Glycosaminoglycans are a potential cause of rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is a chronic, systemic, and inflammatory disease of connective tissue with unknown etiology. We investigated whether aberrant immune responses to glycosaminoglycans (GAGs), a major component of joint cartilage, joint fluid, and other soft connective tissue, causes this disease. Here we show that injection of GAGs such as hyaluronic acid, heparin, and chondroitin sulfates A, B, and C induce arthritis, tendosynovitis, dermatitis, and other pathological conditions in mice. We developed a technique by staining tissue specimens with fluorochrome-or biotin-labeled GAGs to visualize the direct binding between cells and GAGs. We discovered that inflammatory infiltrates from the affected tissue are dominated by a distinct phenotype of GAG-binding cells, a significant portion of which are CD4 ؉ T cells. GAG-binding cells seem to be expanded in bone marrow of GAG-immunized mice. Furthermore, we identified GAG-binding cells in inflamed synovial tissue of human patients with RA. Our findings suggest that carbohydrate self-antigenic GAGs provoke autoimmune dysfunctions that involve the expansion of GAG-binding cells which migrate to anatomical sites rich in GAGs. These GAG-binding cells might, in turn, promote the inflammation and pathology seen both in our murine model and in human RA.

Dermatan Sulfate Interacts with Dead Cells and Regulates CD5+ B-Cell Fate

“…Cell culture experiments consistently showed that DS was the most potent in stimulating cell proliferation, whereas others had much lower activity. This observation was in agreement with our earlier assessment 14 and later reports. 15,16 The proliferative effect of DS was dose dependent, and concentrations of 20 g/mL or higher significantly stimulated cell proliferation.…”

“…14 We then determined that DS potently stimulates B-cell proliferation (Figure 1; see also Supplemental Figure S1 at http://ajp.amjpathol.org) and production of immunoglobulin, particularly IgM, in vitro. These findings are in agreement with published results.…”

CD44 Differentially Activates Mouse NK T Cells and Conventional T Cells

“…Overexpression of OPN also is a risk factor for the development of autoimmunity and lymphoproliferative disorders (63). Furthermore, experimental administration of GAGs, including HA, chondroitin sulfates (A, B, and C), and heparin, all natural ligands of CD44, induce autoimmune connective tissue disease in normal mice (55,64). Interestingly, a majority of the pathogenic inflammatory cells in this study are CD4 ϩ , GAG-binding T cells, consistent with an NKT cell population.…”

The Anti-rheumatic Gold Salt Aurothiomalate Suppresses Interleukin-1β-induced Hyaluronan Accumulation by Blocking HAS1 Transcription and by Acting as a COX-2 Transcriptional Repressor

“…Although HA has been considered to be unequivocally beneficial by many physicians, there are clear signs that HA degradation products exert a series of unwanted effects (4,26,27). The strongest support for our working hypothesis that unfettered HA might be detrimental in RA came from an animal study demonstrating that prolonged injection of HA in healthy animals can cause all of the classical signs of RA (28). In addition to many clinical reports questioning the practice of HA injections, another animal study designed to demonstrate the beneficial effects of HA injections also provides evidence of potentially profound adverse effects of such measures (29).…”