Abstract
The so-called antikeratin antibodies (AKA) and the antiperinuclear factor (APF) are the most specific serological markers of RA. Using indirect immunofluorescence, AKA label the stratum corneum of various cornified epithelia and APF the keratohyalin granules of human buccal mucosa epithelium. We recently demonstrated that AKA recognize human epidermal filaggrin. Here, we report the identification of the major APF antigen as a diffuse protein band of 200-400 kD. This protein is seen to be closely related to human epidermal (pro) filaggrin since it was recognized by four antifilaggrin mAbs specific for different epitopes, and since the APF titers of RA sera were found to be correlated to their AKA titers and to their immunoblotting reactivities to filaggrin. Immunoabsorption of RA sera on purified epidermal filaggrin abolished their reactivities to the granules of buccal epithelial cells and to the 200-400-kD antigen. Moreover, antifilaggrin autoantibodies, i.e., AKA, affinity purified from RA sera, were shown to immunodetect the 200-400-kD antigen and to stain these granules. These results indicate that AKA and APF are largely the same autoantibodies. They recognize human epidermal filaggrin and (pro) filaggrin-related proteins of buccal epithelial cells. Identification of the epitopes recognized by these autoantibodies, which we propose to name antifilaggrin autoantibodies, will certainly open new paths of research into the pathophysiology of RA.
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Selected References
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- Aho K., von Essen R., Kurki P., Palosuo T., Heliövaara M. Antikeratin antibody and antiperinuclear factor as markers for subclinical rheumatoid disease process. J Rheumatol. 1993 Aug;20(8):1278–1281. [PubMed] [Google Scholar]
- Arnett F. C., Edworthy S. M., Bloch D. A., McShane D. J., Fries J. F., Cooper N. S., Healey L. A., Kaplan S. R., Liang M. H., Luthra H. S. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988 Mar;31(3):315–324. doi: 10.1002/art.1780310302. [DOI] [PubMed] [Google Scholar]
- Boerbooms A. M., Westgeest A. A., Reekers P., van de Putte L. B. Immunogenetic heterogeneity of seronegative rheumatoid arthritis and the antiperinuclear factor. Ann Rheum Dis. 1990 Jan;49(1):15–17. doi: 10.1136/ard.49.1.15. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chan K. W., Felson D. T., Yood R. A., Walker A. M. The lag time between onset of symptoms and diagnosis of rheumatoid arthritis. Arthritis Rheum. 1994 Jun;37(6):814–820. doi: 10.1002/art.1780370606. [DOI] [PubMed] [Google Scholar]
- Dale B. A., Gown A. M., Fleckman P., Kimball J. R., Resing K. A. Characterization of two monoclonal antibodies to human epidermal keratohyalin: reactivity with filaggrin and related proteins. J Invest Dermatol. 1987 Mar;88(3):306–313. doi: 10.1111/1523-1747.ep12466185. [DOI] [PubMed] [Google Scholar]
- Girbal E., Sebbag M., Gomès-Daudrix V., Simon M., Vincent C., Serre G. Characterisation of the rat oesophagus epithelium antigens defined by the so-called 'antikeratin antibodies', specific for rheumatoid arthritis. Ann Rheum Dis. 1993 Oct;52(10):749–757. doi: 10.1136/ard.52.10.749. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gomès-Daudrix V., Sebbag M., Girbal E., Vincent C., Simon M., Rakotoarivony J., Abbal M., Fournié B., Serre G. Immunoblotting detection of so-called 'antikeratin antibodies': a new assay for the diagnosis of rheumatoid arthritis. Ann Rheum Dis. 1994 Nov;53(11):735–742. doi: 10.1136/ard.53.11.735. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hajiroussou V. J., Skingle J., Gillett A. P., Webley M. Significance of antikeratin antibodies in rheumatoid arthritis. J Rheumatol. 1985 Feb;12(1):57–59. [PubMed] [Google Scholar]
- Hoet R. M., Boerbooms A. M., Arends M., Ruiter D. J., van Venrooij W. J. Antiperinuclear factor, a marker autoantibody for rheumatoid arthritis: colocalisation of the perinuclear factor and profilaggrin. Ann Rheum Dis. 1991 Sep;50(9):611–618. doi: 10.1136/ard.50.9.611. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hoet R. M., Voorsmit R. A., Van Venrooij W. J. The perinuclear factor, a rheumatoid arthritis-specific autoantigen, is not present in keratohyalin granules of cultured buccal mucosa cells. Clin Exp Immunol. 1991 Apr;84(1):59–65. doi: 10.1111/j.1365-2249.1991.tb08124.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Janssens X., Veys E. M., Verbruggen G., Declercq L. The diagnostic significance of the antiperinuclear factor for rheumatoid arthritis. J Rheumatol. 1988 Sep;15(9):1346–1350. [PubMed] [Google Scholar]
- Johnson G. D., Carvalho A., Holborow E. J., Goddard D. H., Russell G. Antiperinuclear factor and keratin antibodies in rheumatoid arthritis. Ann Rheum Dis. 1981 Jun;40(3):263–266. doi: 10.1136/ard.40.3.263. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kataaha P. K., Mortazavi-Milani S. M., Russell G., Holborow E. J. Anti-intermediate filament antibodies, antikeratin antibody, and antiperinuclear factor in rheumatoid arthritis and infectious mononucleosis. Ann Rheum Dis. 1985 Jul;44(7):446–449. doi: 10.1136/ard.44.7.446. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kirstein H., Hjarvard K., Hansen T. M. Antikeratin antibodies in synovial fluid in rheumatoid arthritis. APMIS. 1989 Feb;97(2):185–189. doi: 10.1111/j.1699-0463.1989.tb00775.x. [DOI] [PubMed] [Google Scholar]
- Kirstein H., Mathiesen F. K. Antikeratin antibodies in rheumatoid arthritis. Methods and clinical significance. Scand J Rheumatol. 1987;16(5):331–338. doi: 10.3109/03009748709102504. [DOI] [PubMed] [Google Scholar]
- Kurki P., Aho K., Palosuo T., Heliövaara M. Immunopathology of rheumatoid arthritis. Antikeratin antibodies precede the clinical disease. Arthritis Rheum. 1992 Aug;35(8):914–917. doi: 10.1002/art.1780350810. [DOI] [PubMed] [Google Scholar]
- Mallya R. K., Young B. J., Pepys M. B., Hamblin T. J., Mace B. E., Hamilton E. B. Anti-keratin antibodies in rheumatoid arthritis: frequency and correlation with other features of the disease. Clin Exp Immunol. 1983 Jan;51(1):17–20. [PMC free article] [PubMed] [Google Scholar]
- NIENHUIS R. L., MANDEMA E. A NEW SERUM FACTOR IN PATIENTS WITH RHEUMATOID ARTHRITIS; THE ANTIPERINUCLEAR FACTOR. Ann Rheum Dis. 1964 Jul;23:302–305. doi: 10.1136/ard.23.4.302. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ordeig J., Guardia J. Diagnostic value of antikeratin antibodies in rheumatoid arthritis. J Rheumatol. 1984 Oct;11(5):602–604. [PubMed] [Google Scholar]
- Paimela L., Gripenberg M., Kurki P., Leirisalo-Repo M. Antikeratin antibodies: diagnostic and prognostic markers for early rheumatoid arthritis. Ann Rheum Dis. 1992 Jun;51(6):743–746. doi: 10.1136/ard.51.6.743. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Quismorio F. P., Jr, Kaufman R. L., Beardmore T., Mongan E. S. Reactivity of serum antibodies to the keratin layer of rat esophagus in patients with rheumatoid arthritis. Arthritis Rheum. 1983 Apr;26(4):494–499. doi: 10.1002/art.1780260407. [DOI] [PubMed] [Google Scholar]
- Scherbaum W. A., Youinou P. Y., Le Goff P., Bottazzo G. F. Anti-perinuclear and rheumatoid factor in different forms of autoimmune thyroid disease. Clin Exp Immunol. 1984 Mar;55(3):516–518. [PMC free article] [PubMed] [Google Scholar]
- Senécal J. L., Oliver J. M., Rothfield N. Anticytoskeletal autoantibodies in the connective tissue diseases. Arthritis Rheum. 1985 Aug;28(8):889–898. doi: 10.1002/art.1780280808. [DOI] [PubMed] [Google Scholar]
- Simon M., Girbal E., Sebbag M., Gomès-Daudrix V., Vincent C., Salama G., Serre G. The cytokeratin filament-aggregating protein filaggrin is the target of the so-called "antikeratin antibodies," autoantibodies specific for rheumatoid arthritis. J Clin Invest. 1993 Sep;92(3):1387–1393. doi: 10.1172/JCI116713. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Simon M., Vincent C., Haftek M., Girbal E., Sebbag M., Gomès-Daudrix V., Serre G. The rheumatoid arthritis-associated autoantibodies to filaggrin label the fibrous matrix of the cornified cells but not the profilaggrin-containing keratohyalin granules in human epidermis. Clin Exp Immunol. 1995 Apr;100(1):90–98. doi: 10.1111/j.1365-2249.1995.tb03608.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Smit J. W., Sondag-Tschroots I. R., Aaij C., Feltkamp T. E., Feltkamp-Vroom T. M. The antiperinuclear factor: II. A light microscopical and immunofluorescence study on the antigenic substrate. Ann Rheum Dis. 1980 Aug;39(4):381–386. doi: 10.1136/ard.39.4.381. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Smith S. A., Dale B. A. Immunologic localization of filaggrin in human oral epithelia and correlation with keratinization. J Invest Dermatol. 1986 Feb;86(2):168–172. doi: 10.1111/1523-1747.ep12284213. [DOI] [PubMed] [Google Scholar]
- Sondag-Tschroots I. R., Aaij C., Smit J. W., Feltkamp T. E. The antiperinuclear factor. 1. The diagnostic significance of the antiperinuclear factor for rheumatoid arthritis. Ann Rheum Dis. 1979 Jun;38(3):248–251. doi: 10.1136/ard.38.3.248. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Steiner G., Hartmuth K., Skriner K., Maurer-Fogy I., Sinski A., Thalmann E., Hassfeld W., Barta A., Smolen J. S. Purification and partial sequencing of the nuclear autoantigen RA33 shows that it is indistinguishable from the A2 protein of the heterogeneous nuclear ribonucleoprotein complex. J Clin Invest. 1992 Sep;90(3):1061–1066. doi: 10.1172/JCI115921. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Terato K., Shimozuru Y., Katayama K., Takemitsu Y., Yamashita I., Miyatsu M., Fujii K., Sagara M., Kobayashi S., Goto M. Specificity of antibodies to type II collagen in rheumatoid arthritis. Arthritis Rheum. 1990 Oct;33(10):1493–1500. doi: 10.1002/art.1780331006. [DOI] [PubMed] [Google Scholar]
- Tuaillon N., Muller S., Pasquali J. L., Bordigoni P., Youinou P., Van Regenmortel M. H. Antibodies from patients with rheumatoid arthritis and juvenile chronic arthritis analyzed with core histone synthetic peptides. Int Arch Allergy Appl Immunol. 1990;91(3):297–305. doi: 10.1159/000235131. [DOI] [PubMed] [Google Scholar]
- Vincent C., Serre G., Basile J. P., Lestra H. C., Girbal E., Sebbag M., Soleilhavoup J. P. Subclass distribution of IgG antibodies to the rat oesophagus stratum corneum (so-called anti-keratin antibodies) in rheumatoid arthritis. Clin Exp Immunol. 1990 Jul;81(1):83–89. doi: 10.1111/j.1365-2249.1990.tb05295.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Vincent C., Serre G., Fournié B., Fournié A., Soleilhavoup J. P. Natural IgG to epidermal cytokeratins vs IgG to the stratum corneum of the rat oesophagus epithelium, so-called 'antikeratin antibodies', in rheumatoid arthritis and other rheumatic diseases. J Autoimmun. 1991 Jun;4(3):493–505. doi: 10.1016/0896-8411(91)90161-5. [DOI] [PubMed] [Google Scholar]
- Vincent C., Serre G., Lapeyre F., Fournié B., Ayrolles C., Fournié A., Soleilhavoup J. P. High diagnostic value in rheumatoid arthritis of antibodies to the stratum corneum of rat oesophagus epithelium, so-called 'antikeratin antibodies'. Ann Rheum Dis. 1989 Sep;48(9):712–722. doi: 10.1136/ard.48.9.712. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Vivino F. B., Maul G. G. Histologic and electron microscopic characterization of the antiperinuclear factor antigen. Arthritis Rheum. 1990 Jul;33(7):960–969. doi: 10.1002/art.1780330707. [DOI] [PubMed] [Google Scholar]
- Westgeest A. A., Boerbooms A. M., Jongmans M., Vandenbroucke J. P., Vierwinden G., van de Putte L. B. Antiperinuclear factor: indicator of more severe disease in seronegative rheumatoid arthritis. J Rheumatol. 1987 Oct;14(5):893–897. [PubMed] [Google Scholar]
- Youinou P., Le Goff P., Colaco C. B., Thivolet J., Tater D., Viac J., Shipley M. Antikeratin antibodies in serum and synovial fluid show specificity for rheumatoid arthritis in a study of connective tissue diseases. Ann Rheum Dis. 1985 Jul;44(7):450–454. doi: 10.1136/ard.44.7.450. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Youinou P., Le Goff P., Dumay A., Lelong A., Fauquert P., Jouquan J. The antiperinuclear factor. I. Clinical and serologic associations. Clin Exp Rheumatol. 1990 May-Jun;8(3):259–264. [PubMed] [Google Scholar]
- Young B. J., Mallya R. K., Leslie R. D., Clark C. J., Hamblin T. J. Anti-keratin antibodies in rheumatoid arthritis. Br Med J. 1979 Jul 14;2(6182):97–99. doi: 10.1136/bmj.2.6182.97. [DOI] [PMC free article] [PubMed] [Google Scholar]
- van Muijen G. N., Ruiter D. J., Franke W. W., Achtstätter T., Haasnoot W. H., Ponec M., Warnaar S. O. Cell type heterogeneity of cytokeratin expression in complex epithelia and carcinomas as demonstrated by monoclonal antibodies specific for cytokeratins nos. 4 and 13. Exp Cell Res. 1986 Jan;162(1):97–113. doi: 10.1016/0014-4827(86)90429-5. [DOI] [PubMed] [Google Scholar]
- von Essen R., Kurki P., Isomäki H., Okubo S., Kautiainen H., Aho K. Prospect for an additional laboratory criterion for rheumatoid arthritis. Scand J Rheumatol. 1993;22(6):267–272. doi: 10.3109/03009749309095137. [DOI] [PubMed] [Google Scholar]