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

Nature Immunology volume 3, pages 360–365 (2002)Cite this article

Abstract

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.

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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.

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Acknowledgements

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.).

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Author notes

  1. Mariana Maccioni

    Present address: Depto. de Bioquímica Clínica, Universidad Nacional de Córdoba, Córdoba, 5000, Argentina

Authors and Affiliations

  1. Section on Immunology and Immunogenetics, Joslin Diabetes Center,

    Isao Matsumoto, Mariana Maccioni, Diane Mathis & Christophe Benoist

  2. Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 1 Joslin Place, Boston, 02115, MA, USA

    Isao Matsumoto, Mariana Maccioni, Diane Mathis & Christophe Benoist

  3. Institut de Génétique et de Biologie Moléculaire et Cellulaire (CNRS/INSERM/ULP), Strasbourg, France

    Isao Matsumoto, Diane Mathis & Christophe Benoist

  4. Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, 02115, MA, USA

    David M. Lee & Michael Brenner

  5. Department of Pathology, Harvard Medical School, Boston, 02115, MA, USA

    Madelon Maurice

  6. Department of Orthopedic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, 02115, MA, USA

    Barry Simmons

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Correspondence to Diane Mathis or Christophe Benoist.

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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). https://doi.org/10.1038/ni772

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