Springer Seminars in Immunopathology

, Volume 20, Issue 1–2, pp 181–196 | Cite as

Modulating the Th1/Th2 balance in inflammatory arthritis

  • B. Müller
  • U. Gimsa
  • N. A. Mitchison
  • A. Radbruch
  • J. Sieper
  • Z. Yin


The balance between Th1 and Th2 cells regulates the choice between inflammatory and antibody-mediated immune responses. To an increasing extent this balance is thought to involve the participation of antigen-presenting cells, rather than the entirely autonomous activity of T cells and their cytokines. Here we survey current opinion concerning the working of this balance, and its condition in rheumatoid arthritis and the other inflammatory arthritides. The contrast between Lyme arthritis and reactive arthritis is particularly illuminating, since one is triggered by extracellular and the other by intracellular infection. We describe current approaches to the modulation of this balance. Guided by the principles that genetic polymorphism is likely to identify relevant genes, that any cytokine gene picked up by a virus must matter and that natural immunosuppressive activity at mucosal surfaces should be worth exploiting, we identify as particularly worthy of attention: (i) IL-10, (ii) inhibitors of IL-12 production, (iii) inhibitors of CD40 ligand expression and (iv) oral and nasal tolerance. Other protective T cell subsets are touched on, and the impact of oligonucleotide arrays mentioned.


Rheumatoid Arthritis Arthritis Cell Subset Mucosal Surface Inflammatory Arthritis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Abbas AK, Murphy KM, Sher A (1996) Functional diversity of helper T lymphocytes. Nature 383:787Google Scholar
  2. 2.
    Armant M, Armitage R, Boiani N, Delespesse G, Sarfati M (1996) Functional CD40 ligand expression on T lymphocytes in the absence of T cell receptor engagement: involvement in interleukin-2-induced interleukin-12 and interferon-gamma production. Eur J Immunol 26:1430Google Scholar
  3. 3.
    Austrup F, Vestweber D, Borges E, Lohning M, Brauer R, Herz U, Renz H, Hallmann R, Scheffold A, Radbruch A, Hamann A (1997) P- and E-selectin mediate recruitment of T helper-1 but not T-helper-2 cells into inflammed tissues. Nature 385: 83Google Scholar
  4. 4.
    Bayrak S, Holmdahl R, Travers P, Lauster P, Hesse M, Dolling R, Mitchison NA (1997) T cell response of I-Aq mice to self type II collagen: meshing of the binding motif with the I-Aq molecule with repetitive sequences results in autoreactivity to multiple epitopes. Int Immunol (in press)Google Scholar
  5. 5.
    Berek C, Kim HJ (1997) B-cell activation and development within chronically inflamed synovium in rheumatoid and reactive arthritis. Semin Immunol 9:261Google Scholar
  6. 6.
    Berman RM, Suzuki T, Tahara H, Robbins PD, Narula SK, Lotze MT (1996) Systemic administration of cellular IL-10 induces an effective, specific, and long-lived immune response against established tumors in mice. J Immunol 157:231Google Scholar
  7. 7.
    Borges E, Tietz W, Steegmaier M, Moll T, Hallmann R, Hamann A, Vestweber D (1997) P-selectin glycoprotein ligand-I (PSGL-1) on T helper 1 but not on T helper 2 cells binds to P-selectin and supports migration into inflamed skin. J Exp Med 185:573Google Scholar
  8. 8.
    Braun J, Yin Z, Krause A, Liu L, Spiller I, Sieper J (1997) Peripheral blood cells of reactive arthritis patients secrete more IL-10 and less TNF-α than patients with Lyme or rheumatoid arthritis. Arthritis Rheum 40: S 79Google Scholar
  9. 9.
    Brunner MC, Larsen S, Sette A, Mitchison NA (1995) Altered Th1/Th2 balance associated with the immunosuppressive/protective effect of the H-2Ab allele on the response to allo-HPPD. Eur J Immunol 25:3285Google Scholar
  10. 10.
    Bucht A, Larsson P, Weisbrot L, Thorne C, Pisa P, Smedegard G, Keystone EC, Gronberg A (1996) Expression of interferon-gamma (IFN-gamma), IL-10, IL-12 and transforming growth factor-beta (TGF-beta) mRNA in synovial fluid cells from patients in the early and late phases of rheumatoid arthritis (RA). Clin Exp Immunol 103: 357Google Scholar
  11. 11.
    Burmester GR, Daser A, Kamradt T, Krause A, Mitchison NA, Sieper J, Wolf N (1995) Immunology of reactive arthritides. Annu Rev Immunol 13: 229Google Scholar
  12. 12.
    Cella M, Scheidegger D, Palmer Lehmann K, Lane P, Lanzavecchia A, Alber G (1996) Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T cell stimulatory capacity: TT help via APC activation. J Exp Med 184: 747Google Scholar
  13. 13.
    Chomarat P, Vannier E, Dechanet J, Rissoan MC, Banchereau J, Dinarello CA, Miossec P (1995) Balance of IL-1 receptor antagonist/IL-1 beta in rheumatoid synovium and its regulation by IL-4 and IL-10. J Immunol 154:1432Google Scholar
  14. 14.
    Constant SL, Bottomly K (1997) Induction of Th1 and Th2 CD4+ T cell responses: the alternative approaches. Annu Rev Immunol 15:297Google Scholar
  15. 15.
    Cowell L, Kepler T, Janitz M, Lauster R, Mitchison NA (1998) The distribution of variation in regulatory gene segments, as present in MHC class II promoters. Genomic Res (in press)Google Scholar
  16. 16.
    D'Ambrosio D, Cocciolo MG, Di Lucia P, Lang R, Cippitelli M, Mazzeo D, Sinigaglia F, Panina-Bordignon P (1997) Inhibition of IL-12 production by 1,25-dihydroxyvitamin D3: involvement of NF-κB downregulation in transcription of the p40 gene. J Clin Invest (in press)Google Scholar
  17. 17.
    Dolhain RJ, Heiden AN van der, Haar NT ter, Breedveld FC, Miltenburg AM (1996) Shift toward T lymphocytes with a T helper 1 cytokine-secretion profile in the joints of patients with rheumatoid arthritis. Arthritis Rheum 39: 1961Google Scholar
  18. 18.
    Eskdale J, Wordsworth P, Bowman S, Field M, Gallagher G (1997) Association between polymorphisms at the human IL-10 locus and systemic lupus erythematosus. Tissue Antigens 49: 635Google Scholar
  19. 19.
    Feldmann M, Brennan FM, Maim RN (1996) Role of cytokines in rheumatoid arthritis. Annu Rev Immunol 14:397Google Scholar
  20. 20.
    Reference deletedGoogle Scholar
  21. 21.
    Gascoigne NR, Crispe IN (1984) Suppression of the cytotoxic T cell response to minor alloantigens in vivo. Linked recognition by suppressor T cells. Eur J Immunol 14: 210Google Scholar
  22. 22.
    Gimsa U, Mitchison A (1997) New perspectives on the Th1/Th2 paradigm. Curr Opin Organ Transplant 2:18Google Scholar
  23. 23.
    Gimsa U, Mitchison A, Allen R (1997) Inhibitors of Src-family tyrosine kinases favour Th2 differentiation. Immunobiology 197:219Google Scholar
  24. 24.
    Gimsa U, Sieper J, Braun J, Mitchison NA (1997) Type II collagen serology: a guide to clinical responsiveness to oral tolerance? Int Rheumatol 16: 237Google Scholar
  25. 25.
    Gorham JD, Guler ML, Murphy KM (1997) Genetic control of interleukin 12 responsiveness: implications for disease pathogenesis. J Mol Med 75:502Google Scholar
  26. 26.
    Grewal IS, Flavell RA (1997) The CD40 ligand. At the center of the immune universe? Immunol Res 16:59Google Scholar
  27. 27.
    Groux H, O'Garra A, Bigler M, Rouleau M, Antonenko S, Vries JE de, Roncarlo MG (1997) A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389: 737Google Scholar
  28. 28.
    Guardiola J, Maffei A, Lauster R, Mitchison NA, Accolla RS, Sartoris S (1996) Functional significance of polymorphism among MHC class II gene promoters. Tissue Antigens 48:615Google Scholar
  29. 29.
    Guery JC, Ria F, Galbiati F, Adorini L (1997) Normal B cells fail to secrete interleukin-12. Eur J Immunol 27: 1632Google Scholar
  30. 30.
    Guler ML, Jacobson NG, Gubler U, Murphy KM (1997) T cell genetic background determines maintenance of IL-12 signaling: effects on BALB/c and B l0.D2 T helper cell type 1 phenotype development. J Immunol 159: 1767Google Scholar
  31. 31.
    Hamann D, Hilkens CM, Grogan JL, Lens SM, Kapsenberg ML, Yazdanbakhsh M, Lier RA van (1996) CD30 expression does not discriminate between human Th1- and Th2-type T cells. J Immunol 156: 1387Google Scholar
  32. 32.
    Hanke JH, Gardner JP, Dow RL, Changelian PS, Brissette WH, Weringer EJ, Pollok BA, Connelly PA (1996) Discovery of a novel, potent, and Src family-selective tyrosine kinase inhibitor. Study of Lck-and FynT-dependent T cell activation. J Biol Chem 271: 695Google Scholar
  33. 33.
    Hesse M, Bayrak S, Mitchison A (1996) Protective major histocompatibility complex genes and the role of interleukin-4 in collagen-induced arthritis. Eur J Immunol 26: 3234Google Scholar
  34. 34.
    Holmdahl R (1995) Female preponderance for development of arthritis in rats is influenced by both sex chromosomes and sex steroids. Scand J Immunol 42:104Google Scholar
  35. 35.
    Isomaki P, Luukkainen R, Saario R, Toivanen P, Punnonen J (1996) Interleukin-10 functions as an antiinflammatory cytokine in rheumatoid synovium. Arthritis Rheum 39: 386Google Scholar
  36. 36.
    Jacobson NG, Szabo SJ, Weber NR, Zhong Z, Schreiber RD, Darnell JJ, Murphy KM (1995) Interleukin 12 signaling in T helper type 1 (Th1) cells involves tyrosine phosphorylation of signal transducer and activator of transcription (Stat)3 and Stat4. J Exp Med 181: 1755Google Scholar
  37. 37.
    Janitz M, Mitchison A, Reiners-Schramm L, Lauster R (1997) Polymorphic MHC class II promoters exhibit distinct patterns in various antigen presenting cell lines. Tissue Antigens 49: 99Google Scholar
  38. 38.
    Kalinski P, Hilkens CM, Snijders A, Snijdewint FG, Kapsenberg ML (1997) IL-12-deficient dendritic cells, generated in the presence of prostaglandin E2, promote type 2 cytokine production in maturing human naive T helper cells. J Immunol 159: 28Google Scholar
  39. 39.
    Kamradt T, Burmester G-R (1997) Cytokines and arthritis: is the Th1/Th2 paradigm useful for understanding pathogenesis? J Rheumatol (in press)Google Scholar
  40. 40.
    Kanik KS, Hagiwara E, Yarboro CH, et al (1997) Distinct patterns of cytokine secretion characterize new onset synovitis versus chronic rheumatoid arthritis. J Rheumatol (in press)Google Scholar
  41. 41.
    Kato T, Hakamada R, Yamane H, Nariuchi H (1996) Induction of IL-12 p40 messenger RNA expression and IL-12 production of macrophages via CD40-CD40 ligand interaction. J Immunol 156:3932Google Scholar
  42. 42.
    Katsikis PD, Chu CQ, Brennan FM, Maim RN, Feldmann M (1994) Immunoregulatory role of interleukin 10 in rheumatoid arthritis. J Exp Med 179: 1517Google Scholar
  43. 43.
    Kennedy MK, Picha KS, Fanslow WC, Grabstein KH, Alderson MR, Clifford KN, Chin WA, Mohler KM (1996) CD40/CD40-ligand interactions are required for T cell-dependent production of interleukin-12 by mouse macrophages. Eur J Immunol 26:370Google Scholar
  44. 44.
    Koch F, Stanzl U, Jennewein P, Janke K, Heufler C, Kampgen E, Romani N, Schuler G (1996) High level IL-12 production by marine dendritic cells: upregulation via MHC class II and CD40 molecules and downregulation by IL-4 and IL-10. J Exp Med 184:741Google Scholar
  45. 45.
    Kotake S, Schumacher HR, Yarboro CH, Arayssi TK, Pando JA, Kanik KS, Gourley MF, Klippel JH, Wilder RL (1997) In vivo gene expression of type 1 and type 2 cytokines in synovial tissues from patients in early stages of rheumatoid, reactive, and undifferentiated arthritis. Proc Assoc Am Physicians 109:286Google Scholar
  46. 46.
    Lahesmaa R, Yssel H, Batsford S, Luukkainen R, Mottonen T, Steinman L, Peltz G (1992)Yersinia enterocolitica activates a T helper type 1-like T cell subset in reactive arthritis. J Immunol 148: 3079Google Scholar
  47. 47.
    Langhorne J, Cross C, Seixas E, Li C, Weid T von der (1998) Regulation of CD4+ T cell function in B cell knockout mice infected with the malaria parasitePlasmodium chabaudi. Proc Natl Acad Sci USA (in press)Google Scholar
  48. 48.
    Lazarus M, Hajeer AH, Turner D, Sinnott P, Worthington J, Ollier WE, Hutchinson IV (1997) Genetic variation in the interleukin 10 gene promoter and systemic lupus erythematosus. J Rheumatol 24: 2314Google Scholar
  49. 49.
    Lohning M, Stroehmann A, Coyle AJ, Grogan JL, Lin S, Gutierrez-Ramos JC, Levinson D, Radbruch A, Kamradt T (1998) T1/ST2 is preferentially expressed on murine Th2 cells, independent of interleukin 4, interleukin 5, and interleukin 10, and important for Th2 effector function. Proc Natl Acad Sci USA 95:6930Google Scholar
  50. 50.
    Ma SW, Zhao DL, Yin ZQ, Mukherjee R, Singh B, Qin HY, Stiller CR, Jevnikar AM (1997) Transgenic plants expressing autoantigens fed to mice to induce oral immune tolerance. Nat Med 3:793Google Scholar
  51. 51.
    Macatonia SE, Hosken NA, Litton M, Vieira P, Hsieh CS, Culpepper JA, Wysocka M, Trinchieri G, Murphy KM, O'Garra A (1995) Dendritic cells produce IL-12 and direct the development of Th1 cells from naive CD4+ T cells. J Immunol 154: 5071Google Scholar
  52. 52.
    Mathisen PM, Yu M, Johnson JM, Drazba JA, Tuohy VK (1997) Treatment of experimental autoimmune encephalomyelitis with genetically modified memory T cells. J Exp Med 186:159Google Scholar
  53. 53.
    Mauri C, Williams RO, Walmsley M, Feldmann M (1996) Relationship between Th1/Th2 cytokine patterns and the arthritogenic response in collagen-induced arthritis. Eur J Immunol 26: 1511Google Scholar
  54. 54.
    Maurice MM, Lankester AC, Bezemer AC, Geertsma MF, Tak PP, Breedveld FC, Lier RA van, Verweij CL (1997) Defective TCR-mediated signaling in synovial T cells in rheumatoid arthritis. J Immunol 159:2973Google Scholar
  55. 55.
    Mitchison NA (1997) Partitioning of genetic variation between regulatory and coding gene-segments: the predominance of software variation. Immunogenetics 46:46Google Scholar
  56. 56.
    Mitchison NA, Simon K (1990) Dominant reduced responsiveness controlled by H-2(Kb)Ab. A new pattern evoked by Thy-1 antigen and F liver antigen. Immunogenetics 32:104Google Scholar
  57. 57.
    Müller B, Mitchison NA (1997) The importance of the back-signal from T cells into antigen-presenting cells in determining susceptibility to parasites. Philos Trans R Soc Lond B Biol Sci 352: 1327Google Scholar
  58. 58.
    Nakamura T, Lee RK, Nam SY, Al-Ramadi BK, Koni PA, Bottomly K, Podack ER, Flavell RA (1997) Reciprocal regulation of CD30 expression on CD4+ T cells by IL-4 and IFN-gamma. J Immunol 158:2090Google Scholar
  59. 59.
    Oliveira DB, Mitchison NA (1989) Immune suppression genes. Clin Exp Immunol 75: 167Google Scholar
  60. 60.
    Panina-Bordignon P, Mazzeo D, Di Lucia P, D'Ambrosio D, Lang R, Fabbri L, Self C, Singaglia F (1997) β2-agonists prevent Thl development by selective inhibition of IL-12. J Clin Invest 100: 1513Google Scholar
  61. 61.
    Piccinni MP, Giudizi MG, Biagiotti R, Beloni L, Giannarini L, Sampognaro S, Parronchi P, R Manetti, F Annunziato, C Livi, Romagnani S (1995) Progesterone favors the development of human T helper cells producing Th2-type cytokines and promotes both IL-4 production and membrane CD30 expression in established Th1 cell clones. J Immunol 155: 128Google Scholar
  62. 62.
    Pladevall VM, Delclos GL, Varas C, Guyer H, Brugues TJ, Anglada AA (1996) Controversy of oral contraceptives and risk of rheumatoid arthritis: meta-analysis of conflicting studies and review of conflicting meta-analyses with special emphasis on analysis of heterogeneity. Am J Epidemiol 144: 1Google Scholar
  63. 63.
    Powrie F, Carlino J, Leach MW, Mauze S, Coffman RL (1996) A critical role for transforming growth factor-beta but not interleukin 4 in the suppression of T helper type 1-mediated colitis by CD45RB(low) CD4+ T cells. J Exp Med 183: 2669Google Scholar
  64. 64.
    Rocken M, Racke M, Shevach EM (1996) IL-4-induced immune deviation as antigen-specific therapy for inflammatory autoimmune disease. Immunol Today 17: 225Google Scholar
  65. 65.
    Rogge L, Barberis-Maino L, Biffi M, Passim N, Presky DH, Gubler U, Sinigaglia F (1997) Selective expression of an interleukin-12 receptor component by human T helper 1 cells. J Exp Med 185: 825Google Scholar
  66. 66.
    Romagnani S, Parronchi P, D'Elios MM, Romagnani P, Annunziato F, Piccinni MP, Manetti R, Sampognaro S, Mavilia C, De Carli M, Maggi EG, Del Preti GF (1997) An update on human Th1 and Th2 cells. Int Arch Allergy Immunol 113:153Google Scholar
  67. 67.
    Sallusto F, Mackay CR, Lanzavecchia A (1997) Selective expression of the eotaxin receptor CCR3 by human T helper 2 cells. Science 277: 2005Google Scholar
  68. 68.
    Schlaak J, Hermann E, Ringhoffer M, Probst P, Gallati H, Meyer zum Buschenfelde KH, Fleischer B (1992) Predominance of Th1-type T cells in synovial fluid of patients with Yersinia-induced reactive arthritis. Eur J Immunol 22:2771Google Scholar
  69. 69.
    Reference deletedGoogle Scholar
  70. 70.
    Schulze-Koop SH, Davis LS, Haverty TP, Wacholtz MC, Lipsky PE (1997) Reduction of Th1 cell activity in patients with rheumatoid arthritis after treatment with a non-depleting monoclonal antibody to CD4. Arthritis Rheum 40: S 191Google Scholar
  71. 71.
    Seder RA, Paul WE (1994) Acquisition of lymphokine-producing phenotype by CD4+ T cells. Annu Rev Immunol 12: 635Google Scholar
  72. 72.
    Segal BM, Dwyer BK, Shevach EM (1998) An interleukin (IL) 10/IL-12 immunoregulatory circuit controls susceptibility to autoimmune disease. J Exp Med 187 (in press)Google Scholar
  73. 73.
    Seitzer U, Scheel TD, Hahn M, Heinemann G, Mattern T, Flad HD, Gerdes J (1997) Comparative study of CD26 as a Th1-like and CD30 as a potential Th2-like operational marker in leprosy. Adv Exp Med Biol 421:217Google Scholar
  74. 74.
    Shaw MK, Lorens JB, Dhawan A, DalCanto R, Tse HY, Tran AB, Bonpane C, Eswaran SL, Brocke S, Sarvemick N, Steinman L (1997) Local delivery of interleukin 4 by retrovirus-transduced T lymphocytes ameliorates experimental autoimmune encephalomyelitis. J Exp Med 185: 1711Google Scholar
  75. 75.
    Sher A, Jankovic D, Cheever A, Wynn T (1996) An IL-12-based vaccine approach for preventing immunopathology in schistosomiasis. Ann N Y Acad Sci 795: 202Google Scholar
  76. 76.
    Shu U, Kiniwa M, Wu C, Maliszewski C, Vezzio N, Hakimi J, Gately M, Delespesse G (1995) Activated T cells induce interleukin-12 production by monocytes via CD40-CD40 ligand interaction. Eur J Immunol 25:1125Google Scholar
  77. 77.
    Sieper J, Katy S, Sorensen H, Alten R, Eggens U, Huge W, Hiepe F, Kuhne A, Listing J, Ulbrich N, Braun J, Zink A, Mitchison NA (1996) Oral type II collagen treatment in early rheumatoid arthritis. A double-blind, placebo-controlled, randomized trial. Arthritis Rheum 39:41Google Scholar
  78. 78.
    Simon AK, Seipelt E, Wu P, Wenzel B, Braun J, Sieper J (1993) Analysis of cytokine profiles in synovial T cell clones from chlamydial reactive arthritis patients: predominance of the Th1 subset. Clin Exp Immunol 94:122Google Scholar
  79. 79.
    Simon AK, Seipelt E, Sieper J (1994) Divergent T-cell cytokine patterns in inflammatory arthritis. Proc Natl Acad Sci USA 91:8562Google Scholar
  80. 80.
    Spinozzi F, Agea E, Piattoni S, Falini B, Grignani F, Bertotto A (1997) Lack of correlation between membrane CD30 expression and cytokine secretion pattern in allergen-primed naive cord blood T-cell lines and clones. Scand J Immunol 45:417Google Scholar
  81. 81.
    Stockinger B, Zal T, Zal A, Gray D (1996) B cells solicit their own help from T cells. J Exp Med 183: 891Google Scholar
  82. 82.
    Sundstedt A, Hoiden I, Rosendahl A, Kalland T, Rooijen N van, Dohlsten M (1997) Immunoregulatory role of IL-10 during superantigen-induced hyporesponsiveness in vivo. J Immunol 158: 180Google Scholar
  83. 83.
    Trinchieri G (1997) Cytokines acting on or secreted by macrophages during intracellular infection (IL-10, 1L-12, IFN-gamma). Curr Opin Immunol 9: 17Google Scholar
  84. 84.
    Ulfgren AK, Lindblad S, Klareskog L, Andersson J, Andersson U (1995) Detection of cytokine producing cells in the synovial membrane from patients with rheumatoid arthritis. Ann Rheum Dis 54:654Google Scholar
  85. 85.
    Wilder RL (1995) Neuroendocrine-immune system interactions and autoimmunity. Annu Rev Immunol 13:307Google Scholar
  86. 86.
    Xu D, Chan WL, Leung BP, Huang F, Wheeler R, Piedrafita D, Robinson JH, Liew FY (1998) Selective expression of a stable cell surface molecule on type 2 but not type 1 helper cells. J Exp Med 187 (in press)Google Scholar
  87. 87.
    Yin Z, Braun J, Neure L, Wu P, Eggens U, Krause A, Kamradt T, Sieper J (1997) T cell cytokine pattern in the joints of patients with Lyme arthritis and its regulation by cytokines and anticytokines. Arthritis Rheum 40: 69Google Scholar
  88. 88.
    Yin Z, Braun J, Neure L, Wu P, Liu L, Eggens U, Sieper J (1997) Crucial role of interleukin-10/interleukin-12 balance in the regulation of the type 2 T helper cytokine response in reactive arthritis. Arthritis Rheum 40:1788Google Scholar
  89. 89.
    Yin Z, Neure L, Grolms M, Eggens U, Radbruch A, Braun J, Sieper J (1997) Th1/Th2 cytokine pattern in the joint of rheumatoid arthritis and reactive arthritis patients: analysis at the single cell level. Arthritis Rheum 40: S 37Google Scholar
  90. 90.
    Yssel H, Shanafelt MC, Soderberg C, Schneider PV, Anzola J, Peltz G (1991)Borrelia burgdorferi activates a T helper type 1-like T cell subset in Lyme arthritis. J Exp Med 174: 593Google Scholar

Copyright information

© Springer-Verlag 1998

Authors and Affiliations

  • B. Müller
    • 1
  • U. Gimsa
    • 1
  • N. A. Mitchison
    • 3
  • A. Radbruch
    • 1
  • J. Sieper
    • 1
    • 2
  • Z. Yin
    • 1
    • 2
  1. 1.Deutsches Rheuma Forschungs ZentrumBerlinGermany
  2. 2.Department of Medicine, Division of Nephrology and Rheumatology, Klinikum Benjamin FranklinFree UniversityBerlinGermany
  3. 3.Department of ImmunologyUCL Medical SchoolLondonUK

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