2 P1 P4 P6 P7 P

Size: px

Start display at page:

Download "2 P1 P4 P6 P7 P"

きみえたておか
5 years ago
Views:

1 1

2 2 P1 P4 P6 P7 P

3 3

4 4

5 5

6 HLA 6

7 γ α 7

8 8

9 A W (DRA) (DQA1*0302) CD4+ F N HLA-DR4 (DRB1*0405 DRB1*0406) DRB1*0405 (37 Y 57 S 74 A 86 G) WxxFxN F L D M I T Y Y I I W V L V S V M F A A M DRB1*0406 (37 S 57 D 74 E 86 V) P1 P4 P6 P1 P4 P6 FxxLxS I I N M M I Y V Q W F V L A T V T D A M B DQ4(DQA1*0302-DQB1*0401) CD4 + P1 P9 LxxxxxxxR I L V I W M L R F V Y H M (DQB1*0401) A HLA-DQ4 P G DQB1*0302 DQB1*0303 ( 57; Ala) ( 57; Asp) C (DQA1* 0302) CD4+ Y W 57 (DQB1* 0302 vs 0303) HLA-DQ8 vs DQ9 T P1 P4 P8 YxxWxxxI KE DQ TN RH SV LM WF YG P1 P4 P8 YxxWxxxT LI VR MY FW 9

10 10

11 A FVNQHLCGSHLVEALYLVCGERGFFYTPKT GIVEQCCTSICSLYQLENYCN B [ IC50 ( M) ] DRB1* 0405 DRB1* 0406 ( cpm X 10-3 ) Me >500 > >500 > K-Ins p1-10 KK-Ins p8-21 K-Ins p1-18 K-Ins p

12 12

13 13

14 14 β β

15 HLA-DRB1* YK b 0101/0701 DR1 (DRB1*0101) p MK 0301/0407 DR53 (DRB4*0103) p SA 0405/0802 DR53 (DRB4*0103) p DR8 (DRB1*0802) p NT NT c 0901/0901 DR9 (DRB1*0901) p SY 0901/0901 DP2 (DPA1*01-DPB1*0201) p MS d 0405/0803 DP2 (DPA1*0201-DPB1*0201) p a NT NT NT NT NT P L S H Q E Q F L N VD W IFN- (300ng/ml) CD4 T AChR p75-87 TCR IL- 4 (<10 ng/ml) DQ6 DQA1*0102 DQB1*

16 α α α α α γ 16

17 A MBP(85-99) ENPVVHFFKNIVTPR HLA-DR2 HLA-DQ6 TCR TCR ---VVHFFKNIVT--- HLA-II ---VVHFFKNIVT--- HLA-II B mimic peptides Set VHFFK INYYR LQ W AF V M L F I Y A W M Set 2 ---VVHFFK--- IIN YR LLQ W AAF V MM L I A M Set VHFFK IFYY LYWW AMVV M LL II C MBP(85-99) ENPVVHFFKNIVTPR DR2 TGGVYHFVKKHVHES YRNLVWFIKKNTRYP MARAAFLFKTVGFGG GGRRLFFVKAHVRES DQ6 FRQLVHFVRDFAQLL DFEVVTFLKDVLPEF DRLLMLFAKDVVSRN IGGRVHFFKDISPIA 17

18 18

19 HLA MS (n=40) HLA MS (n=46) (n=113) DR2(DRB1*1501) - DR51(DRB5*0101) 7.5%* 37.0%** 14.2% MS (n=44) MS (n=46) (n=92) DP5 (DPB1*0501) 88.6%** 71.7% 63.0% * MS p (p c<0.05) ** MS p (p c<0.05) 19

20 20

21 Lehmann PV et al : Immunol Today 14, 203, 1993 ) 21

22 peptides to DR and DQ molecules of rheumatoid arthritis-susceptible and non-susceptible haplotypes. Int. Immunol. 1996, 8: Oiso M, Nishimura Y, Nishi T, et al.: Differential peptide binding to DQ8 and DQ9 differing only at b57. Human Immunol. 1997, 52: Germain RN: MHC-dependent antigen processing and peptide presentation:providing ligands for T lymphocute activation. Cell 1994, 76: Stern LJ, Jardetzy TS, Gorga JC, et al.: Crystal structure of the human class II MHC protein HLA-DR1 complexed with an influenza virus peptide. Nature 1994, 368: Hammer J, Gallazzi F, Bono E, et al.: Peptide binding specificity of HLA-DR4 molecules: Correlation with rheumatoid arthritis association. J.Exp.Med. 1995, 181: Rammensee H-G, Friede T, & Stevanovic S.: MHC ligands and peptide motifs: first listing. Immunogenet. 1995, 41: Oiso M., Matsushita S., Nishi T., et al. Differential binding of peptides substituted at a putative C-terminal anchor residue to I-A g7 b 56 His 57 Ser and I-A g7 b 56 Pro 57 Asp. Immunogenetics 1998, 28: Tisch R., McDevitt H., Steinman L., et al : Reviews on autoimmunity (IDDM, MS, SLE, RA and genetics). Cell 1996, 85: Ota K, Matsui M, Milford EL, et al. T-cell recognition of an immunodominant myelin basic protein epitope in multiple sclerosis. Nature 1990, 346: Ohashi T, Yamamura T, Inobe J, et al. Analysis of proteolipid protein (PLP)-specific T cells in multiple sclerosis: identification of PLP as an HLA-DR2, w15-associated determinant. Int Immunol 1995, 7: Kaufman DL, Clare-Salzler M, Tian J, et al. Spontaneous loss of T-cell tolerance to glutamic acid decarboxylase in murine insulin-dependent diabetes. Nature 1993, 366: Matsushita S, Takahashi K, Motoki M, et al. Allele specificity of structural requirement for peptides bound to HLA-DRB1* 0405 and DRB1*0406 complexes: Implication for the HLA-associated susceptibility to methimazoleinduced insulin autoimmune syndrome. J. Exp. Med. 1994, 180: Matsushita S, Nishi T, Yamaoka K, et al. : HLA-DQ-binding peptide motifs. I. Comparative binding analysis of type II collagen-derived 14. Atkinson MA, Kaufman DL, Campbell L,et al. Response of peripheral blood mononuclear cells to glutamine decarboxylase in insulin-dependent diabetes. Lancet 1992, 339: Balasa B, Deng C, Lee J, et al. Interferon g (IFN-g) is necessary for the genesis of acetylcholine receptor-induced clinical experimental autoimmune myasthenia gravis in mice. J.Exp.Med. 1997, 186:

23 16. Engel AG, Myasthenia gravis and myasthenic syndromes. Ann Neurol. 1984, 16:519 cell clones specific for myelin basic protein. Cell 1995, 80: Kira J-I, Kanai T, Nishimura Y, et al.: Western vs. Asian types of multiple sclerosis: immunogenetically and clinically distinct disorders Ann. Neurol. 1996, 40: Wakitani, S., Murata, N., Toda, Y., et al. The relationship between HLA-DRB1 alleles and disease subsets of rheumatoid arthritis in Japanese. Brit.J.Rheumatol. 1997, 36: Londei M, Savill CM, Verhoef A, et al. Persistence of collagen type II-specific T-cell clones in the synovial membrane of a patient with rheumatoid arthritis. Proc. Natl. Acad. Sci. USA 1989, 86: Miyazaki T, Uno M, Uehara M, et al.: Direct evidence for the contribution of the unique I-ANOD to the development of insulitis in nonobese diabetic mice. Nature 1990, 345: Tabata, H., Kanai, T., Yoshizumi, H., et al. : Characterization of self-glutamic acid decarboxylase 65-reactive CD4 + T cell clones established from Japanese patients with insulin dependent diabetes mellitus. Human Immunol. 1998,59, Ito, H., Yamasaki, K., Kawano, Y., et al.: HLA-DP -associated susceptibility to opticospinal from of multiple sclerosis in the Japanese. Tissue Antigens 1998, 52: Lehman, P. V., Forsthuber, T., Miller, A. et al.: Spreading of T-cell autoimmunity to cryptic determinants of an autoantigen. Nature 1992, 358: Matsuki K, Juji T, Tokunaga K, et al. : HLA antigens in Japanese patients with myasthenia gravis. J.Clin.Invest. 1990, 86: Kanai, T., Nomura, Y., Segawa, M., et al. Immuno-suppressive peptides for a human T cell clone autoreactive to a unique acetylcholine receptor a subunit peptide presented by the disease susceptible HLA-DQ6 in infant-onset myasthenia gravis. Human Immunol. 1997, 56: Wucherpfennig KW, and Strominger JL Molecular mimicry in T cell-mediated autoimmunity: viral peptides activate human T 23

α β αβ α β α β γ δ ε ζ α β α ζ β α β α α β

α β αβ α β α β γ δ ε ζ α β α ζ β α β α α β α β αβ α β αβ γδε ζ α β α ζ β αβ α α β A P-1 Lys N P2 Val P3 Lys P5 Asn P8 Lys P11 Thr C P-2 Pro P4 Gln P7 Leu P10 Ala P6 Thr P9 Leu B P1Tyr 1-1-N N P 4 P 6 P 7 P 9 1 1 C 1-N 1- T (TCR) C V HLA II 2 CD4