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. 1976 May;57(5):1308–1319. doi: 10.1172/JCI108399

Circulating and intra-articular immune complexes in patients with rheumatoid arthritis. Correlation of 125I-Clq binding activity with clinical and biological features of the disease.

R H Zubler, U Nydegger, L H Perrin, k Fehr, J McCormick, P H Lambert, P A Miescher
PMCID: PMC436784  PMID: 944196

Abstract

The correlation between the incidence and level of immune complexes in serum and synovial fluid and the various clinical and biological manifestations of rheumatoid arthritis has been studied. Immune complexes were quantitated using a sensitive radioimmunoassay, the 125I-Clq binding test, in unheated native sera and synovial fluids from 50 patients with seropositive (RA +) and 45 with seronegative (RA -) rheumatoid arthritis, 17 with other inflammatory arthritis, and 37 with degenerative and post-traumatic joint disease. The following observations were made: (a) when compared to the results from patients with degenerative and post-traumatic joint diseases, the 125I-Clq binding activity (Clq-BA) in synovial fluid was found to be increased (by more than 2 SD) in most of the patients with RA + (80%) and RA - (71%) and in 29% of patients with other inflammatory arthritis; the serum Clq-BA was also frequently increased in both RA + (76%) and RA - (49%) patients, but only exceptionally in patients with other inflammatory arthritis (6%); (b) a significant negative correlation existed between the Clq-BA and the immunochemical C4 level in synovial fluids from patients with RA + and RA -; (c) neither the serum nor the synovial fluid Clq-BA in rheumatoid arthritis significantly correlated with the erythrocyte sedimentation rate, the clinical stage of the disease, or the IgM rheumatoid factor titer; and (d) the serum Clq-BA in patients with rheumatoid arthritis and extra-articular disease manifestations (40 +/- 34% in those with RA +,32 +/- 29% in those with RA -) was significantly increased as compared to the serum Clq-BA in patients with joint disease alone (24 +/- 30% in those with RA +, 10 +/- 13% in those with RA -). Experimental studies were carried out in order to characterize the Clq binding material in rheumatoid arthritis. This material had properties similar to immune complexes: it sedimented in a high molecular weight range on sucrose density gradients (10-30S) and lost the ability to bind Clq after reduction and alkylation, or after acid dissociation at pH 3.8, or after passage through an anti-IgG immunoabsorbant. DNase did not affect the Clq BA. These results support the hypothesis that circulating as well as intra-articular immune complexes may play an important role in some pathogenetic aspects of rheumatoid arthritis. The 125I-Clq binding test may also be of some practical clinical value in detecting patients who have a higher risk of developing vasculitis.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Agnello V., Winchester R. J., Kunkel H. G. Precipitin reactions of the C1q component of complement with aggregated gamma-globulin and immune complexes in gel diffusion. Immunology. 1970 Dec;19(6):909–919. [PMC free article] [PubMed] [Google Scholar]
  2. Augener W., Grey H. M., Cooper N. R., Müller-Eberhard H. J. The reaction of monomeric and aggregated immunoglobulins with C1. Immunochemistry. 1971 Nov;8(11):1011–1020. doi: 10.1016/0019-2791(71)90489-7. [DOI] [PubMed] [Google Scholar]
  3. CHODIRKER W. B., TOMASI T. B., Jr Low-molecular-weight rheumatoid factor. J Clin Invest. 1963 Jun;42:876–884. doi: 10.1172/JCI104780. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Conn D. L., McDuffie F. C., Dyck P. J. Immunopathologic study of sural nerves in rheumatoid arthritis. Arthritis Rheum. 1972 Mar-Apr;15(2):135–143. doi: 10.1002/art.1780150202. [DOI] [PubMed] [Google Scholar]
  5. Cowdery J. S., Jr, Treadwell P. E., Fritz R. B. A radioimmunoassay for human antigen-antibody complexes in clinical material. J Immunol. 1975 Jan;114(1 Pt 1):5–9. [PubMed] [Google Scholar]
  6. FRANKLIN E. C., HOLMAN H. R., MULLER-EBERHARD H. J., KUNKEL H. G. An unusual protein component of high molecular weight in the serum of certain patients with rheumatoid arthritis. J Exp Med. 1957 May 1;105(5):425–438. doi: 10.1084/jem.105.5.425. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Hannestad K. Presence of aggregated gamma-G-globulin in certain rheumatoid synovial effusions. Clin Exp Immunol. 1967 Jul;2(4):511–529. [PMC free article] [PubMed] [Google Scholar]
  8. Hannestad K. Rheumatoid factors reacting with autologous native gamma-G-globulin and joint fluid gamma-G aggregates. Clin Exp Immunol. 1968 Sep;3(7):671–690. [PMC free article] [PubMed] [Google Scholar]
  9. Heusser C., Boesman M., Nordin J. H., Isliker H. Effect of chemical and enzymatic radioiodination on in vitro human Clq activities. J Immunol. 1973 Mar;110(3):820–828. [PubMed] [Google Scholar]
  10. KUNKEL H. G., MULLER-EBERHARD H. J., FUDENBERG H. H., TOMASI T. B. Gamma globulin complexes in rheumatoid arthritis and certain other conditions. J Clin Invest. 1961 Jan;40:117–129. doi: 10.1172/JCI104224. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Kaplan M. H., Volanakis J. E. Interaction of C-reactive protein complexes with the complement system. I. Consumption of human complement associated with the reaction of C-reactive protein with pneumococcal C-polysaccharide and with the choline phosphatides, lecithin and sphingomyelin. J Immunol. 1974 Jun;112(6):2135–2147. [PubMed] [Google Scholar]
  12. Kinsella T. D., Baum J., Ziff M. Immunofluorescent demonstration of an IgG-B1C complex in synovial lining cells of rheumatoid synovial membrane. Clin Exp Immunol. 1969 Feb;4(2):265–271. [PMC free article] [PubMed] [Google Scholar]
  13. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  14. Lambert P. H., Nydegger U. E., Perrin L. H., McCormic J., Fehr K., Miescher P. A. Complement activation in seropositive and seronegative rheumatoid arthritis. 125I-C1q binding capacity and complement breakdown products in serum and synovial fluid. Rheumatology. 1975;6:52–59. [PubMed] [Google Scholar]
  15. Luthra H. S., McDuffie F. C., Hunder G. G., Samayoa E. A. Immune complexes in sera and synovial fluids of patients with rheumatoid arthritis. Radioimmunoassay with monocylonal rheumatoid factor. J Clin Invest. 1975 Aug;56(2):458–466. doi: 10.1172/JCI108112. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. MARTIN R. G., AMES B. N. A method for determining the sedimentation behavior of enzymes: application to protein mixtures. J Biol Chem. 1961 May;236:1372–1379. [PubMed] [Google Scholar]
  17. Mahieu P., Lambert P. H., Miescher P. A. Detection of anti-glomerular basement membrane antibodies by radioimmunological technique. Clinical application in human nephropathies. J Clin Invest. 1974 Jul;54(1):128–137. doi: 10.1172/JCI107734. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Marcus R. L., Townes A. S. The occurrence of cryoproteins in synovial fluid; the association of a complement-fixing activity in rheumatoid synovial fluid with cold-precipitable protein. J Clin Invest. 1971 Feb;50(2):282–293. doi: 10.1172/JCI106493. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Munthe E., Natvig J. B. Characterization of IgG complexes in eluates from rheumatoid tissue. Clin Exp Immunol. 1971 Feb;8(2):249–262. [PMC free article] [PubMed] [Google Scholar]
  20. Nydegger U. E., Achermann L. M., Lambert P. H., Miescher P. A. A simple automated method for complement estimation in a continuous flow system. J Immunol. 1972 Oct;109(4):910–913. [PubMed] [Google Scholar]
  21. Nydegger U. E., Lambert P. H., Gerber H., Miescher P. A. Circulating immune complexes in the serum in systemic lupus erythematosus and in carriers of hepatitis B antigen. Quantitation by binding to radiolabeled C1q. J Clin Invest. 1974 Aug;54(2):297–309. doi: 10.1172/JCI107765. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Onyewotu I. I., Johnson P. M., Johnson G. D., Holborow E. J. Enhanced uptake by guinea-pig macrophages of radio-iodinated human aggregated immunoglobulin G in the presence of sera from rheumatoid patients with cutaneous vasculitis. Clin Exp Immunol. 1975 Feb;19(2):267–280. [PMC free article] [PubMed] [Google Scholar]
  23. PERNIS B., BALLABIO C. B., CHIAPPINO G. PRESENZA DEL FATTORE REUMATOIDE NELLE LESIONI VASCOLARI IN CASI DI ARTRITE REUMATOIDE AGGRAVATA (MALIGNA). STUDIO CON ANTICORPI FLUORESCENTI. Reumatismo. 1963 May-Jun;15:187–199. [PubMed] [Google Scholar]
  24. Perrin L. H., Lambert P. H., Miescher P. A. Complement breakdown products in plasma from patients with systemic lupus erythematosus and patients with membranoproliferative or other glomerulonephritis. J Clin Invest. 1975 Jul;56(1):165–176. doi: 10.1172/JCI108065. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Perrin L. H., Lambert P. H., Miescher P. A. Properdin levels in systemic lupus erythematosus and membranoproleferative glomerulonephritis. Clin Exp Immunol. 1974 Apr;16(4):575–581. [PMC free article] [PubMed] [Google Scholar]
  26. Perrin L. H., Shiraishi S., Stroud R. M., Lambert P. H. Detection and quantitation in plasma and synovial fluid of a fragment of human C4 with alpha mobility generated during the activation of the complement system. J Immunol. 1975 Jul;115(1):32–35. [PubMed] [Google Scholar]
  27. Pope R. M., Mannik M., Gilliland B. C., Teller D. C. The hyperviscosity syndrome in rheumatoid arthritis due to intermediate complexes formed by self-association of IgG-rheumatoid factors. Arthritis Rheum. 1975 Mar-Apr;18(2):97–106. doi: 10.1002/art.1780180201. [DOI] [PubMed] [Google Scholar]
  28. ROPES M. W., BENNETT G. A., COBB S., JACOX R., JESSAR R. A. 1958 Revision of diagnostic criteria for rheumatoid arthritis. Bull Rheum Dis. 1958 Dec;9(4):175–176. [PubMed] [Google Scholar]
  29. Robitaille P., Zvaifler N. J., Tan E. M. Antinuclear antibodies and nuclear antigens in rheumatoid synovial fluids. Clin Immunol Immunopathol. 1973 Apr;1(3):385–397. doi: 10.1016/0090-1229(73)90055-x. [DOI] [PubMed] [Google Scholar]
  30. SCHEIDEGGER J. J. Une micro-méthode de l'immuno-electrophorèse. Int Arch Allergy Appl Immunol. 1955;7(2):103–110. [PubMed] [Google Scholar]
  31. Schrohenloher R. E. Characterization of the gamma-globulin complexes present in certain sera having high titers of anti-gamma-globulin activity. J Clin Invest. 1966 Apr;45(4):501–512. doi: 10.1172/JCI105364. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Schur P. H., Austen K. F. Complement in human disease. Annu Rev Med. 1968;19:1–24. doi: 10.1146/annurev.me.19.020168.000245. [DOI] [PubMed] [Google Scholar]
  33. Volanakis J. E., Stroud R. M. Rabbit C1q: purification, functional and structural studies. J Immunol Methods. 1972 Nov;2(1):25–34. doi: 10.1016/0022-1759(72)90014-2. [DOI] [PubMed] [Google Scholar]
  34. WIEDERMANN G., MIESCHER P. A., FRANKLIN E. C. Effect of mercaptoethanol on complement binding ability of human 7 S gammaglobulin. Proc Soc Exp Biol Med. 1963 Jul;113:609–613. doi: 10.3181/00379727-113-28440. [DOI] [PubMed] [Google Scholar]
  35. Weinstein A., Peters K., Brown D., Bluestone R. Metabolism of the third component of complement (C3) in patients with rheumatoid arthritis. Arthritis Rheum. 1972 Jan-Feb;15(1):49–56. doi: 10.1002/art.1780150108. [DOI] [PubMed] [Google Scholar]
  36. Weisman M., Zvaifler N. Cryoimmunoglobulinemia in rheumatoid arthritis. Significance in serum of patients with rheumatoid vasculitis. J Clin Invest. 1975 Sep;56(3):725–739. doi: 10.1172/JCI108144. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Winchester R. J., Agnello V., Kunkel H. G. Gamma globulin complexes in synovial fluids of patients with rheumatoid arthritis. Partial characterization and relationship to lowered complement levels. Clin Exp Immunol. 1970 May;6(5):689–706. [PMC free article] [PubMed] [Google Scholar]
  38. Winchester R. J., Kunkel H. G., Agnello V. Occurrence of -globulin complexes in serum and joint fluid of rheumatoid arthritis patients: use of monoclonal rheumatoid factors as reagents for their demonstration. J Exp Med. 1971 Sep 1;134(3 Pt 2):286s–295s. [PubMed] [Google Scholar]
  39. Zubler R. H., Lange G., Lambert P. H., Miescher P. A. Detection of immune complexes in unheated sera by modified 125I-Clq binding test. Effect of heating on the binding of Clq by immune complexes and application of the test to systemic lupus erythematosus. J Immunol. 1976 Jan;116(1):232–235. [PubMed] [Google Scholar]
  40. Zvaifler N. J. Breakdown products of C 3 in human synovial fluids. J Clin Invest. 1969 Aug;48(8):1532–1542. doi: 10.1172/JCI106119. [DOI] [PMC free article] [PubMed] [Google Scholar]

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