Abstract
Dendritic cells (DCs) in the rheumatoid arthritis (RA) joint mediate the immunopathological process and act as a potent antigen presenting cell. We compared the expression of co‐stimulatory and adhesion molecules on DCs in RA patients versus controls with traumatic joint lesions and evalulated the correlation between the immunophenotypical presentation of DCs and the clinical status of the disease. Samples of peripheral venous blood, synovial fluid (SF) and synovial tissue (ST) were obtained from 10 patients with RA at the time of hip or knee replacement and from 9 control patients with knee arthroscopy for traumatic lesions. Clinical status was appreciated using the DAS28 score. Blood, SF and dissociated ST cell populations were separated by centrifugation and analyzed by flow cytometry. Cells phenotypes were identified using three‐color flow cytometry analysis for the following receptors HLA‐DR, CD80, CD83, CD86, CD11c, CD18, CD54, CD58, CD3, CD4, CD8, CD19, CD20, CD14, CD16, CD56. HLA‐DR molecules, co‐stimulatory receptors CD80, CD86, CD83 and adhesion molecules CD18, CD11c, CD54, CD58, were analyzed by two‐color immunofluorescence microscopy on ST serial sections. In patients with active RA (DAS28>5.1) we found a highly differentiated subpopulation of DCs in the ST and SF that expressed an activated phenotype (HLA‐DR, CD86+, CD80+, CD83+, CD11c+, CD54+, CD58+). No differences were found between circulating DCs from RA patients and control patients. Our data suggest an interrelationship between clinical outcome and the immunophenotypical presentation of DCs. Clinical active RA (DAS28>5.1) is associated with high incidence of activated DCs population in the ST and SF as demonstrated by expression of adhesion and co‐stimulatory molecules.
Keywords: dendritic cells, co‐stimulatory molecules, adhesion molecules, synovial fluid, synovial tissue
References
- 1. Weyand C., Goronzy J., The molecular basis of rheumatoid arthritis. J. Mol. Med., 75: 772–785, 1997. [DOI] [PubMed] [Google Scholar]
- 2. Anjuere, F. , Martines del Hoyo G., Martin P., Ardavin C., Langerhans cells acquire a CD8+ dendritic cell fenotype on maturation by CD40 ligation. J. Leucocyte Biol., 67: 206–211, 2000. [DOI] [PubMed] [Google Scholar]
- 3. Banchereau J., Steinman R., Dendritic cells and the control of immunity. Nature, 392: 245–254, 1998. [DOI] [PubMed] [Google Scholar]
- 4. Ruedl C., Koebel P., Bachmann M., Hess M., Karjalainen K., Anatomical origin of dendritic cells determines their life span in peripheral lymph nodes. J. Immunol., 165: 4910–16, 2000. [DOI] [PubMed] [Google Scholar]
- 5. Inaba K., Turley S., Iyoda T., The formation of immunogenic major histocompatibility complex class II‐peptide ligands in lysosomal compartments of dendritic cells is regulated by inflammatory stimuli. J. Exp. Med., 191: 927–936, 2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Cella M., Sallusto F., Lanzavecchia A., Origin, maturation and antigen presenting function of dendritic cells. Curr. Opin. Immunol., 9: 10–15, 1997. [DOI] [PubMed] [Google Scholar]
- 7. Quaratino S., Duddy L., Londei M., Fully competent dendritic cells as inducers of T cell anergy in autoimmunity. Proc. Natl. Acad. Sci., 97: 10911–16, 2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Grabbe S., Kampgen E., Schuler G., Dendritic cells: multi‐linear and multi‐functional. Immunol. Today, 21: 431–433, 2000. [DOI] [PubMed] [Google Scholar]
- 9. Nakajima A., Manipulation of co‐stimulatory pathways in autoimmune diseases. Mod. Rheumatol., 11: 184–191, 2001. [DOI] [PubMed] [Google Scholar]
- 10. Robertson S., Young S., Viner N., Bacon P., Enhanced co‐stimulatory ability of synovial fluid accessory cells in rheumatoid arthritis. Br. J. Rheumatol., 36: 413–419, 1997. [DOI] [PubMed] [Google Scholar]
- 11. Balsa A., Differential expression of the co‐ stimulatory molecules B7.1 (CD80) and B7.2 (CD86) in rheumatoid ST. Br. J. Rheumatol., 35: 33–37, 1996. [DOI] [PubMed] [Google Scholar]
- 12. Flores‐Romo L., In vivo maturation and migration of dendritic cells. Immunology, 102: 255–62, 2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Larsen C., Ritchie S., Hendrix R., Regulation of immunostimulatory function and costimulatory molecule (B7‐1 and B7‐2) expression on murine dendritic cells. J. Immunol., 152: 5208–19, 1994. [PubMed] [Google Scholar]
- 14. Reid S., Penna G., Adorini L., The control of T cell responses by dendritic cell subsets. Curr. Opin. Immunol., 12: 114–120, 2000. [DOI] [PubMed] [Google Scholar]
- 15. Bresnihan B., Cunnane G., Youssef P., Microscopic measurement of synovial membrane inflammation in rheumatoid arthritis: proposals for the evaluation of tissue samples by quantitative analysis. Br. J. Rheumatol., 37: 636–642, 1998. [DOI] [PubMed] [Google Scholar]
- 16. Highton J., Kean A., Hessian P., Cells expressing dendritic cell markers are present in the rheumatoid nodules. J. Rheumatol., 27: 339–345, 2000. [PubMed] [Google Scholar]
- 17. Pulendran B., Banchereau E., Maraskovsky E., Modulating the immune response with dendritic cells and their growth factors. Trend Immunol., 22: 41–48, 2001. [DOI] [PubMed] [Google Scholar]
- 18. Santiago‐Schwarz F., Anand P., Liu S., Carsons S., Dendritic cells in rheumatoid arthritis: progenitor cells and soluble factors contained in RA synovial fluid yield a subset of myeloid DCs that preferentially activate Th1 inflammatory‐type responses. J. Immunol., 167: 1758–68, 2001. [DOI] [PubMed] [Google Scholar]
- 19. Pulendran B., Smith J., Caspary G., Distinct dendritic cells subsets differentially regulate the class of immune response in vivo , Proc. Natl. Acad. Sci. USA, 96: 1036–1042, 1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Thomas R. et al., Dendritic cells and the pathogenesis of rheumatoid arthritis. J. Leukoc. Biol., 66: 286–92, 1999. [DOI] [PubMed] [Google Scholar]
- 21. Littler A., Buckley C., Wordsworth P., A distinct profile of six soluble adhesion molecules (ICAM‐1, ICAM‐3, E‐selectin, L‐selectin, P‐selectine) in rheumatoid arthritis. Br. J. Rheumatol., 36: 164–167, 1997. [DOI] [PubMed] [Google Scholar]
- 22. Steinman R., A guide to some mysteries of dendritic cells. Cell, 100: 491–494, 2000. [DOI] [PubMed] [Google Scholar]
- 23. Imamura F., Aono H., Hasunuma T., Monoclonal expansion of synoviocytes in rheumatoid arthritis. Arthritis Rheum., 41: 1979–1986, 1998. [DOI] [PubMed] [Google Scholar]
- 24. Tak P., Taylor P., Breedveld F., Decrease in cellularity and expression of adhesion molecules by anti‐TNF alpha monoclonal antibody treatment in patients with rheumatoid arthritis. Arthritis Rheum., 39: 1077–81, 1996. [DOI] [PubMed] [Google Scholar]
- 25. Thomas R., Lipsky P., Presentation of self peptides by dendritic cells: a possible implications for the pathogenesis of rheumatoid arthritis. Arthritis Rheum., 39: 183–190, 1996. [DOI] [PubMed] [Google Scholar]
- 26. Thomas R., Quinn C., Functional differentiation od dendritic cells in rheumatoid arthritis: role of CD86 in the synovium. J. Immunol., 156: 3074–3086, 1996. [PubMed] [Google Scholar]
- 27. Firestein G., Rheumatoid synovitis and pannus in Rheumatology, Vol. 1 (eds. Klippel J. & Dieppe P.) 5.13.5–6 Mosby, London , 1998. [Google Scholar]
- 28. Kraan M., Immunohistological analysis of ST for differential diagnosis in early arthritis, Rheumatology, 1074–1080, 1999. [DOI] [PubMed]
- 29. Kraan M., Haringman J., Ahern M., Breedveld F., Quantificaion of the cell infiltrate in synovial tissue by digital image analysis. Rheumatology, 39: 43–49, 2000. [DOI] [PubMed] [Google Scholar]
- 30. Pettit A., MacDonald K., O'Sullivan B., Thomas R., Differentiated dendritic cells expressing nuclear RelB are predominantly located in rheumaoid synovial tissue perivascular mononuclear cell aggregates. Arthritis Rheum., 43: 791–800, 2000. [DOI] [PubMed] [Google Scholar]
- 31. Thomas R., Davis L., Lipsky P., Rheumatoid synovium is enriched in mature presenting dendritic cells. J. Immunol., 152: 2613–2622, 1994. [PubMed] [Google Scholar]
- 32. Youssef P., Smeets T., Bresnihan B., Microscopic measurement of cellular infiltration in the rheumatoid arthritis synovial membrane: a comparison of semiquantitative and quantitative analysis. Br. J. Rheumatol., 37: 1003–1007, 1998. [DOI] [PubMed] [Google Scholar]
- 33. Moser M., Murphy K., Dendritic cell regulation of Th1‐Th2 development. Nat. Immunol., 1: 199–205, 2000. [DOI] [PubMed] [Google Scholar]
- 34. Smeets T., Dayer J., Kraan M., The effects of interferon‐beta treatment of synovial inflammation and expression of metalloproteinases in patients with rheumatoid arthritis. Arthritis Rheum., 43: 270–4, 2000. [DOI] [PubMed] [Google Scholar]
- 35. Kraan M., Versendaal H., Jonker M., Asympto matic synovitis precedes clinically manifest arthritis. Arthritis Rheum, 41, 1481–8 1998. [DOI] [PubMed] [Google Scholar]
- 36. Pettit A., Association of clinical, radiological and synovial immunopathological responses to anti‐ rheumatic treatment in rheumatoid arthritis. Rheumatology, 40: 1243–55, 2001. [DOI] [PubMed] [Google Scholar]
- 37. Soden M., Rooney M., Whelan A., Feighery C., Bresnihan B., Immunohistological analysis of the synovial mambrane: search for predictors of the clinical course in rheumatoid arthritis. Ann. Rheum. Dis., 50: 673–676, 1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38. Tak P., Smeets T., Daha M., Analysis of the synovial cell infiltrate in early rheumatoid synovial tissuein relation to local disease activity. Arthritis. Rheum., 40: 217–225, 1997. [DOI] [PubMed] [Google Scholar]
- 39. Pettit A., Quinn C., MacDonald K., Rheumatoid arthritis synovial tissue and not synovial fluid dendritic cells express high levels of nuclear RELB. Arthritis. Rheum., 40:S132, 1997. [Google Scholar]
- 40. Pettit A., Thomas R., Dendritic cells: the driving force behind autoimmunity in rheumatoid arthritis. Immun. Cell Biol., 77: 420–7, 1999. [DOI] [PubMed] [Google Scholar]
- 41. Tak P., Lessons learnt from the synovial tissue response to anti‐rheumatic treatment. Rheumatology, 39: 817–820, 2000. [DOI] [PubMed] [Google Scholar]
- 42. Pettit A., Ahern M., Zehntner S., Smith M., Thomas R., Comparison of differentiaded dendritic cell infiltration of autoimmune and osteoarthritic synovial tissue. Arthritis Rheum., 44: 105–10, 2001. [DOI] [PubMed] [Google Scholar]
- 43. MacDonald K., Nishioka N., Lipsky P., Thomas R., Functional CD40‐ligand is expressed by T cells in rheumatoid arthritis. J. Clin. Invest., 100: 2404–2414, 1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44. Ming‐Fei L., Yang C., Chao S., Distribution of Double‐Negative (CD4‐, CD8‐, DN) T subsets in blood and synovial fluid from patients with rheumatoid arthritis. Clin. Rheumatol., 18: 227–231, 1999. [DOI] [PubMed] [Google Scholar]
- 45. Steinbrik K., Paragnik L., Jonuleit H., Induction of dendritic cell maturation and modulation of dendritic cell‐induced immune responses by prostaglandins. Arch. Dermatol. Res., 292: 437–444, 2000. [DOI] [PubMed] [Google Scholar]
- 46. Dolhain R., Tak P., Dijkmans B., Methotrexate reduces inflammatory cell numbers, expression of monokines and adhesion molecules in synovial tissue of patients with rheumatoid arthritis. Br. J. Rheumatol., 37: 502–508, 1998. [DOI] [PubMed] [Google Scholar]
- 47. Youssef P., Haynes D., Triantafillou S., Parker A., Effects of pulse methylprednisolone on inflammatory mediators in peripheral blood, synovial fluid and synovial membrane in rheumatoid arthritis. Arthritis Rheum., 40: 1400–1408, 1997. [DOI] [PubMed] [Google Scholar]