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17.391 -10 Td
(Immunol 2000;18:423-49.)Tj
-17.359 -10 Td
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0.2 Tw 17.472 -10 Td
(Activation-induced expression of human programmed death-1 gene)Tj
0 Tw 0.075 -10 Td
[(in )6.375 (T)125.125 (-lymphocytes. Exp Cell Res 1997;232:25-8.)]TJ
-17.515 -10 Td
(35.)Tj
0.138 Tw 17 0 Td
[(Groux H, O\325Garra A, Bigler M, et al. )63.375 (A)]TJ
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-128.923 -10 Td
[(antigen-specific )7.5 (T)]TJ
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(1997;389:737-42.)Tj
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(36.)Tj
0.2 Tw 17 0 Td
(Plebanski M, Flanagan KL, Lee EA, et al. Interleukin 10-mediated)Tj
0.542 -10 Td
[(immunosuppression by a variant CD4 )32.25 (T)]TJ
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-130.888 -10 Td
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-17.537 -10 Td
(37.)Tj
0.117 Tw 17 0 Td
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-66.538 -10 Td
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(infection. J Immunol 1998;160:1804-10.)Tj
246.338 140 Td
[(38.)-875 (Y)]TJ
0.2 Tw 22.027 0 Td
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0.16901 Tw -151.005 -10 Td
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-17.522 -10 Td
[(39.)-875 (W)62.625 (aterhouse P, Marengere LE, Mittrucker HW, Mak TW. CTLA-4, a)]TJ
17.613 -10 Td
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-17.641 -10 Td
(40.)Tj
0.2 Tw 17 0 Td
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(oday 1999;20:367-75.)Tj
-102.64 -10 Td
[(41.)-875 (W)]TJ
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[(T)-274.8 (cells or )-24.5 (T)25.2 (r1 cells in RA)-299.5 (joints.)]TJ
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[(While CD4+ )-44.2 (T)]TJ
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(memory/activation markers, PD-1+ cells also coexpressed)Tj
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/TT0 10 Tf
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2.043 Tw 7 0 Td
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0.688 Tw -31.668 -12 Td
(negative signals from B7 molecules or PD-L. On the other)Tj
0.75301 Tw 0.027 -12 Td
(hand, CD26, another costimulatory molecule that mediates)Tj
-0.10201 Tw 0.012 -12 Td
(activation signals and is considered to be one of the markers)Tj
0 Tw 0.022 -12 Td
(for Th1-type cells)Tj
/TT0 6.25 Tf
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(40,41)Tj
/TT0 10 Tf
0.336 Tw 1 0 0 1 140.081 606 Tm
[(, rarely coexpressed PD-1 on CD4+ )0.3 (T)]TJ
1.186 Tw -86.799 -12 Td
(cells from RA)Tj
0 Tw 62.277 0 Td
[(SF)74.7 (.)]TJ
1.136 Tw 16.373 0 Td
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-0.159 Tw -78.53 -12 Td
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0 Tw 154.567 0 Td
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[(about the role of CD4+ )25.8 (T)]TJ
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(T)Tj
1.15199 Tw 5.358 0 Td
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(synovial)Tj
0.759 Tw -205.863 -12 Td
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0.201 Tw -0.05 -12 Td
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0.377 Tw -0.077 -12 Td
(4 but not CD26 coexpression, and by IL-10 production and)Tj
0.951 Tw 0.017 -12 Td
(to a lesser degree IL-2 production. Further examination of)Tj
2.427 Tw 0.027 -12 Td
[(these unique cells may clarify the mechanism of )28.4 (T)]TJ
0 Tw 225.51 0 Td
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/TT1 10 Tf
-133.023 -24 Td
(REFERENCES)Tj
/TT0 8 Tf
7.236 -10 Td
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0.172 Tw 13 0 Td
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0.2 Tw 0.3 -10 Td
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0 Tw -0.025 -10 Td
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0.059 -10 Td
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-13.441 -10 Td
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0.16901 Tw 13 0 Td
(Kurosaka M, Ziff M. Immunoelectron microscopic study of the)Tj
0 Tw 0.413 -10 Td
[(distribution of )-18.125 (T)]TJ
0.2 Tw 54.842 0 Td
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0 Tw -54.811 -10 Td
(1983;158:1191-210.)Tj
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0.2 Tw 13 0 Td
(Thomas R, Lipsky PE. Presentation of self-peptides by dendritic)Tj
0.538 -10 Td
(cells: possible implications for the pathogenesis of rheumatoid)Tj
0 Tw -0.17 -10 Td
(arthritis. Arthritis Rheum 1996;39:183-90.)Tj
-13.439 -10 Td
(4.)Tj
0.2 Tw 13 0 Td
[(Firestein GS, Zvaifler NJ. How important are )32.625 (T)]TJ
0 Tw 155.588 0 Td
(cells in chronic)Tj
-154.979 -10 Td
[(rheumatoid synovitis?: II. )-11.25 (T)-281.125 (cell-independent mechanisms from)]TJ
-0.027 -10 Td
(beginning to end. Arthritis Rheum 2002;46:298-308.)Tj
-13.652 -10 Td
[(5.)-875 (Kohem CL, Brezinschek RI, )-99.125 (W)31.375 (isbey H, )12.5 (T)31.375 (ortorella C, Lipsky PE,)]TJ
13.707 -10 Td
(Oppenheimer-Marks N. Enrichment of differentiated)Tj
-0.208 -10 Td
[(CD45RBdim,CD27\320 memory )-49.5 (T)-218.625 (cells in the peripheral blood,)]TJ
0.2 Tw 0.146 -10 Td
(synovial fluid, and synovial tissue of patients with rheumatoid)Tj
0 Tw -0.095 -10 Td
(arthritis. Arthritis Rheum 1996;39:844-54.)Tj
-13.439 -10 Td
[(6.)-875 (Ishida )6.375 (Y,)-93.875 (Agata )6.5 (Y)156.125 (, Shibahara K, Honjo )-68.5 (T)31.375 (. Induced expression of)]TJ
0.2 Tw 13.555 -10 Td
[(PD-1, a novel member of the immunoglobulin gene superfamily)96.75 (,)]TJ
0 Tw -0.138 -10 Td
[(upon programmed cell death. EMBO)-379.625 (J 1992;11:3887-95.)]TJ
-13.418 -10 Td
[(7.)-875 (Okazaki )6.75 (T)62.625 (, Maeda A, Nishimura H, Kurosaki )-56 (T)62.625 (, Honjo )-18.75 (T)62.625 (. PD-1)]TJ
13.376 -10 Td
(immunoreceptor inhibits B cell receptor-mediated signaling by)Tj
0.2 Tw -0.023 -10 Td
(recruiting src homology 2-domain-containing tyrosine phosphatase)Tj
0.379 Tw 0.09 -10 Td
(2 to phosphotyrosine. Proc Natl Acad Sci USA2001;98:13866-71.)Tj
0 Tw -13.588 -10 Td
(8.)Tj
0.2 Tw 13 0 Td
[(Nishimura H, Nose M, Hiai H, Minato N, Honjo )0.125 (T)]TJ
0 Tw 163.73 0 Td
(. Development of)Tj
0.2 Tw -163.088 -10 Td
(lupus-like autoimmune diseases by disruption of the PD-1 gene)Tj
0 Tw -0.072 -10 Td
(encoding an ITIM motif-carrying immunoreceptor. Immunity)Tj
0.027 -10 Td
(1999;11:141-51.)Tj
-13.391 -10 Td
[(9.)-875 (Nishimura H, Okazaki )]TJ
0.5 Tc 87.553 0 Td
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0 Tc 12.523 0 Td
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0.2 Tw -86.786 -10 Td
(cardiomyopathy in PD-1 receptor-deficient mice. Science)Tj
0 Tw 0.121 -10 Td
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[(10.)-875 (Agata )37.75 (Y)]TJ
0.14999 Tw 42.579 0 Td
(, Kawasaki A, Nishimura H, et al. Expression of the PD-1)Tj
0.2 Tw -25.203 -10 Td
[(antigen on the surface of stimulated mouse )33.625 (T)]TJ
0 Tw 147.58 0 Td
(and B lymphocytes.)Tj
-147.58 -10 Td
(Int Immunol 1996;8:765-72.)Tj
246.728 639.25 Td
[(1)31.25 (1.)]TJ
0.2 Tw 16.75 0 Td
[(Nishimura H, Minato N, Nakano )0.5 (T)]TJ
0 Tw 112.453 0 Td
[(, Honjo )-50 (T)93.875 (. Immunological)]TJ
0.2 Tw -111.884 -10 Td
(studies on PD-1 deficient mice: implication of PD-1 as a negative)Tj
-0.078 -10 Td
(regulator for B cell responses. Int Immunol 1998;10:1563-72.)Tj
0 Tw -17.33 -10 Td
(12.)Tj
0.117 Tw 17 0 Td
(Arnett FC, Edworthy SM, Bloch DA, et al. The American)Tj
0 Tw 0.324 -10 Td
(Rheumatism Association 1987 revised criteria for the classification)Tj
0.174 -10 Td
(of rheumatoid arthritis. Arthritis Rheum 1988;31:315-24.)Tj
-17.691 -10 Td
[(13.)-875 (Sakurada S, Kato )-74.75 (T)93.875 (, Okamoto )-49.625 (T)]TJ
0.2 Tw 119.813 0 Td
(. Induction of cytokines and )Tj
-102.215 -10 Td
(ICAM-1 by proinflammatory cytokines in primary rheumatoid)Tj
-0.148 -10 Td
(synovial fibroblasts and inhibition by N-acetyl-L-cysteine and)Tj
0 Tw 0.013 -10 Td
(aspirin. Int Immunol 1996;8:1483-93.)Tj
-17.298 -10 Td
[(14.)-875 (Iwai )37.625 (Y)124.875 (, Okazaki )-49.5 (T)93.875 (, Nishimura H, Kawasaki A, )-62.375 (Y)93.625 (agita H, Honjo )-43.25 (T.)]TJ
0.2 Tw 17.34 -10 Td
(Microanatomical localization of PD-1 in human tonsils. Immunol)Tj
0 Tw 0.138 -10 Td
(Lett 2002;83:215-20.)Tj
-17.558 -10 Td
(15.)Tj
0.144 Tw 17 0 Td
(Larsen A, Dale K, Eek M. Radiographic evaluation of rheumatoid)Tj
0 Tw 0.538 -10 Td
(arthritis and related conditions by standard reference films. Acta)Tj
0.022 -10 Td
(Radiol Diagn Stockh 1977;18:481-91.)Tj
-17.685 -10 Td
[(16.)-875 (Latchman )-24 (Y,Wood CR, Chernova )-74.625 (T)]TJ
0.2 Tw 133.272 0 Td
(, et al. PD-L2 is a second ligand)Tj
0 Tw -115.678 -10 Td
[(for PD-1 and inhibits )-68.375 (T)-249.875 (cell activation. Nature Immunol)]TJ
-0.002 -10 Td
(2001;2:261-8.)Tj
-17.391 -10 Td
[(17.)-875 (Sfikakis PP)]TJ
1 Tc 53.321 0 Td
(,V)Tj
0 Tc 0.2 Tw 9.277 0 Td
(ia CS. Expression of CD28, CTLA4, CD80, and)Tj
-45.162 -10 Td
(CD86 molecules in patients with autoimmune rheumatic diseases:)Tj
0 Tw -0.061 -10 Td
(implications for immunotherapy. Clin Immunol Immunopathol)Tj
0.004 -10 Td
(1997;83:195-8.)Tj
-17.391 -10 Td
[(18.)-875 (V)]TJ
0.2 Tw 22.027 0 Td
(erwilghen J, Lovis R, De Boer M, et al. Expression of functional)Tj
-4.702 -10 Td
[(B7 and CTLA4 on rheumatoid synovial )32.75 (T)]TJ
0 Tw 137.403 0 Td
(cells. J Immunol)Tj
-137.245 -10 Td
(1994;153:1378-85.)Tj
-17.641 -10 Td
[(19.)-875 (Lenschow DJ, )-50.25 (W)]TJ
0.2 Tw 71.971 0 Td
[(alunas TL, Bluestone JA. CD28/B7 system of )32.25 (T)]TJ
0 Tw -54.307 -10 Td
(cell costimulation. Annu Rev Immunol 1996;14:233-58.)Tj
-17.547 -10 Td
[(20.)-875 (McAdam AJ, Schweitzer AN, Sharpe AH. The role of B7 )]TJ
0.2 Tw 17.344 -10 Td
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0.104 -10 Td
(T)Tj
0 Tw 6.887 0 Td
(cells. Immunol Rev 1998;165:231-47.)Tj
-24.412 -10 Td
[(21.)-875 (Dong H, Zhu G, )-69.125 (T)]TJ
0.2 Tw 76.406 0 Td
(amada K, Chen L. B7-H1, a third member of the)Tj
0 Tw -58.938 -10 Td
[(B7 family, co-stimulates )20.375 (T)93.875 (-cell proliferation and interleukin-10)]TJ
0.028 -10 Td
(secretion. Nature Med 1999;5:1365-9.)Tj
-17.486 -10 Td
[(22.)-875 (Freeman GJ, Long AJ, Iwai )-31.125 (Y)]TJ
0.2 Tw 112.898 0 Td
(, et al. Engagement of the PD-1)Tj
-95.441 -10 Td
(immunoinhibitory receptor by a novel B7 family member leads to)Tj
0.14 -10 Td
(negative regulation of lymphocyte activation. J Exp Med)Tj
0 Tw -0.178 -10 Td
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-17.391 -10 Td
[(23.)-875 (T)]TJ
0.138 Tw 21.137 0 Td
(seng SY, Otsuji M, Gorski K, et al. B7-DC, a new dendritic cell)Tj
0.2 Tw -3.713 -10 Td
[(molecule with potent costimulatory properties for )34.25 (T)]TJ
0 Tw 168.935 0 Td
(cells. J Exp)Tj
-168.94 -10 Td
(Med 2001;193:839-46.)Tj
-17.527 -10 Td
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0.2 Tw 17 0 Td
(Eppihimer MJ, Gunn J, Freeman GJ, et al. Expression and )Tj
0.664 -10 Td
(regulation of the PD-L1 immunoinhibitory molecule on )Tj
0 Tw -0.159 -10 Td
(microvascular endothelial cells. Microcirculation 2002;9:133-45.)Tj
-17.317 -10 Td
[(25.)-875 (T)]TJ
0.35899 Tw 21.137 0 Td
[(sai C, Diaz LAJr, Singer NG, et al. Responsiveness of human )32.1125 (T)]TJ
0.2 Tw -3.807 -10 Td
(lymphocytes to bacterial superantigens presented by cultured)Tj
0 Tw 0.192 -10 Td
(rheumatoid arthritis synoviocytes. Arthritis Rheum 1996;39:125-36.)Tj
-17.582 -10 Td
(26.)Tj
0.175 Tw 17 0 Td
(Howell M, Smith J, Cawley M. The rheumatoid synovium: a model)Tj
0 Tw 0.395 -10 Td
[(for )6.25 (T)62.625 (-cell anergy? [letter]. Immunol )-35.125 (T)62.625 (oday 1992;13:191.)]TJ
-17.331 -10 Td
(27.)Tj
0.14999 Tw 17 0 Td
(Howard M, O\325Garra A, Ishida H, et al. Biological properties of)Tj
0.2 Tw 0.414 -10 Td
(interleukin 10. J Clin Immunol 1992;12:239-47.)Tj
0 Tw -17.508 -10 Td
[(28.)-875 (de )6.375 (W)]TJ
0.14999 Tw 33.552 0 Td
[(aal Malefyt R, Yssel H, Roncarolo MG, Spits H, de )0.7375 (V)]TJ
0 Tw 173.867 0 Td
(ries JE.)Tj
-189.999 -10 Td
(Interleukin-10. Curr Opin Immunol 1992;4:314-20.)Tj
-17.333 -10 Td
[(29.)-875 (van Roon JA, Lafeber FP, Bijlsma JW. Synergistic activity of )]TJ
0.2 Tw 17.5 -10 Td
(interleukin-4 and interleukin-10 in suppression of inflammation and)Tj
0 Tw -0.092 -10 Td
(joint destruction in rheumatoid arthritis. Arthritis Rheum)Tj
-0.077 -10 Td
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-17.391 -10 Td
(30.)Tj
0.2 Tw 17 0 Td
(Feldmann M, Brennan FM, Maini RN. Role of cytokines in)Tj
0 Tw 0.452 -10 Td
(rheumatoid arthritis. Annu Rev Immunol 1996;14:397-440.)Tj
-17.578 -10 Td
[(31.)-875 (Sakaguchi S. Regulatory )-74 (T)-249.875 (cells: key controllers of immunologic)]TJ
17.58 -10 Td
(self-tolerance. Cell 2000;101:455-8.)Tj
-17.381 -10 Td
(32.)Tj
0.2 Tw 17 0 Td
(Sakaguchi S, Sakaguchi N, Shimizu J, et al. Immunologic tolerance)Tj
0.421 -10 Td
[(maintained by CD25+ CD4+ regulatory )32.75 (T)]TJ
0 Tw 137.305 0 Td
(cells: their common role)Tj
-137.423 -10 Td
(in controlling autoimmunity, tumor immunity, and transplantation)Tj
0.231 -10 Td
(tolerance. Immunol Rev 2001;182:18-32.)Tj
ET
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419.25 750.75 137 10.25 re
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53.25 54.25 504 1 re
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BT
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(The Journal of Rheumatology 2003; 30:7)Tj
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(1418)Tj
ET
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108.75 49.25 396 10.25 re
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/Im0 Do
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W n
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(Personal, non-commercial use only. The Journal of Rheumatology Copyrig\
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ET
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(explanation is that PD-1+ cells may survive because the PD-)Tj
2.44299 Tw 0.027 -12 Td
(1-mediated system causes cell cycle arrest but does not)Tj
0 Tw 0.022 -12 Td
(mediate a death signal)Tj
/TT0 6.25 Tf
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(16)Tj
/TT0 10 Tf
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(.)Tj
-84.5 -12 Td
(A)Tj
1.70399 Tw 10.722 0 Td
(number of studies have examined the expression of)Tj
0.161 Tc 0 Tw -22.604 -12 Td
(costimulatory )Tj
0.159 Tc 63.49 0 Td
(molecules, )Tj
0 Tc 51.042 0 Td
[(the )-424.7 (CD28 )-425.2 (family, )-449.4 (and )-424.8 (their)]TJ
1.304 Tw -114.524 -12 Td
(ligands, the B7 family, in RA)Tj
/TT0 6.25 Tf
0 Tw 1.04 0 0 1.04 178.019 389.25 Tm
(17)Tj
/TT0 10 Tf
1.45399 Tw 1 0 0 1 184.519 386 Tm
(. CTLA-4 is expressed on)Tj
0 Tw -131.146 -12 Td
[(about 15% of SF )-64 (T)]TJ
0.222 Tw 79.248 0 Td
[(cells, but scarcely at all on PB )1.6 (T)]TJ
0 Tw 133.466 0 Td
(cells)Tj
/TT0 6.25 Tf
1.04 0 0 1.04 284.413 377.25 Tm
(18)Tj
/TT0 10 Tf
1 0 0 1 290.913 374 Tm
(.)Tj
1.55901 Tw -237.5 -12 Td
(While we observed simultaneous expression of PD-1 and)Tj
2.47099 Tw 0.029 -12 Td
(CTLA-4, the tissue distribution of their ligands is quite)Tj
0.554 Tw 0.024 -12 Td
(different. CD80 and CD86, common ligands for CD28 and)Tj
2.84 Tw -0.05 -12 Td
(CTLA-4, are expressed mainly on professional antigen-)Tj
0.362 Tw 0.027 -12 Td
(presenting cells in lymphoid organs)Tj
/TT0 6.25 Tf
0 Tw 1.04 0 0 1.04 197.644 317.25 Tm
(19,20)Tj
/TT0 10 Tf
0.424 Tw 1 0 0 1 212.456 314 Tm
(. On the other hand,)Tj
0.214 Tw -159.13 -12 Td
(mRNAof 2 ligands for PD-1 \(PD-L\), PD-L1/B7-H1)Tj
/TT0 6.25 Tf
0 Tw 1.04 0 0 1.04 261.847 305.25 Tm
(21,22)Tj
/TT0 10 Tf
1 0 0 1 278.91 302 Tm
(and)Tj
-225.562 -12 Td
(PD-L2/B7-DC)Tj
/TT0 6.25 Tf
1.04 0 0 1.04 112.49 293.25 Tm
(16,23)Tj
/TT0 10 Tf
2.45599 Tw 1 0 0 1 126.802 290 Tm
(, are expressed in nonlymphoid organs)Tj
0 Tw -73.311 -12 Td
(such as placenta, heart, lung, kidney, and liver as well as on)Tj
-0.083 -12 Td
(lymphoid organs. In human monocytes, IFN-)Tj
/TT1 10 Tf
180.675 0 Td
(g)Tj
/TT0 10 Tf
6.611 0 Td
(but not TNF-)Tj
/TT1 10 Tf
-187.426 -12 Td
(a)Tj
/TT0 10 Tf
1.47 Tw 10.309 0 Td
(treatment results in expression of both ligands)Tj
/TT0 6.25 Tf
0 Tw 1.04 0 0 1.04 256.805 257.25 Tm
(22)Tj
/TT0 10 Tf
1.47 Tw 1 0 0 1 263.305 254 Tm
(. IFN-)Tj
/TT1 10 Tf
26.163 0 Td
(g)Tj
/TT0 10 Tf
0.125 Tc 0 Tw -236.139 -12 Td
(treatment )Tj
0 Tc 45.259 0 Td
[(can )-424.7 (also )-424.8 (induce )-474.5 (PD-L1 )]TJ
0.136 Tc 111.362 0 Td
(expression )Tj
0 Tc 50.519 0 Td
[(in )-399.8 (non-)]TJ
0.13901 Tc -207.142 -12 Td
(lymphoid )Tj
0 Tc 45.835 0 Td
[(cells )-474.5 (such )-425 (as )]TJ
0.14301 Tc 65.485 0 Td
(keratinocytes )Tj
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(and )Tj
0.136 Tc 21.188 0 Td
(endothelial)Tj
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(cells)Tj
/TT0 6.25 Tf
1.04 0 0 1.04 71.651 221.25 Tm
(22,24)Tj
/TT0 10 Tf
1 0 0 1 86.464 218 Tm
(.)Tj
0.19501 Tw 4.5 0 Td
(As for synoviocytes, FLS were negative for CD80)Tj
1.371 Tw -37.561 -12 Td
[(and CD86 in RA)-325.1 (synovium even after IFN-)]TJ
/TT1 10 Tf
182.562 0 Td
(g)Tj
/TT0 10 Tf
7.861 0 Td
(treatment )Tj
/TT2 10 Tf
0 Tw 41.88 0 Td
(in)Tj
-232.222 -12 Td
[(vitr)50.3 (o)]TJ
/TT0 10 Tf
1.744 Tw 22.637 0 Td
(as reported)Tj
/TT0 6.25 Tf
0 Tw 1.04 0 0 1.04 122.01 197.25 Tm
(25)Tj
/TT0 10 Tf
1.744 Tw 1 0 0 1 128.51 194 Tm
(. On the other hand, PD-L1 expression)Tj
0 Tw -75.122 -12 Td
(was induced on FLS treated with IFN-)Tj
/TT1 10 Tf
154.086 0 Td
(g)Tj
/TT0 10 Tf
6.611 0 Td
(but not with TNF-)Tj
/TT1 10 Tf
72.919 0 Td
(a)Tj
/TT0 10 Tf
2.75101 Tw -233.691 -12 Td
(or IL-1\247. These data imply that the PD-1/PD-L)Tj
0 Tw 212.297 0 Td
(system)Tj
1.15199 Tw -212.222 -12 Td
(rather than CTLA-4/B7 system may play a critical role in)Tj
2.14999 Tw 0.02 -12 Td
[(the maintenance of peripheral tolerance and/or establish)4 (-)]TJ
0.25 Tw 0.02 -12 Td
(ment of autoimmune disease in local joints.)Tj
0.20599 Tw 11.881 -12 Td
(Intracellular cytokine staining showed that CD4+ PD-1+)Tj
-11.976 -12 Td
(T)Tj
2.22099 Tw 10.858 0 Td
[(cells have unique characteristics. )77.2 (A)-425.2 (sizable amount of)]TJ
0 Tw -10.754 -12 Td
(IFN-)Tj
/TT1 10 Tf
[-0.3 (g)]TJ
/TT0 10 Tf
0.675 Tw 26.804 0 Td
(production and no IL-4 production suggest that they)Tj
2.13699 Tw -26.955 -12 Td
[(are Th1-type cells. )26.4 (W)100.2 (e observed low production of IL-2)]TJ
0 Tw 0.179 -12 Td
[(from PD-1+ )-2.9 (T)-224.8 (cells in this study, which seems to imply that)]TJ
0.97301 Tw 263.894 639 Td
[(PD-1+ cells include anergic )26.5 (T)-299.8 (cells. Howell, )]TJ
/TT2 10 Tf
0 Tw 186.395 0 Td
(et al)Tj
/TT0 6.25 Tf
1.04 0 0 1.04 522.472 716.25 Tm
(26)Tj
/TT0 10 Tf
1 0 0 1 532.472 713 Tm
(postu-)Tj
-215 -12 Td
[(lated that )-31 (T)-249.8 (cells from RA)]TJ
0.286 Tw 107.835 0 Td
(SF are anergic because they lack)Tj
-0.3 Tw -108.05 -12 Td
(IL-2 protein production despite the presence of IL-2 mRNA.)Tj
0.453 Tw 0.029 -12 Td
[(They suggested that )0.8 (T)]TJ
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[(cell anergy and lack of IL-2 produc)2 (-)]TJ
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(tion might be induced when Th1 clones are stimulated via)Tj
3.73801 Tw -0.062 -12 Td
[(their )0.5 (T)-599.8 (cell receptors in the absence of costimulatory)]TJ
0 Tw 0.138 -12 Td
(signals)Tj
/TT0 6.25 Tf
1.04 0 0 1.04 345.242 644.25 Tm
(26)Tj
/TT0 10 Tf
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(. Since then, the large majority of reports of anergy)Tj
1.439 Tw -34.395 -12 Td
[(have described the inhibition of IL-2 secretion by )27.8 (T)]TJ
0 Tw 221.862 0 Td
(cells)Tj
0.257 Tw -221.925 -12 Td
(that are normally capable of secreting IL-2 upon activation.)Tj
0 Tw 0.017 -12 Td
[(Thus CD4+ PD-1+ )55.4 (T)-224.8 (cells are believed to be involved in the)]TJ
-0.024 -12 Td
[(establishment of anergy in RA)-323.7 (joints.)]TJ
12.174 -12 Td
[(CD4+ PD-1+ )-43.4 (T)]TJ
0.34 Tw 65.322 0 Td
(cells produced a higher concentration of)Tj
0.448 Tw -77.284 -12 Td
(IL-10 than did CD4+ PD-1\320 cells in RAjoints. It should be)Tj
0.69 Tw -0.172 -12 Td
(noted that IL-10 production was detected only in RA)Tj
0 Tw 219.886 0 Td
[(SF )-44.3 (T)]TJ
0.533 Tw -219.829 -12 Td
[(cells, but not in PB )26.1 (T)]TJ
0 Tw 90.162 0 Td
(cells )Tj
/TT2 10 Tf
21.608 0 Td
[(in vitr)-2.8 (o)]TJ
/TT0 10 Tf
0.533 Tw (. It is of interest that IL-)Tj
0.565 Tw -111.801 -12 Td
[(10 has been identified as a critical cytokine in the suppres)3.1 (-)]TJ
3.315 Tw 0.019 -12 Td
(sion of multiple activities in the immune response)Tj
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0 Tw 1.04 0 0 1.04 540.253 524.25 Tm
(27,28)Tj
/TT0 10 Tf
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(.)Tj
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(Recent reports have highlighted the capacity of IL-10 to)Tj
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(inhibit inflammation and joint destruction )Tj
/TT2 10 Tf
0 Tw 168.22 0 Td
[(in vitr)55 (o)]TJ
/TT0 10 Tf
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(in patients)Tj
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[(with RA)-475 (and )]TJ
/TT2 10 Tf
[0.1 (in vivo)]TJ
/TT0 10 Tf
95.939 0 Td
(in experimental arthritis models)Tj
/TT0 6.25 Tf
0 Tw 1.04 0 0 1.04 548.308 488.25 Tm
(29)Tj
/TT0 10 Tf
1 0 0 1 554.808 485 Tm
(.)Tj
0.38 Tw -237.5 -12 Td
(Thus, IL-10 may play an important role in the maintenance)Tj
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(of peripheral tolerance, although IL-10 production from)Tj
1.30499 Tw 0.022 -12 Td
[(CD4+ PD-1+ )-0.5 (T)-349.8 (cells may be insufficient to downregulate)]TJ
1.75 Tw 0.004 -12 Td
(chronic inflammation in RA)Tj
1.58299 Tw 122.032 0 Td
(joints. Another possibility is)Tj
1.959 Tw -121.911 -12 Td
(that they may secrete IL-10 in an autocrine or paracrine)Tj
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[(manner to inactivate themselves because they are autoreac)4.5 (-)]TJ
1.25301 Tw -0.233 -12 Td
[(tive )25.4 (T)]TJ
1.153 Tw 28.357 0 Td
(cells. As antiinflammatory cytokines \(IL-10, IL-13,)Tj
0 Tw -28.178 -12 Td
[(transforming growth factor-\247\) and antagonists of inflamma)-58.4 (-)]TJ
3.226 Tw -0.016 -12 Td
(tory mediators \(IL-1R)Tj
/TT1 10 Tf
94.763 0 Td
(a)Tj
/TT0 10 Tf
3.164 Tw 12.059 0 Td
(and soluble TNF receptor\) are)Tj
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(present in significant amounts in RAjoints)Tj
/TT0 6.25 Tf
0 Tw 1.04 0 0 1.04 488.265 368.25 Tm
(30)Tj
/TT0 10 Tf
1 0 0 1 494.765 365 Tm
(, it should be of)Tj
1.638 Tw -177.284 -12 Td
(considerable interest to clarify the role of PD-1+ cells in)Tj
0.21899 Tw -0.221 -12 Td
(producing such factors or their effect on PD-1+ cells.)Tj
0 Tw 12.071 -12.25 Td
[(CD4+ PD-1+ )-59.4 (T)-249.8 (cells from RA)-283.5 (SF expressed CD45RB)]TJ
/TT0 6.25 Tf
1.04 0 0 1.04 547.683 332 Tm
(low)Tj
/TT0 10 Tf
0.65199 Tw 1 0 0 1 317.308 316.5 Tm
(and CTLA-4 with IL-10 secretion, and their characteristics)Tj
0.45599 Tw 0.029 -12 Td
[(appear similar to that of CD4+ CD25+ regulatory )2.2 (T)]TJ
0 Tw 212.934 0 Td
(cells)Tj
/TT0 6.25 Tf
1.04 0 0 1.04 548.597 307.75 Tm
(31-)Tj
-222.374 -11.784 Td
(33)Tj
/TT0 10 Tf
1 0 0 1 323.928 292.25 Tm
[(.)-225 (W)]TJ
-0.103 Tw 13.438 0 Td
(e do not think, however, that the former are identical to)Tj
1.261 Tw -19.996 -12.25 Td
[(the latter, for 2 reasons. First, CD4+ CD25+ regulatory )26.9 (T)]TJ
3.30701 Tw 0.108 -12.25 Td
(cells are by definition nonprimed cells, while PD-1 is)Tj
2.679 Tw -0.226 -12.25 Td
[(expressed only after activation on normal PB )27 (T)]TJ
0 Tw 212.871 0 Td
(cells)Tj
/TT0 6.25 Tf
1.04 0 0 1.04 548.45 259 Tm
(34)Tj
/TT0 10 Tf
1 0 0 1 554.95 255.5 Tm
(.)Tj
0.82899 Tw -237.5 -12 Td
[(Second, our data showed that CD4+ PD-1+ SF )24.9 (T)]TJ
0 Tw 205.371 0 Td
(cells did)Tj
0.25 Tw -205.567 -12.25 Td
(not always display CD25 expression.)Tj
1.142 Tw 12.094 -12 Td
[(Another CD4+ )0.1 (T)-324.8 (cell subset similar to CD4+ PD-1+ )1.2 (T)]TJ
0 Tw -12.081 -12 Td
[(cells is )31.8 (T)]TJ
-0.157 Tw 35.29 0 Td
(r1. This subset is characterized by low proliferation)Tj
0.286 Tw -35.303 -12 Td
(capacity and by high IL-10 production with low production)Tj
0.517 Tw 0.015 -12 Td
(of IL-2 and IL-4)Tj
/TT0 6.25 Tf
0 Tw 1.04 0 0 1.04 384.627 186.5 Tm
(35)Tj
/TT0 10 Tf
1 0 0 1 391.127 183.25 Tm
(.)Tj
0.517 Tw 5 0 Td
[(Although involvement of )26.1 (T)25.2 (r1 cells with)]TJ
2.92599 Tw -78.774 -12 Td
(autoimmune diseases is not determined, involvement in)Tj
1.87399 Tw 0.012 -12 Td
(infectious diseases has been reported)Tj
/TT0 6.25 Tf
0 Tw 1.04 0 0 1.04 472.587 162.5 Tm
(36,37)Tj
/TT0 10 Tf
1 0 0 1 487.149 159.25 Tm
(.)Tj
1.87399 Tw 6.75 0 Td
[(Thus, )25 (T)25.2 (r1 cells)]TJ
0.28799 Tw -176.489 -12 Td
(may arise and contribute to the persisting immune response)Tj
0 Tw 0.022 -12 Td
[(of the host. )-36.8 (T)]TJ
0.207 Tw 53.446 0 Td
(r1 cells reportedly consist of no more than 5%)Tj
1.98199 Tw -53.392 -12 Td
[(of CD4+ )24.8 (T)-424.8 (cells of peripheral blood and synovial tissue)]TJ
0 Tw -0.104 -12 Td
(from patients with RA)Tj
/TT0 6.25 Tf
1.04 0 0 1.04 406.303 114.5 Tm
(38)Tj
/TT0 10 Tf
1 0 0 1 412.803 111.25 Tm
(.)Tj
-0.26401 Tw 4.5 0 Td
(This is in contrast to the abundance)Tj
0 Tw -99.955 -12 Td
[(of PD-1+ cells from RA)-307.5 (SF observed in this study. It would)]TJ
1.38699 Tw 0.031 -12 Td
(be highly relevant to investigate the mechanism of CD4+)Tj
1.089 Tw 0.012 -12 Td
[(PD-1+ )-0.3 (T)-324.8 (cells, and to clarify the correlation or distinction)]TJ
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(Figure 7.)Tj
/TT0 8 Tf
0.82001 Tw 32.844 0 Td
[(Correlation between PD-1 expression on CD3+ SF )-30.7375 (T)]TJ
0 Tw 178.093 0 Td
(cells and)Tj
0.61301 Tw -210.969 -10 Td
[(Larsen grade for RApatients. Percentages of PD-1+ cells among CD3+ )33.2625 (T)]TJ
1.00101 Tw -0.049 -10 Td
[(cells from RA)-343.25 (SF are plotted for each Larsen grade group. )32.7625 (V)124.875 (alues show)]TJ
0.2 Tw 0 -10 TD
(means \261 SD. *p = 0.043.)Tj
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/TT0 10 Tf
0.62601 Tw 53.349 448 Td
[(percentage of PD-1 expression on CD3+ SF )25.61 (T)]TJ
0 Tw 191.904 0 Td
(cells tended)Tj
0.95599 Tw -191.894 -12 Td
(to increase as the knee erosion progressed from grade I to)Tj
1.804 Tw 0.032 -12 Td
(grade III, and was significantly higher for grade III than)Tj
0 Tw 0.037 -12 Td
[(grade IV)-253.6 (\(p = 0.043\) \(Figure 7\). On the other hand, in joints)]TJ
2.075 Tw -0.08 -12 Td
(of Larsen grade IV, activation markers of RA)Tj
2.25301 Tw 200.675 0 Td
(tended to)Tj
0 Tw -200.563 -12 Td
[(decrease, reflecting the diminished inflammation. )-14.9 (W)75.2 (e found)]TJ
1.3 Tw -0.007 -12 Td
(no significant correlation between PD-1+ percentages and)Tj
0 Tw 0.025 -12 Td
(other )Tj
0.194 Tc 28.047 0 Td
(clinical )Tj
0.16701 Tc 37.679 0 Td
(features )Tj
0 Tc 39.896 0 Td
[(such )-500 (as )-425 (age, )-499.7 (sex, )]TJ
0.175 Tc 88.117 0 Td
(medication)Tj
0 Tc 1.96201 Tw 70.179 350 Td
(\(methotrexate or steroids\), disease duration, or activation)Tj
0.582 Tw 0.027 -12 Td
(markers [erythrocyte sedimentation rate, C-reactive protein)Tj
1.595 Tw 0.027 -12 Td
(\(CRP\), white blood cell \(WBC\) count, hemoglobin level,)Tj
2.47501 Tw 0.015 -12 Td
(platelet count, and rheumatoid factor \(RF\) of peripheral)Tj
0.58299 Tw 0.022 -12 Td
(blood] in patients with RA\(data not shown\).)Tj
/TT1 10 Tf
0 Tw -0.133 -26.5 Td
(DISCUSSION)Tj
/TT0 10 Tf
0.133 -12 Td
[(We )-274.7 (determined )-399 (that )-374.5 (PD-1+ )-375.3 (T)-599.8 (cells )-374.5 (accumulate )-398.7 (in )-374.8 (the)]TJ
0.461 Tw -0.19 -12 Td
(synovial fluid of patients with RA. The percentages of PD-)Tj
0.563 Tw -0.042 -12 Td
[(1 expression on CD3+ SF )-0.1 (T)-274.8 (cells were significantly higher)]TJ
0 Tw 0.073 -12 Td
[(for Larsen grade III, the most active state, than for grade IV)151.4 (,)]TJ
0.811 Tw 0.076 -12 Td
(the less inflammatory state, while there was no correlation)Tj
0 Tw 0.027 -12 Td
[(between PD-1 expression and systemic markers for the acti)46.3 (-)]TJ
1.90401 Tw 0.037 -12 Td
[(vation status of RA)-374.6 (such as CRP)124.8 (,)-425 (WBC counts, and RF)75.21 (.)]TJ
1.873 Tw -0.152 -12 Td
(These findings suggest that PD-1 expression on synovial)Tj
0 Tw 0.029 -12 Td
[(fluid )-57.1 (T)]TJ
0.82401 Tw 31.319 0 Td
[(cells may reflect local rather than systemic inflam)4 (-)]TJ
0 Tw -31.262 -12 Td
(mation in RA.)Tj
11.943 -12 Td
[(PD-1 )-500.3 (was )]TJ
0.179 Tc 51.165 0 Td
(mainly )Tj
0.2 Tc 35.523 0 Td
(expressed )Tj
0 Tc 47.929 0 Td
[(on )-450 (CD4+ )-500.1 (CD45RO+)]TJ
-146.546 -12 Td
(CD45RB)Tj
/TT0 6.25 Tf
1.04 0 0 1.04 354.647 498.75 Tm
(low)Tj
/TT0 10 Tf
1.52901 Tw 1 0 0 1 368.272 495.5 Tm
[(CXCR3+ )-0.1 (T)-374.8 (cells. In addition, the increase in)]TJ
1.16 Tw -50.918 -12 Td
[(PD-1 expression was associated with the shift of CD4+ )0.4 (T)]TJ
0 Tw -0.036 -12 Td
(cells from CD45RB)Tj
/TT0 6.25 Tf
1.04 0 0 1.04 397.826 474.75 Tm
(high)Tj
/TT0 10 Tf
1 0 0 1 412.187 471.5 Tm
(to CD45RB)Tj
/TT0 6.25 Tf
1.04 0 0 1.04 459.952 474.75 Tm
(low)Tj
/TT0 10 Tf
1 0 0 1 472.327 471.5 Tm
[(phenotype upon acti)-74.9 (-)]TJ
0.336 Tw -155.071 -12 Td
(vation in both RA)Tj
0.286 Tw 75.451 0 Td
(and control peripheral blood cells. These)Tj
0.698 Tw -75.294 -12 Td
(results indicate that PD-1+ cells have the characteristics of)Tj
3.075 Tw 0.029 -12 Td
[(memory/activated )26.8 (T)-524.8 (cells. PD-1 has been shown to be)]TJ
1.875 Tw 0.05 -12 Td
(involved in the negative regulation of immune responses)Tj
0.30499 Tw -0.235 -12 Td
(and is supposed to play a role in peripheral tolerance)Tj
/TT0 6.25 Tf
0 Tw 1.04 0 0 1.04 530.769 414.75 Tm
[(6,8,10,1)46.64 (1)]TJ
/TT0 10 Tf
1 0 0 1 554.956 411.5 Tm
(.)Tj
2.43201 Tw -237.5 -12 Td
[(If activated )26.2 (T)-474.8 (cells in RA)-424.4 (joints expressed PD-1 in the)]TJ
1.194 Tw -0.182 -12 Td
(course of chronic inflammation and were inactivated by a)Tj
1.91901 Tw 0.017 -12 Td
(negative signal through PD-1, then it is puzzling that so)Tj
2.578 Tw 0.017 -12 Td
[(many CD4+ PD-1+ )24.8 (T)-499.8 (cells remained accumulated. One)]TJ
ET
1 g
419.25 750.75 137 10.25 re
f
0 g
53.25 54.25 504 1 re
f
BT
/TT2 8 Tf
0.2 Tw 423.605 36.75 Td
(The Journal of Rheumatology 2003; 30:7)Tj
0 Tw -370.352 -0.25 Td
(1416)Tj
ET
q
30 31 552 730 re
W n
1 g
407.25 745.75 150 25 re
f
407.25 745.75 150 15.25 re
f
0 g
54.25 54.25 504 1 re
f
BT
/TT2 8 Tf
52.49 714.25 Td
(T)Tj
1.028 Tw 3.699 0 Td
(able 3. )Tj
/TT0 8 Tf
28.579 0 Td
[(Cytokine production from CD4+ )1.125 (T)-374.875 (cells after PMA)-312 (plus iono)0.25 (-)]TJ
0.114 Tw -32.376 -10 Td
(mycin stimulation in synovial fluid from RApatients. Results are shown a\
s)Tj
0.658 Tw 0.001 -10 Td
(the mean \261 SD percentages of positive cells obtained from 7 individua\
ls.)Tj
0.802 Tw 0.02 -10 Td
(Representative data are illustrated in Figure 5B. Relative percentages f\
or)Tj
0.2 Tw 0.022 -10 Td
(PD-1+ and PD-1\320 cells are shown in parentheses.)Tj
0 Tw 129.349 -20 Td
[(CD4+ )-25.125 (T)-281.125 (cells)]TJ
-26.378 -10 Td
(PD-1+)Tj
73.652 0 Td
(PD-1\320)Tj
-176.609 -20 Td
(IFN-)Tj
/TT3 8 Tf
15.305 0 Td
(g)Tj
/TT0 8 Tf
-9.961 -10 Td
(MFI)Tj
91.727 0 Td
[(20.3 \261 8.5)-4878.625 (35.5 \261 20.9)]TJ
-91.668 -10 Td
(%)Tj
89.664 0 Td
[(28.9 \261 12.0)-4628.625 (15.2 \261 12.0)]TJ
-95.168 -10 Td
(IL-2)Tj
5.465 -10 Td
(MFI)Tj
85.727 0 Td
[(39.9 \261 21.2**)-3378.625 (172.3 \261 86.8**)]TJ
-85.668 -10 Td
(%)Tj
91.664 0 Td
[(15.4 \261 7.0)-4878.625 (17.4 \261 10.6)]TJ
-97.168 -10 Td
(IL-4)Tj
5.465 -10 Td
(MFI)Tj
93.727 0 Td
(8.2 \261 1.9)Tj
71.791 0 Td
[(1)31.25 (1.0 \261 3.6)]TJ
-165.459 -10 Td
(%)Tj
93.664 0 Td
(2.7 \261 2.0)Tj
73.541 0 Td
(2.0 \261 1.8)Tj
-172.709 -10 Td
(IL-10)Tj
5.465 -10 Td
(MFI)Tj
92.477 0 Td
(8.1 \261 2.2)Tj
/TT0 5 Tf
1.04 0 0 1.04 179.113 527 Tm
(\240)Tj
/TT0 8 Tf
1 0 0 1 223.863 524.25 Tm
(5.7 \261 1.6)Tj
/TT0 5 Tf
1.04 0 0 1.04 252.653 527 Tm
(\240)Tj
/TT0 8 Tf
1 0 0 1 57.903 514.25 Tm
(%)Tj
90.914 0 Td
(8.3 \261 3.8)Tj
/TT0 5 Tf
1.04 0 0 1.04 177.858 517 Tm
(\240\240)Tj
/TT0 8 Tf
1 0 0 1 222.608 514.25 Tm
(0.9 \261 0.7)Tj
/TT0 5 Tf
1.04 0 0 1.04 251.399 517 Tm
(\240\240)Tj
/TT0 8 Tf
-0.26199 Tw 1 0 0 1 52.399 494.25 Tm
(** p = 0.006, )Tj
/TT0 5 Tf
1.04 0 0 1.04 95.864 497 Tm
(\240)Tj
/TT0 8 Tf
0 Tw 1 0 0 1 100.114 494.25 Tm
(p = 0.04, )Tj
/TT0 5 Tf
1.04 0 0 1.04 129.842 497 Tm
(\240\240)Tj
/TT0 8 Tf
-0.26199 Tw 1 0 0 1 136.842 494.25 Tm
(p = 0.002. PMA: phorbol myristate acetate, MFI:)Tj
0 Tw -84.452 -10 Td
[(mean fluorescence intensity)14.375 (.)]TJ
ET
52.25 667.75 239.5 0.5 re
f
52.25 637.25 240 0.5 re
f
52.25 506.5 239.5 0.5 re
f
Q
q
0 g
385 0 0 226.5 117.25 110.25 cm
/Im0 Do
Q
BT
/TT2 8 Tf
125.337 104.25 Td
(Figure 6.)Tj
/TT0 8 Tf
-0.17 Tw 30.99 0 Td
(Expression of CD80, CD86, and PD-L1 on synoviocytes from RApatients. Fib\
roblast-like synoviocytes)Tj
0 Tw -30.896 -10 Td
(\(FLS\) from a patient with RAwere incubated with or without IFN-)Tj
/TT3 8 Tf
212.677 0 Td
(g)Tj
/TT0 8 Tf
-0.142 Tw 5.289 0 Td
(\(100 ng/ml\) for 24 h. Cells were stained with)Tj
0.38901 Tw -217.941 -10 Td
(an isotype control \(broken line\) or anti-human Mab against CD80, CD86,\
and PD-L1 \(solid line\). MFI \(broken)Tj
0.2 Tw 0.043 -10 Td
(line/solid line\) and positive percentages for each of the molecules \(%\
M1; broken line/solid line\) are shown.)Tj
ET
1 g
108.25 48.75 397 11.25 re
f
108.75 49.25 396 10.25 re
f
q
0 g
397 0 0 11.25 108.25 48.75 cm
/Im1 Do
Q
q
0 0 612 792 re
W n
BT
0 0 0 rg
/T1_0 8 Tf
0 Tw 117.48 51 Td
(Personal, non-commercial use only. The Journal of Rheumatology Copyrig\
ht \251 2003. All rights reserved.)Tj
ET
Q
BT
0 g
/T1_1 1 Tf
0 Tw 10 0 0 10 540 17 Tm
( )Tj
0 0.48627 0.77255 rg
-7.22298 0 Td
(www.jrheum.org)Tj
0 g
-16.72996 0 Td
(Downloaded on March 19, 2024 from )Tj
ET
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