How antibodies to a ubiquitous cytoplasmic enzyme may provoke joint-specific autoimmune disease


Arthritis in the K/BxN mouse model results from pathogenic immunoglobulins (Igs) that recognize the ubiquitous cytoplasmic enzyme glucose-6-phosphate isomerase (GPI). But how is a joint-specific disease of autoimmune and inflammatory nature induced by systemic self-reactivity? No unusual amounts or sequence, splice or modification variants of GPI expression were found in joints. Instead, immunohistological examination revealed the accumulation of extracellular GPI on the lining of the normal articular cavity, most visibly along the cartilage surface. In arthritic mice, these GPI deposits were amplified and localized with IgG and C3 complement. Similar deposits were found in human arthritic joints. We propose that GPI–anti-GPI complexes on articular surfaces initiate an inflammatory cascade via the alternative complement pathway, which is unbridled because the cartilage surface lacks the usual cellular inhibitors. This may constitute a generic scenario of arthritogenesis, in which extra-articular proteins coat the cartilage or joint extracellular matrix.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: No joint-specific form of GPI.
Figure 2: No overexpression of GPI in joints.
Figure 3: Presence of GPI on joint surfaces.
Figure 4: Circulating GPI or GPI–anti-GPI immune complexes.
Figure 5: GPI deposits on a human RA pannus.


  1. 1

    Lanchbury, J. S. & Pitzalis, C. Cellular immune mechanisms in rheumatoid arthritis and other inflammatory arthritides. Curr. Biol. 5, 918–924 (1993).

    CAS  Google Scholar 

  2. 2

    Kouskoff, V. et al. Organ-specific disease provoked by systemic autoreactivity. Cell 87, 811–822 (1996).

    CAS  Article  Google Scholar 

  3. 3

    Korganow, A.-S. et al. From systemic T cell self-reactivity to organ-specific autoimmune disease via immunoglobulins. Immunity 10, 451–461 (1999).

    CAS  Article  Google Scholar 

  4. 4

    Matsumoto, I., Staub, A., Benoist, C. & Mathis, D. Arthritis provoked by linked T and B cell recognition a glycolytic enzyme. Science 286, 1732–1735 (1999).

    CAS  Article  Google Scholar 

  5. 5

    Basu, D., Horvath, S., Matsumoto, I., Fremont, D. H. & Allen, P. M. Molecular basis for recognition of an arthritic peptide and a foreign epitope on distinct MHC molecules by a single TCR. J. Immunol. 164, 5788–5796 (2000).

    CAS  Article  Google Scholar 

  6. 6

    Maccioni, M. et al. Arthritogenic monoclonal antibodies from K/BxN mice. J. Exp. Med. (in the press, 2002).

  7. 7

    Ji, H. et al. Arthritis critically dependent on innate immune system players. Immunity 16, 157–168 (2002).

    CAS  Article  Google Scholar 

  8. 8

    West, J. D., Flockhart, J. H., Peters, J. & Ball, S. T. Death of mouse embryos that lack a functional gene for glucose phosphate isomerase. Genet. Res. 56, 223–236 (1990).

    CAS  Article  Google Scholar 

  9. 9

    Frohman, M. A., Dush, M. K. & Martin, G. R. Rapid production of full-length cDNAs from rare transcripts: amplification using a single gene–specific oligonucleotide primer. Proc. Natl Acad. Sci. USA 85, 8998–9002 (1988).

    CAS  Article  Google Scholar 

  10. 10

    Schaller, M., Burton, D. R. & Ditzel, H. J. Autoantibodies to GPI in rheumatoid arthritis: linkage between animal model and human disease. Nature Immunol. 2, 746–753 (2001).

    CAS  Article  Google Scholar 

  11. 11

    Ishikawa, H., Smiley, J. D. & Ziff, M. Electron microscopic demonstration of immunoglobulin deposition in rheumatoid cartilage. Arthritis Rheum. 18, 563–576 (1975).

    CAS  Article  Google Scholar 

  12. 12

    Cooke, T. D., Hurd, E. R., Jasin, H. E., Bienenstock, J. & Ziff, M. Identification of immunoglobulins and complement in rheumatoid articular collagenous tissues. Arthritis Rheum. 18, 541–551 (1975).

    CAS  Article  Google Scholar 

  13. 13

    Vetto, A. A., Mannik, M., Zatarain-Rios, E. & Wener, M. H. Immune deposits in articular cartilage of patients with rheumatoid arthritis have a granular pattern not seen in osteoarthritis. Rheumatol. Int. 10, 13–19 (1990).

    CAS  Article  Google Scholar 

  14. 14

    Pangburn, M. K. in The Complement System (eds Rother, K., Till, G. O. & Hansch, G. M.) 93–115 (Springer-Verlag Berlin, Heidelberg, 1998).

    Google Scholar 

  15. 15

    Vivanco, F., Munoz, E., Vidarte, L. & Pastor, C. The covalent interaction of C3 with IgG immune complexes. Mol. Immunol. 36, 843–852 (1999).

    CAS  Article  Google Scholar 

  16. 16

    Shohet, J. M., Pemberton, P. & Carroll, M. C. Identification of a major binding site for complement C3 on the IgG1 heavy chain. J. Biol. Chem. 268, 5866–5871 (1993).

    CAS  PubMed  Google Scholar 

  17. 17

    Fries, L. F., Gaither, T. A., Hammer, C. H. & Frank, M. M. C3b covalently bound to IgG demonstrates a reduced rate of inactivation by factors H and I. J. Exp. Med. 160, 1640–1655 (1984).

    CAS  Article  Google Scholar 

  18. 18

    Jelezarova, E., Vogt, A. & Lutz, H. U. Interaction of C3b2-IgG complexes with complement proteins properdin, factor B and factor H: implications for amplification. Biochem. J. 349, 217–223 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Schwaeble, W. J. & Reid, K. B. M. Does properdin crosslink the cellular and the humoral immune response? Immunol. Today 20, 17–21 (1999).

    CAS  Article  Google Scholar 

  20. 20

    Fearon, D. T. Regulation by membrane sialic acid of β1H-dependent decay-dissociation of amplification C3 convertase of the alternative complement pathway. Proc. Natl Acad. Sci. USA 75, 1971–1975 (1978).

    CAS  Article  Google Scholar 

  21. 21

    Meri, S. & Pangburn, M. K. Discrimination between activators and nonactivators of the alternative pathway of complement: regulation via a sialic acid/polyanion binding site on factor H. Proc. Natl Acad. Sci. USA 87, 3982–3986 (1990).

    CAS  Article  Google Scholar 

  22. 22

    Takahashi, S. et al. Cloning and cDNA sequence analysis of nephritogenic monoclonal antibodies derived from an MRL/lpr lupus mouse. Mol. Immunol. 30, 177–182 (1993).

    CAS  Article  Google Scholar 

  23. 23

    Gonzalez, M. L. & Waxman, F. J. Glomerular deposition of immune complexes made with IgG2a monoclonal antibodies. J. Immunol. 164, 1071–1077 (2000).

    CAS  Article  Google Scholar 

  24. 24

    Watanabe, H. et al. Modulation of Renal Disease in MRL/lpr Mice Genetically Deficient in the Alternative Complement Pathway Factor B. J. Immunol. 164, 786–794 (2000).

    CAS  Article  Google Scholar 

  25. 25

    Watanabe, H. et al. Purification of human tumor cell autocrine motility factor and molecular cloning of its receptor. J. Biol. Chem. 266, 13442–13448 (1991).

    CAS  PubMed  Google Scholar 

  26. 26

    Jeffery, C. J., Bahnson, B. J., Chien, W., Ringe, D. & Petsko, G. A. Crystal structure of rabbit phosphoglucose isomerase, a glycolitic enzyme that moonlights as neuroleukin, autocrine motility factor and differentiation mediator. Biochemistry 39, 955–964 (2000).

    CAS  Article  Google Scholar 

  27. 27

    Sun, Y. J. et al. The crystal structure of a multifunctional protein: phosphoglucose isomerase/autocrine motility factor/neuroleukin. Proc. Natl Acad. Sci. USA 96, 5412–5417 (1999).

    CAS  Article  Google Scholar 

  28. 28

    Wipke, B. T., Wang, Z., Kim, J., McCarthy, T. J. & Allen, P. M. Dynamic visualization of a joint-specific autoimmune response through positron emission topography. Nature Immunol. 3, 368–374 (2002).

    Article  Google Scholar 

  29. 29

    Zvaifler, N. J. The immunopathology of joint inflammation in rheumatoid arthritis. Adv. Immunol. 265, 265–336 (1973).

    Article  Google Scholar 

  30. 30

    Jasin, H. E. Immune mediated cartilage destruction. Scand. J. Immunol. 76, 111–116 (1988).

    CAS  Google Scholar 

  31. 31

    Auffray, C. & Rougeon, F. Purification of mouse immunoglobulin heavy-chain messenger RNAs from total myeloma tumor RNA. Eur. J. Biochem. 107, 303–314 (1980).

    CAS  Article  Google Scholar 

  32. 32

    Ji, H. et al. Genetic influences on the end-stage effector phase of arthritis. J. Exp. Med. 194, 321–330 (2001).

    CAS  Article  Google Scholar 

Download references


We thank J. L. Pasquali for enlightening discussions; J. Hergueux, S. Johnson and Q. M. Pham for managing the KRN colony; C. Cahill for help with confocal microscopy; P. Gerber for ELISAs and chromatography; and D. Bowman and A. Calderone for sections. Supported by institutional funds from the INSERM, CNRS and the Centre Hospitalo-Universitaire and by grants from the Association pour la Recherche contre la Polyarthrite and the NIH (1R01 AR/AI46580-01, to D. M. and C. B), the Arthritis Foundation (I. M.), the Fondation pour la Recherche Medicale and CONICET (M. M.) and the Howard Hughes Medical Institute (D. L.).

Author information



Corresponding authors

Correspondence to Diane Mathis or Christophe Benoist.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Matsumoto, I., Maccioni, M., Lee, D. et al. How antibodies to a ubiquitous cytoplasmic enzyme may provoke joint-specific autoimmune disease. Nat Immunol 3, 360–365 (2002).

Download citation

Further reading