Functional regulatory immune responses against human cartilage glycoprotein-39 in health versus proinflammatory responses in rheumatoid arthritis

The class of immune response against autoantigens could profoundly influence the onset and/or outcome of autoimmune diseases. Until now, there is only limited information on the antigen-specific balance between proinflammatory and regulatory responses in humans. Here we analyzed the natural immune response against a candidate autoantigen in rheumatoid arthritis, Human Cartilage gp-39 (HC gp-39).

Peripheral blood mononuclear cells from healthy individuals reacted against HC gp-39 with the production of IL-10, but not interferon gamma (Fig. 1). Ex vivo assays indicated that the naturally occurring HC gp-39-specific immune response in bulk is powerful enough to suppress antigen-specific recall responses, demonstrating that, rather than being unresponsive, the HC gp-39-directed immune response in healthy individuals shows a strong bias towards a regulatory phenotype. Moreover, CD4⁺ T-cell lines directed against HC gp-39 expressed CD25, GITR and Foxp3 molecules and were capable of suppressing antigen-specific T-cell responses. Cell–cell contact was required for this suppression. As opposed to healthy individuals, the HC gp-39-directed immune response in 50% of patients with rheumatoid arthritis exhibits polarization towards a proinflammatory Th1 phenotype and is significantly less powerful in suppressing antigen-specific recall responses.

Human Cartilage gp-39 (HC gp-39)-specific immune reactivity in healthy donors. (a) Peripheral blood mononuclear cells from healthy donors (n = 31) react against HC gp-39 by production of IL-10 but not interferon gamma (IFN-γ). (b) 'Control' recall antigen-induced responses are dominated by IFN-γ production.

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Together these findings indicate that the presence of HC gp-39-specific immune responses in healthy individuals may have an inhibitory effect on inflammatory responses in areas where HC gp-39 is present. Furthermore, these data indicate that the class of HC gp-39-directed immune response in RA patients has shifted from an anti-inflammatory towards a proinflammatory phenotype.