Raised levels of anti-glucose-6-phosphate isomerase IgG in serum and synovial fluid from patients with inflammatory arthritis.

BACKGROUND: In K/BxN mice, anti-glucose-6-phosphate isomerase (GPI) antibodies (Abs) are arthritogenic, and their transfer into naive mice induces arthritis. Anti-GPI Abs develop in many human patients with RA and are associated with more severe forms of the disease. OBJECTIVE: To elucidate the serum and synovial fluid (SF) anti-GPI IgG profiles among different patient groups with a variety of arthritides. METHODS: Blood and SF obtained concomitantly from 91 patients with clinically well defined arthritis were tested for concentrations of total anti-GPI IgG, anti-GPI IgG subclasses, B lymphocyte stimulator (BLyS), and APRIL by ELISA. RESULTS: Anti-GPI IgG was detected in sera and SF of patients with many arthritic diseases, but was preferentially associated with inflammatory arthritis, in general, and RA, in particular. The anti-GPI IgG subclass usage was skewed and varied among the different arthritic disease groups. Inverse correlations between serum levels of BLyS and anti-GPI IgG and positive correlations between serum levels of APRIL and anti-GPI IgG were seen among immune based arthritic patients and patients with RA but not among non-immune based patients. No correlations were found in SF from any group of arthritic patients. CONCLUSION: Raised circulating anti-GPI Abs are not unique to patients with RA but are present in many patients with inflammatory arthritis. The difference in anti-GPI IgG subclass usage among disease groups may influence effector function and disease outcome. The inverse correlation between serum BLyS and anti-GPI IgG levels suggests that anti-GPI B cells may be regulated differently from other autoantibody producing B cells. Anti-GPI Abs may serve a pathogenic function in humans by promoting the maintenance of existing disease.

Superantigen-driven, CD8+ T cell-mediated down-regulation: CD95 (Fas)-dependent down-regulation of human Ig responses despite CD95-independent killing of activated B cells.

Staphylococcal superantigens, including staphylococcal enterotoxin B (SEB), promote vigorous T cell-dependent Ig responses at low dose (0.01 ng/ml). In contrast, more mitogenic high dose SEB (100 ng/ml) profoundly inhibits the Ig responses. To assess the contribution of CD8+ T cells to this inhibition, high dose SEB-dependent killing of activated B cells and down-regulation of Ig responses were determined. Rapid killing (4 h) of activated B cells was effected by high dose SEB-activated CD8+ T cells (CD8*), but not by high-dose SEB-activated CD4+ T cells (CD4*), and required the presence of high dose SEB during the cytotoxicity assay. This killing was abrogated by chelation of extracellular calcium or by treatment with concanamycin A but was only modestly affected by treatment with brefeldin A, suggesting a perforin-based pathway of killing. Despite their widely disparate abilities to rapidly kill activated B cells, CD8* and CD4* demonstrated similar quantitative abilities to effect high dose SEB-dependent down-regulation of Ig responses. Antagonist anti-CD95 mAb substantially reversed high dose SEB-dependent downregulation effected by CD8* but had no appreciable effects on high dose SEB-dependent killing of activated B cells. These observations strongly suggest that the small fraction of activated B cells that secrete Ig are selectively sensitive to CD95-based killing but resistant to CD95-independent killing. This finding may help explain why clinical autoimmunity associated with increased titers of autoantibodies is a predominant feature of defects in CD95 or CD95 ligand.

A quantitative assay for experimental allergic encephalomyelitis in the rat based on permeability of spinal cords to 125I-human gamma-globulin.

We have developed a quantitative assay for experimental allergic encephalomyelitis (EAE) in the rat based on permeability of the spinal cord to 125I-human gamma-globulin (HGG). This assay is highly reproducible and eliminates many of the drawbacks of assaying for EAE on the basis of clinical and/or histologic criteria. Using the assay, we have shown a direct correlation between onset of histologic changes in the spinal cord and onset of permeability changes in the spinal cord. No rat without histologic lesions manifest permeability alterations, and all rats with histologic lesions did manifest increased permeability to 125I-HGG. Furthermore, strains of rats susceptible to EAE demonstrated permeability changes, whereas resistant rats did not. In addition, we demonstrated by permeability and histologic criteria that guinea pig myelin basic protein emulsified with incomplete Freund's adjuvant is encephalitogenic in the Lewis rat. We also demonstrated that recipients of passive transfer of sensitized cells develop permeability changes along with histologic lesions. We conclude that measuring permeability to 125I-HGG in the spinal cords of rats is a valid assay for EAE, and its improves upon current indices of EAE in that it is readily quantifiable.