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Increased levels of lactoferrin in synovial fluid but not in serum from patients with rheumatoid arthritis

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International Journal of Clinical and Laboratory Research

Abstract

Lactoferrin is a multifunctional immunoregulatory protein, stored in specific granules of neutrophil granulocytes, from which it is released following cell activation. As activated neutrophils play a crucial role in the destruction of synovial joints in rheumatoid arthritis, we evaluated lactoferrin concentration in synovial fluid and sera from 21 patients with rheumatoid arthritis and 11 patients with osteoarthritis. We also measured lactoferrin levels in sera from 12 healthy controls. Lactoferrin was measured by a solid-phase inhibition immunoassay. Median lactoferrin levels were significantly higher in synovial fluid from rheumatoid arthritis than from osteoarthritis patients (P=0.0002). In contrast, no significant difference was found between serum lactoferrin from patients with rheumatoid arthritis or osteoarthritis compared with normal controls. In patients with rheumatoid arthritis, lactoferrin concentrations were higher in synovial fluid than in sera (P=0.036). In both rheumatoid arthritis and osteoarthritis no correlation was found between serum and synovial fluid lactoferrin (P=0.51 andP=0.5, respectively). In synovial fluid from patients with rheumatoid arthritis, lactoferrin concentrations correlated with neutrophil granulocyte count (P<0.0001), but neither serum nor synovial lactoferrin levels correlated with disease activity (P=0.32 andP=0.25, respectively). In conclusion, lactoferrin is a reliable marker of neutrophil activation at sites of inflammation in rheumatoid synovitis, but does not represent a marker of disease activity.

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References

  1. Anderson BF, Baker HM, Dodson EJ, Norris GE, Rumball SV, Waters JM, Baker EN. Structure of human lactoferrin at 3.2-A resolution. Proc Natl Acad USA 1987; 84:1769.

    Article  CAS  Google Scholar 

  2. Masson PL, Heremans JF, Dive C. An iron binding protein common to many external secretions. Clin Chim Acta 1966; 14:735.

    Article  CAS  Google Scholar 

  3. Brock JH. Lactoferrin in human milk: its role in iron absorption and protection against enteric infection in the new-born infant. Arch Dis Child 1980; 55:417.

    PubMed  CAS  Google Scholar 

  4. Baggiolini M, Duve C de, Masson PL, Heremans JF. Association of lactoferrin with specific granules in rabbit heterophil leucocytes. J Exp Med 1970; 131:559.

    Article  PubMed  CAS  Google Scholar 

  5. Leffel MS, Spitznagel JK. Association of lactoferrin with lysozyme in granules of human polymorphonuclear leucocytes. Infect Immun 1972; 6:761.

    Google Scholar 

  6. Zucali RJ, Broxmeyer HE, Levy D, Morse C. Lactoferrin decreases monocyte-induced fibroblast production of myeloid colony-stimulating activity by suppressing monocyte release of interleukin-1. Blood 1989; 74:1531.

    PubMed  CAS  Google Scholar 

  7. Machnicki M, Zimecki M, Zagulski T. Lactoferrin regulates the release of tumor necrosis factor alpha and interleukin 6 in vivo. Int J Exp Pathol 1993; 74:433.

    PubMed  CAS  Google Scholar 

  8. Crouch SPM, Slater KJ, Fletcher J. Regulation of cytokine release from mononuclear cells by the iron-binding protein lactoferrin. Blood 1992; 80:235.

    PubMed  CAS  Google Scholar 

  9. McCormick JA, Markey GM, Morris TCM. Lactoferrin-inducible monocyte cytotoxicity for K562 cells and decay of natural killer lymphocyte cytotoxicity. Clin Exp Immunol 1991; 83:154.

    PubMed  CAS  Google Scholar 

  10. Shau H, Kim A, Golub SH, Modulation of natural killer and lymphokine-activated killer cell cytotoxicity by lactoferrin. J Leukoc Biol 1992; 51:343.

    PubMed  CAS  Google Scholar 

  11. Kievits F, Kijlstra A. Inhibition of C3 deposition on solid-phase bound immune complexes by lactoferrin. Immunology 1985; 54:449.

    PubMed  CAS  Google Scholar 

  12. Kuizenga A, Haeringern NJ van, Kijlstra A. Inhibition of hydroxyl radical formation by human tears. Invest Ophthalmol Vis Sci 1987; 28:205.

    Google Scholar 

  13. Arnold RR, Cole MF, McGhee JR. A bactericidal effect for human lactoferrin. Science 1977; 197:263.

    Article  PubMed  CAS  Google Scholar 

  14. Ellison RT III, Giehl TJ, La Force FM. Damage of the outer membrane of enteric Gram-negative bacteria by lactoferrin and transferrin. Infect Immun 1988: 56:2774.

    PubMed  CAS  Google Scholar 

  15. Ellison RT III, Giehl TJ. Killing of Gram-negative bacteria by lactoferrin and lysozyme. J Clin Invest 1991; 88:1080.

    Article  PubMed  CAS  Google Scholar 

  16. Bellamy W, Takase M, Yamauchi K, Wakabayashi H, Kawase K, Tomita M. Identification of the bactericidal domain of lactoferrin. Biochim Biophys Acta 1992; 1121:130.

    PubMed  CAS  Google Scholar 

  17. Bennet RM, Eddi-Quartey AC, Holt PJL. Lactoferrin — an iron binding protein in synovial fluid. Arthritis Rheum 1973; 16:186.

    Article  Google Scholar 

  18. Adeyemi EO, Campos LB, Loizou S, Walport MJ, Hodgson HJF. Plasma lactoferrin and neutrophil elastase in rheumatoid arthritis and systemic lupus erythematosus. Br J Rheumatol 1990; 29:15.

    Article  PubMed  CAS  Google Scholar 

  19. Mulder AHL, Heeringa P, Brouwer E, Limburg PC, Lallemberg CGM. Activation of granulocytes by anti-neutrophil cytoplasmic antibodies (ANCA): a Fcg RII-dependent process. Clin Exp Immunol 1994; 98:270.

    PubMed  CAS  Google Scholar 

  20. Blake DR, Merry P, Unsworth J, Outhwait J, Morris CJ, Gray L, Lunec J. Hypoxic-reperfusion injury in the inflammed human joint. Lancet 1989; I:289.

    Article  Google Scholar 

  21. Coremans IEM, Hagen EC, Daha MR, Woude FJ van der, Voort EAM van der, Kleijburg-van der Keur C, Bredveld FC. Antilactoferrin antibodies in patients with rheumatoid arthritis are associated with vasculitis. Arthritis Rheum 1992; 35:1466.

    Article  PubMed  CAS  Google Scholar 

  22. Mulder AHL, Horst G, Leeuwen MA van, Limburg PC, Kallemberg CGM. Antineutrophil cytoplasmic antibodies in rheumatoid arthritis: characterization and clinical correlations. Arthritis Rheum 1993; 36:1054.

    Article  PubMed  CAS  Google Scholar 

  23. Afeltra A, Sebastiani GD, Galeazzi M, Caccavo D, Ferri GM, Marcolongo R, Bonomo L. Antineutrophil cytoplasmic antibodies in synovial fluid and in serum of patients with rheumatoid arthritis and other types of synovitis. J Rheumatol 1996; 23:10.

    PubMed  CAS  Google Scholar 

  24. Caccavo D, Afeltra A, Guido F, Di Monaco C, Ferri GM, Amoroso A, Vaccaro F, Bonomo L. Two spatially distant epitopes of human lactoferrin. Hybridoma 1996; 15:263.

    PubMed  CAS  Google Scholar 

  25. Afeltra A, Caccavo D, Ferri GM, Addessi MA, De Rosa FG, Amoroso A, Bonomo L. Expression of lactoferrin on human granulocytes: analysis with polyclonal and monoclonal antibodies. Clin Exp Immunol 1997; 109:279.

    Article  PubMed  CAS  Google Scholar 

  26. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS, Medsger TA Jr, Mitchell DM, Neustadt DH, Pinals RS, Schaller JC, Sharp JT, Wilder RL, Hunder GG. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988; 31:315.

    Article  PubMed  CAS  Google Scholar 

  27. Altman R, Asch E, Bloch D, Bole D, Borenstein D, Brandt K, Christy W, Cooke TD, Greenwald R, Hochberg M, Howell D, Kaplan D, Koopman W, Longley S III, Mankin H, McShane DJ, Medsger T Jr, Meenan R, Mikkelsen W, Moskowitz R, Murphy W, Rothschild B, Segal M, Sokoloff L, Wolfe F. Development of criteria for the classification and reporting of osteoarthritis: classification of osteoarthritis of the knee. Arthritis Rheum 1986; 29:1039.

    Article  PubMed  CAS  Google Scholar 

  28. Temponi M, Kageshita T, Perosa F, Ono R, Okada H, Ferrone S. Purification of murine IgG monoclonal antibodies by precipitation with caprylic acid: comparison with other methods of purification. Hybridoma 1989; 8:85.

    Article  PubMed  CAS  Google Scholar 

  29. Laemmli UK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 1970; 227:680.

    Article  PubMed  CAS  Google Scholar 

  30. Streicher HZ, Cuttitta F, Buckenmeyer GK, Kawamura H, Minna J, Berzofski JA. Mapping of the idiotopes of a monoclonal anti-myoglobin antibody with syngeneic monoclonal anti-idiotypic antibodies: detection of a common idiotope. J Immunol 1986; 136:1007.

    PubMed  CAS  Google Scholar 

  31. Thompson RJ, Jackson AP, Langlois N. Circulating antibodies to mouse monoclonal immunoglobulins in normal subjects: incidence, species specificity, and effects on a two-site assay for creatin kinase-MB isoenzyme. Clin Chem 1986; 32:476.

    PubMed  CAS  Google Scholar 

  32. Perosa F, Rizzi R, Pulpito V, Dammacco F. Soluble CD4 antigen reactivity in intravenous immunoglobulin preparations: is it specific? Clin Exp Immunol 1995; 99:16.

    Article  PubMed  CAS  Google Scholar 

  33. Britigan BE, Rosen GM, Thompson BY, Chai Y, Cohen MS. Stimulated neutrophils limit iron-catalyzed hydroxyl radical formation as detected by spin trapping techniques. J Biol Chem 1986; 261:17026.

    PubMed  CAS  Google Scholar 

  34. Britigan BE, Serody JS, Hayek MB, Charniga LM, Cohen MS, Uptake of lactoferrin by mononuclear phagocytes inhibits their ability to form hydroxyl radical and protects them from membrane autoperoxidation. J Immunol 1991; 147:4271.

    PubMed  CAS  Google Scholar 

  35. Britigan BE, Lewis TS, Olakanmi O, McCormick ML, Miller RA. The impact of phagocyte-lactoferrin interactions on inflammation. In: Hutchens TW, Lonnerdal B, eds. Lactoferrin: interactions and biological function. Totowa, New Jersey: Humana Press; 1997:211.

    Google Scholar 

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Caccavo, D., Sebastiani, G.D., Di Monaco, C. et al. Increased levels of lactoferrin in synovial fluid but not in serum from patients with rheumatoid arthritis. Int J Clin Lab Res 29, 30–35 (1999). https://doi.org/10.1007/s005990050059

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  • DOI: https://doi.org/10.1007/s005990050059

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