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Autoantibodies to GPI in rheumatoid arthritis: linkage between an animal model and human disease

Nature Immunology volume 2, pages 746–753 (2001)Cite this article

Abstract

In K/BxN T cell receptor–transgenic mice, spontaneous inflammatory arthritis exhibiting many of the features of human rheumatoid arthritis (RA) is initiated by T cells, but is almost entirely sustained by antibodies to the self-antigen glucose-6-phosphate isomerase (GPI). The relevance of these observations to human disease has been questioned. Here we show that 64% of humans with RA, but not controls, had increased concentrations of anti-GPI immunoglobulin G (IgG) in serum and synovial fluid. In addition, the concentrations of soluble GPI in the sera and synovial fluids of RA patients were also elevated, which led to immune complex formation. Using phage-display methods, we cloned a panel of specific high-affinity human monoclonal anti-GPI IgGs from a patient with RA. These antibodies were highly somatically mutated, which was indicative of an affinity-matured response that was antigen driven. Immunohistochemistry of RA synovium showed high concentrations of GPI on the surface of the synovial lining and on the endothelial cell surface of arterioles; this indicated a mechanism by which antibodies to GPI may precipitate joint disease. The results indicate that the immunological events that lead to the development of autoimmune disease in the K/BxN mouse model may also occur in human RA. This data may be used to develop new strategies for therapeutic intervention.

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Figure 1: Sera from RA patients contained anti-GPI IgG, as measured by ELISA and immunoblotting.
Figure 2: Human monoclonal IgG-Fab fragments bound specifically to GPI.
Figure 3: Anti-GPI IgGs cloned from a RA patient were highly somatically mutated and exhibited high R:S ratios.
Figure 4: Synovial fluids from patients with active RA contained anti-GPI IgG.
Figure 5: Sera and synovial fluid of RA patients contained significantly increased GPI concentrations.
Figure 6: RA synovial fluid contained free and immune-complexed GPI and anti–GPI IgG.
Figure 7: Distribution of GPI in synovial tissue of patients with active RA.

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Acknowledgements

We thank K. Bigford, F.C. Breedveld, C. Colwell Jr., P. Davis, M. Elliott, R. Fox, J. Johansen and M. Lotz for patient samples and A. Raz for the rabbit anti-GPI. Supported in part by NIH grant AI041590 (to H. J. D.) and the Swiss National Science Foundation (M. S.).

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  1. Department of Immunology, IMM2, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, 92037, CA, USA

    Monica Schaller, Dennis R. Burton & Henrik J. Ditzel

  2. Department of Molecular Biology, IMM2, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, 92037, CA, USA

    Dennis R. Burton

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Correspondence to Henrik J. Ditzel.

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Schaller, M., Burton, D. & Ditzel, H. Autoantibodies to GPI in rheumatoid arthritis: linkage between an animal model and human disease. Nat Immunol 2, 746–753 (2001). https://doi.org/10.1038/90696

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