class IA B CNoofpolymorphismsE F G
  44. 44. Polymorphism in MHC Class II genesOver 700 human MHC class II alleles have been identified -some are null alleles, synonyms or differ in regions outside thecoding region3494231192866Data from www.anthonynolan.org.uk/HIG/index.html September 2005733 alleles(668 in October 2003)(492 in July 2000)4 7 9 9DR DPDQ DM DOClass IIA B1 A1 B1A1 B1NoofpolymorphismsA B A B
  45. 45. 28629 62510Class I - ~100 antigensClass II - ~40 antigens(Figure hasn’t changed since October 2003)A B DQ DPC DRNoofserologically-definedantigensDiversity of MHC Class I and II antigensBecause so many MHC class I & II alleles are null, or containsynonymous mutations, the diversity of MHC molecules thatcan be identified by antibodies i.e. SEROLOGICALLY, isconsiderably fewer than that by DNA sequencingData from www.anthonynolan.org.uk/HIG/index.html September 2005
  46. 46. Evolution of pathogens to evade MHC-mediated antigenpresentation60% of individuals in south east China & Papua New Guinea express HLA-A11HLA-A11 binds an important peptide of Epstein Barr VirusMany EBV isolates from these areas have mutated this peptide so that it cannot bind to HLA-A11 MHC moleculesSuggests that selective pressures may operate on MHC polymorphismReplacement substitutions occur at a higherfrequency than silent substitutionEvolution of the MHC to eliminate pathogensIn west Africa where malaria is endemic HLA-B53 is commonlyassociated with recovery from a potentially lethal form ofmalariaMost polymorphisms are point mutations
  47. 47. How diverse are MHC molecules in the population?~6 x 1015 unique combinationsIF • each individual had 6 types of MHC• the alleles of each MHC type were randomlydistributed in the population• any of the 1,200 alleles could be present with anyother alleleIn reality MHC alleles areNOT randomlydistributed in thepopulationAlleles segregate withlineage and race15.1828.6513.384.460.025.7218.888.449.921.884.4824.632.641.760.01CAU AFR ASIFrequency (%)HLA-A1HLA- A2HLA- A3HLA- A28HLA- A36Group of alleles
  48. 48. B C ADP DQ DR1PolygenyB C ADP DQ DR1Variant allelespolymorphismGenes in the MHC are tightly LINKED and usually inherited ina unit called an MHC HAPLOTYPEInherited as 2 sets (one from father, one from mother)B C ADP DQ DR1Additional set ofvariant alleles onsecondchromosomeMHC molecules are CODOMINANTLY expressedTwo of each of the six types of MHC molecule are expressedDiversity of MHC molecules in the individualHAPLOTYPE 1HAPLOTYPE 2
  49. 49. Inheritance of MHC haplotypesB C ADP DQ DRB C ADP DQ DRB C ADP DQ DRB C ADP DQ DRXParentsDP-1,2DQ-3,4DR-5,6B-7,8C-9,10A-11,12DP-9,8DQ-7,6DR-5,4B-3,2C-1,8A-9,10DP-1,8DQ-3,6DR-5,4B-7,2C-9,8A-11,10DP-1,9DQ-3,7DR-5,5B-7,3C-9,1A-11,9DP-2,8DQ-4,6DR-6,4B-8,2C-10,8A-12,10DP-2,9DQ-4,7DR-6,5B-8,3C-10,10A-12,9B C ADP DQ DRB C ADP DQ DRB C ADP DQ DRB C ADP DQ DRB C ADP DQ DRB C ADP DQ DRB C ADP DQ DRB C ADP DQ DRChildren
  50. 50. Errors in the inheritance of haplotypes generate polymorphismin the MHC by gene conversion and recombinationMultiple distinctbut closely relatedMHC genesA B CDuring meiosischromosomes misalignA B CChromosomes separate aftermeiosis DNA is exchangedbetween haplotypesA B CA B CA B CA B CIn both mechanisms the type of MHC molecule remains the same, but anew allelic variant may be generated.However, Crossover Rate Is Low 0.5%GENE CONVERSIONRECOMBINATION between haplotypes
  51. 51. MHC polymorphism andOrgan Transplants & Autoimmune disorders• Developing T cells that recognize complexes of peptide andMHC molecules on HEALTY tissue (self-peptides presented by selfMHC) are DESTROYED• This results in the preservation of T cells that recognize non-selfMHC (allogenic MHC). Called alloreactive T cells (1-10%) of totalT-cell repertoire• It is primed for REJECTION OF FOREIGN ORGANS that expressallogenic MHC•Those MHC of healthy tissue that are unable to present peptidesto developing T cells, leads to the production of T & B cells thatare autoreactive causing AUTOIMMUNE DISORDERS
  52. 52. A clinically relevant application of MHC genetics:Matching of transplant donors and recipientsThe biology, diversity and complexity of the MHC locus and itspattern of inheritance explains:• The need to match the MHC of the recipient of a graft withthe donor• The difficulties faced in matching unrelated donors withrecipients• The ~20% chance of finding a match in siblings
  53. 53. If unmatched MHC transplantation takes place ,,, than T cellsrecognize them as foreign and generate an immune response, that can lead to graft failure .Rejection of transplanted tissue was associated withinflammation and lymphocyte infiltrationIMMUNE GRAFT REJECTION
  54. 54. AUTOIMMUNITY AND MHC It is well recognized that certain immunedisorders predominate in families. Determined by family studies. Genetic links have occurred between diseasesand HLA antigens Sometimes,,, there is another non MHC genecause that is related to a specific MHC gene thatis related to autoimmune disease. The mechanisms of tissue damage inautoimmune diseases are essentially the same asthose that operate in protective immunity.
  55. 55. Association of HLA Serotype with Susceptibilityto Autoimmune DiseasesHip jointsEyesKidneysCNSThyroidMusclesSystemicPancreasSmall jointsSkinThyroid
  56. 56. Population studies show association of susceptibility toinsulin-dependent diabetes mellitus (IDDM) with HLAgenotype
  57. 57. MHC IIn particular, cell surface MHC class Iglycoproteins gather from the cell’sbiosynthetic pathway fragments ofproteins derived from infectingviruses, intracellular parasites, or selfmolecules, either normally expressedor dysregulated by tumorigenesis,and then display these molecularfragments at the cell surface.Anucleate erythrocytes can not supportvirus replication - hence no MHC class I.Some pathogens exploit this - e.g.Plasmodium species.
  58. 58. MHC IPeptides derivedfrom proteins foundin the cytosol thatare then degraded bythe multiproteolyticproteasome complexinto peptides. As FewAs 100 Peptide/MHCComplex Can ActivateTC
  59. 59. MHC I The MHC-I molecule, theability to interact withTCR, then allows theAPC bearing a particularMHC–peptide complex toengage an appropriateTCR as the first stepin the activation of aCD8+ cellular programthat might lead tocytolysis of the APC as atarget and/or to thesecretion of lymphokinesby the T cell.
  60. 60. MHC II MHC class IImolecules bindpeptides derivedfrom thedegradation ofproteins ingested byMHC-II–expressingAPC, and displaythem at the cellsurface forrecognition byspecific T-lymphocytes.
  61. 61. MHC IIThe MHC-II antigenpresentationpathway is basedon the initialassembly of theMHC-IIheterodimer with adual functionmolecule.
  62. 62. MHC IIThe invariantchain (Ii) thatserves as achaperone to directthe heterodimerto anendosomal, acidicprotein–processinglocation.
  63. 63. MHC IIWhere Ii encountersantigenic peptides, itserves to protect theantigen-binding site ofthe MHC-II moleculeso that it preferentiallywill be loaded withantigenic peptides inthis endosomal–lysosomal location.
  64. 64. MHC IIThe loading of theMHC-II molecule withantigenic peptide, aprocess dependent onthe release of the Ii-derived CLIPpeptide, in partdependent on theMHC-II-like moleculeleads to the cellsurface expression ofMHC-II peptidecomplexes.
  65. 65. MHC molecules on the cell surface displaypeptide fragmentsTH 1Eg HIVTH 2
  66. 66.  Expression Is Regulated By Many Cytokines IFN , IFN , IFN and TNF Increase MHC expression Transcription Factors That Increase MHC geneExpression CIITA (Transactivator), RFX (Transactivator) Some Viruses Decrease MHC Expression CMV, HBV, Ad12 Reduction Of MHC May Allow For ImmuneSystem EvasionMHC Expression