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

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.

Systemic humoral autoimmunity but joint‐specific inflammation: The syndrome of rheumatoid arthritis

“…Arthritis does not develop in the MT mutant mouse, which lacks B cells (6,7). Further studies established that direct interaction of T cells and B cells through CD40/CD40L is necessary for the elaboration of arthritogenic anti-GPI antibodies (4).…”

“…Initiation of arthritis in the K/BxN mouse is attributable to the breakdown of T cell tolerance, with collaboration of autoreactive B cells (3)(4)(5)(6)(7). Arthritis does not develop in the MT mutant mouse, which lacks B cells (6,7).…”

“…Mast celldeficient mouse strains (W/W v or Sl/Sl d ) are resistant to arthritis induction by serum transfer; mast cell transfer restores susceptibility in the W/W v strain (11). Proinflammatory cytokines, particularly interleukin-1␤ (IL-1␤), tumor necrosis factor ␣ (TNF␣), and IL-6 are up-regulated in arthritis (6,7). Whereas some TNF␣-deficient mouse strains can develop robust disease in the K/BxN mouse serum-transfer model, IL-1 Ϫ/Ϫ and IL-1 receptor (IL-1R) Ϫ/Ϫ mice are resistant (11).…”

“…This ubiquitous glycolytic enzyme catalyzes the interconversion of glucose-6-phosphate and fructose-6-phosphate in the second step of glycolysis. Purified anti-GPI IgG transfers the disease phenotype (6,7). Thus, in this model, KRN T cells recognize GPI and provide help to GPI-specific B cells to produce arthritogenic IgG.…”

“…Disease is initiated by IgG and can be induced in lymphocytedeficient recipients, indicating independence of T cells and B cells in this passive-transfer model. Similar to human RA, joint-specific immune complex formation occurs, with subsequent leukocyte recruitment and inflammation (6,7,10) (Table 1). However, the passive antibody-transfer model does not result in pannus formation.…”