Historical definition of Antigen. An antigen is a foreign substance that elicits the production of antibodies that specifically binds to the antigen.

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1 Historical definition of Antigen An antigen is a foreign substance that elicits the production of antibodies that specifically binds to the antigen.

2 Historical definition of Antigen An antigen is a foreign substance that elicits the production of antibodies that specifically binds to the antigen. Any substance able to provoke an immune response in the human body

3 Antibody structure (1)

4 Antibody structure (2)

5 Antibody structure (3)

6 B-cell receptor biology

7 Antibody structure (4)

8 Antigen structure (1) Hen Egg White Lysozyme 1VED

9 Antigen structure (1) Hen Egg White Lysozyme 1VED

10 Antigen structure (2) Sequential Epitope Conformational Epitope Hen Egg White Lysozyme 1VED

11 Antigen structure (3) Hen Egg White Lysozyme 1VED

12 Antigen structure (4) Hen Egg White Lysozyme 1VED

13 Identification of epitope in the target protein sequence (1) sequence scanning by overlapping peptides for sequential epitopes

14 Antigen structure (5) Hen Egg White Lysozyme 1VED

15 Identification of epitope in the target protein sequence (2) scanning of coupled peptide for conformational epitopes

16 Can we identify B-cell epitopes by using bioinformatic approaches?

17

18 Hen Egg White Lysozyme Protein sequence analysis

19 Reverse Vaccinology (protective antibodies)

20 Reverse Vaccinology (protective antibodies) Rappuoli R. Curr Opin Microbiol 2000

21 QUESTION TIME (1)

22 MHC: the Key to how T-cells see the Universe CD4+ T-Cell HLA/peptide/TCR complex CD8+ T-Cell Proteasome Ribosomes Pathogens Exogenous particles etc APC TCR HLA-class II HLA-class I

23 T-cell receptor feature

24 Different evolution of the diversity in the proteins involved in the specific T-cell response Vertebrate only No intraspecie gene variability TCR Multiple gene fragments for variable portions present in the gene Rearrangment of the variable gene portion at somatic level Large repertoire (10 18 different combinations) in each individual for the antigen recognition Antigenic peptide (MHC) HLA Strongly conserved among different phyla Large intraspecie/population variability Gene duplication Codominance of the genes for increasing the possibility of the antigen recognition (from 6 to 14 different proteins for individual in human)

25 Different evolution of the diversity in the proteins involved in the specific T-cell response TCR Antigenic peptide (MHC) HLA Enough large repertoire for antigen recognition... i.e. There will be always one or more TCRs capable to recognise a HLA-peptide complex and start the immune response Determine if a protein portion might be recognised as an antigen... i.e. the binding of a peptide to a MHC

26 MHC/peptide complex peptide MHC molecule cell membrane

27 The Major Histocompatibility Complex (Human Leukocyte Antigen, in Human) The Key to How T Cells See the Universe

28 The discovery Agglutination of the leucocytes of twins with the aid of leuco-agglutination sera Monozygotic twins Leuco-agglutination sera Au Ch Ce Le Bo Te Ro De Ds Rb Vc Ba Pu Lx P.Va J.Va E.Ro H.Ro D.Te B.Te Dizygotic twins L.Go V.Ro Dausset and Brecy, Nature, : 1430

29 The discovery (2) Leuco-agglutination sera formed after blood transfusion Monospecific leuco-agglutination antibodies formed during pregnancy Family studies showing Mendelian segregation Importance in trasplantation and tests of the human transplant failures Development of microtoxicity tests (Terasaky) Computer facility for analysing multiple 2x2 c 2 tables Development of the Mixed Lymphocyte Reaction tests Studies on cousin marriage families (identified thanks to the Roman Catholic church archives) Identification of the cross-over between the different Leukocytes groups identified Idea that it was one genetic system and not different groups (like blood groups) 10 WORKSHOPS in less than 30 years!!! No patent requests and full sharing of reagents betwen groups and setting of a repository

30 The discovery (3) The molecular genetic of HLA Chromosome 6 HLA complex 0 Kb 6p21.3 Class I Class III Class II 4000 Kb

31 Map of the Human MHC from the Human Genome Project 3,838,986 bp 224 genes on chromosome 6 The MHC sequencing consortium Nature 401,

32 Detailed Map of HLA region

33 Map of the HLA Complex - Microsatellites HLA-DRB1

34 Class I MHC heavy (a) chain genes: HLA-A, HLA-B & HLA-C HLA Class I MHC region

35

36 HLA CLASS I

37 CD8 T cell MHC I Cytoplasm Nucleated cell

38 EACH LOCUS ENCODES EITHER AN ALPHA CHAIN GENE OR A BETA CHAIN GENE Genes: TAP and proteosome components HLA class II peptide loading HLA Class II MHC region

39

40 HLA CLASS II

41 CD4 T cell MHC II Intravesicular Antigen presenting cell Extracellular

42 Differential distribution of MHC molecules Tissue MHC class I MHC class II T cells +++ +/- B cells Macrophages Other APC Epithelial cells of thymus Neutrophils Hepatocytes + - Kidney + - Brain + - Erythrocytes - -

43 Genes: TNF, C2, C4, factor B, etc. HLA Class III MHC region

44 WHAT TYPES OF GENES ARE ENCODED BY THE MHC? The MHC basically contains 3 types of genes: Type of gene MHC region Function Class I MHC Class I region Peptide presentation to CD8 T cells Class II MHC Class II region Peptide presentation to CD4 T cells Class III MHC Class III region Multiple: do not involve antigen presentation examples: genes for C4, C3, factor B (Bf)

45 HLA characteristics - Polygenic: many genes: - HLA-A, -B, -C; HLA-DR, -DP, -DQ

46 HLA (genetic products)

47 HLA characteristics - Polygenic: many genes: - HLA-A, -B, -C; HLA-DR, -DP, -DQ - Codominance: - both paternal and maternal genes are expressed

48 Diversity of MHC molecules in the individual DP DQ DR a a 1 a B C A Polygeny HAPLOTYPE 1 DP DQ DR a a 1 a B C A Variant alleles polymorphism HAPLOTYPE 2 DP DQ DR a a 1 a B C A 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 Genes in the MHC are tightly LINKED and usually inherited in a group The combination of alleles on a chromosome is an MHC HAPLOTYPE

49 HLA characteristics - Polygenic: many genes: - HLA-A, -B, -C; HLA-DR, -DP, -DQ - Codominance: - both paternal and maternal genes are expressed - Polyallelic: many gene alleles at each locus (e.g., HLA-B) - HLA-B8, HLA-B15, HLA-B27 - Polymorphic: the HLA molecules are highly polymorphic (variations in primary amino acid sequence) as a consequence of polyallelism

50 A. HLA-A D. HLA-DP B. HLA-B E. HLA-DQ C. HLA-C F. HLA-DRB1

51 Map of the genes in the HLA Database April 2003 update

52 Number of HLA antigens/alleles identified over the years April 2003 update

53 HLA antigens (serological variants) identified HLA-A HLA-B HLA-C HLA-DR HLA-DQ HLA-DP A1 B7 Cw1 DR1 DQ5(1) DPw1 A2 B8 Cw2 DR15(2) DQ6(1) DPw2 A3 B13 Cw3 DR16(2) DQ2 DPw3 A11 B14 Cw4 DR3 DQ7(3) DPw4 A23(9) B15 Cw5 DR4 DQ8(3) DPw5 A24(9) B18 Cw6 DR11(5) DQ9(3) DPw6 A25(10) B27 Cw7 DR12(5) DQ4 A26(10) B35 Cw8 DR13(6) A29(19) B37 Cw9 DR14(6) A30(19) B38(16) Cw10 DR7 A31(19) B39(16) DR8 A32(19) B40 DR9 A33(19) B41 DR10 A34(10) B42 DR52 A36 B44(12) DR53 A43 B45(12) DR51 A66 B46 A68(28) B47 A69(28) B48 A74(19) B49(21) B50(21) B51(5) B52(5) B53 B54(22) B55(22) B56(22) B57(17) B58(17) B59 B67 B73 B78

54 Number of HLA alleles in the HLA/IMGT database Class I A B C E F G H J K L Class II DRA DRB DQA1 DQB1 DPA1 DPB1 DMA DMB DOA DOB HLA-DR DRB1 DRB2 DRB3 DRB4 DRB5 DRB6 DRB7 DRB8 DRB9 TOT Other non-hla genes MICA MICB MICC MICD MICE TAP1 TAP2 LMP2 LMP April 2003 update

55 Nomenclature for factors of HLA alleles Nomenclature HLA HLA-DRB1 HLA-DRB1*13 HLA-DRB1*1301 HLA-DRB1*1301N HLA-DRB1* Indicates the HLA region and prefix for an HLA gene a particular HLA locus, i.e. DRB1 a group of alleles encoding the DR13 specificity a specific HLA allele a null allele an allele which differ by a synonymous mutation HLA-DRB1* an allele which contaning a mutation outside the coding region HLA-DRB1* N a null allele contaning a mutation outside the coding region HLA-DRB1* L an allele contaning a mutation outside the coding region which leads to a lower level of expression By default: HLA-DRB1*

56 How diverse are HLA molecules in the population? IF each individual had 6 types of MHC the alleles of each MHC type were randomly distributed in the population any of the about 2000 alleles could be present with any other allele ~2 x unique combinations In reality MHC alleles are NOT randomly distributed in the population Alleles segregate with lineage and race Group of alleles HLA-A1 HLA- A2 HLA- A3 HLA- A28 HLA- A36 Frequency (%) CAU AFR ASI

57 x x x x Secondary Hot-spots of recombination Primary Hot-spots of recombination

58 HLA ancestral haplotypes Based on: - the full HLA class I and II typing, - microsatellite analysis on class III region (in particular the area of the TNF genes), 53 ancestral haplotype in the HLA genomic region has been identified. Each one include the HLA-B and C and TNF variants They could/couldn t include the HLA-A and/or DR and DQ alleles Nomenclature are based on HLA-B serotype The most frequents are present in >1-3% population i.e. Ancestral Haplotype 8.1: HLA-A1; -Cw7, -B8, TNFA2, DRB1*0301 and DQB1*0201

59 HLA-DR haplotypes expressed genes pseudogenes

60 Inheritance of MHC haplotypes DP-1,2 DQ-3,4 DR-5,6 B-7,8 C-9,10 A-11,12 DP-9,8 DQ-7,6 DR-5,4 B-3,2 C-1,8 A-9,10 Parents DP DQ DR DP DQ DR X DP DQ DR DP DQ DR B C B C B C B C A A A A Children DP-1,9 DQ-3,7 DR-5,5 B-7,3 C-9,1 A-11,9 DP-1,8 DQ-3,6 DR-5,4 B-7,2 C-9,8 A-11,10 DP-2,8 DQ-4,6 DR-6,4 B-8,2 C-10,8 A-12,10 DP-2,9 DQ-4,7 DR-6,5 B-8,3 C-10,10 A-12,9 DP DQ DR DP DQ DR DP DQ DR DP DQ DR DP DQ DR DP DQ DR DP DQ DR DP DQ DR B C B C B C B C B C B C B C B C A A A A A A A A

61 Haplotype HLA identical (share both haplotypes)

62 Haplotype HLA haploidentical ( half -identical; share one haplotype)

63 Haplotype HLA nonidentical no shared haplotypes)

64 Which is the functional role of the polymorphisms of HLA molecules?

65 RIBBON DIAGRAM: PEPTIDE WITHIN THE GROOVE FOR CLASS I MHC SPACE-FILLING DIAGRAM: PEPTIDE WITHIN THE GROOVE FOR CLASS I MHC

66 Class I MHC

67 Class I MHC

68 Class I MHC

69 Interaction between HLA class I and peptide Pocket B Pocket F HLA classe I

70 RIBBON DIAGRAM: PEPTIDE HANGS OUT OF THE GROOVE (CLASS II MHC) SPACE-FILLING DIAGRAM: PEPTIDE HANGS OUT OF THE GROOVE (CLASS II MHC)

71 Interaction between HLA class II and peptide P1 P4 P6 P9 HLA classe II

72 Class II MHC

73 Class II MHC

74 Class II MHC

75 HLA polymorphisms (1) +0.7 A. HLA-DP2(E69) B. HLA-DP2K Berretta et al 2003.

76 HLA polymorphisms (2) HLA-DP2 P4 affinities HLA-DP2k69 P4 affinities V T S P L I D (WT) A Y W R Q N M K H G F E C V T S G C Y W R Q P N M L K I H F E D A (WT) IC 50 M IC 50 M Position P4 of HLA-DP2 preferentially bind polar, aromatic or positive charged residues. Posizione P4 of HLA-DP2k69 bind preferentially only aromatic residues. Berretta et al 2003.

77 HLA supertypes HLA alleles sharing the peptide binding motif perform the same work and are grouped in a supertype Nine HLA-class I supertypes have been identified: A1, A2, A3, A24, B7, B27, B44, B58 and B62 Nine HLA-DR supertypes have been identified: 1, 3, 4, 7, 8, 11, 13, 15, 51 Four HLA-DP supertypes have been identified: 2, 3, 4, 9

78 Non-self Individual peptides derived from a pathogen Simplistic model for HLA molecules encoded by a single chr.: 1 st set of 3 ellipses: potential epitopes presented to CD8 T cells 2 nd set of 4 ellipses: potential epitopes presented to CD4 T cells Being polygenic & polyallelic: many peptides can be presented to CD4 T cells and CD8 T cells

79 For the human population: ~all peptides can be presented to CD4 T cells and CD8 T cells Non-self Potential presentation of any pathogen that contains peptides or proteins!

80 QUESTION TIME (2)

81 Identification of T-cell microbial antigens by reverse immunogenetic

82 HLA molecules are peptide binding molecules Pocket B Pocket F P1 P4 P6 P9 HLA class I HLA class II

83 HLA-A*0201 HLA-A*1101 ANCHOR AMINOACIDS ANCHOR AMINOACIDS Adapted from Janeway et al., Immunobiology (2001)

84 HLA-DRB*0404 SECONDARY ANCHOR AMINOACIDS PRIMARY ANCHOR AMINOACIDS PEPTIDE CORE Adapted from Janeway et al., Immunobiology (2001)

85 Peptide binding motif analysis (1) (qualitative) HLA class I Class I X[LM]XXXXXXX[VL] A*0201 Class I X[LM]XXXXX[VL] A*0201 Class I X[LM]XXXXXX[VL] A*0201 Class I X[L]XXXXXXX[LV] A*0202 Class I X[L]XXXXXX[LV] A*0202 Class I X[L]XXXXX[LV] A*0202 Class I X[L]XXXXXXX[L] A*0204 Class I X[L]XXXXXX[L] A*0204 Class I X[L]XXXXX[L] A*0204 Class I X[VLIMQ]XXXXXX[L] A*0205 Class I X[VLIMQ]XXXXXXX[L] A*0205 Class I X[VLIMQ]XXXXX[L] A*0205 HLA class II Class II [IL]XX[N]X[AS]XX[IL] DRB3*0301 Class II [W]XX[VK]X[DS]XX[N] DRB1*0407 Class II [FY]XX[A]X[NT]XX[Q] DRB1*0407 Class II [A]XX[A]XXXX[T] DRB1*1302 Class II [V]XX[M]X[K]XXX DRB1*1302 Class II XXX[Y]XXXXX DRB1*1302 Class II [I]XX[I]XX[V]XX Class II [L]XX[F]XX[I]XX Class II [V]X[A]XXXXX[V] Class II [IL]XX[L]X[R]XX[Y] Class II [V]XX[V]X[K]XX[F] DRB1*1501 DRB1*1501 DRB1*1201 DRB1*1301 DRB1*1301 Class II [MV]XXX[MY]XX[MV]X DPB1*0201 Class II [FL]XXX[FL]XX[IA]X DPB1*0201

86 Peptide binding motif analysis (2) ( quantitative ) Amicosante M. Sarcoidosis Dif. Lung Dis. 2008

87 ( 3 ) analysis Peptide binding motif Seghrouchni F., Berretta F., Amicosante M.; Curr. Pharmacogen. 2005

88 Pathogen genome Pathogen proteome Pathogen immunome Portion of pathogen derived pepetides recognised by HLA molecules Subject s pathogen immunome (i.e. Pathogen epitopes recognised by the combination of the subject s ( molecules HLA

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