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

Nat Immunol. 2002 Apr;3(4):360-5. doi: 10.1038/ni772. Epub 2002 Mar 18.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Ankle Joint / enzymology
  • Antibodies / immunology
  • Arthritis, Rheumatoid / enzymology*
  • Arthritis, Rheumatoid / immunology
  • Arthritis, Rheumatoid / pathology
  • Base Sequence
  • Cartilage, Articular
  • Cytoplasm / enzymology
  • DNA, Complementary
  • Disease Models, Animal
  • Female
  • Glucose-6-Phosphate Isomerase / genetics
  • Glucose-6-Phosphate Isomerase / immunology
  • Glucose-6-Phosphate Isomerase / metabolism*
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, Transgenic
  • Molecular Sequence Data


  • Antibodies
  • DNA, Complementary
  • Glucose-6-Phosphate Isomerase