title: Functional regulatory immune responses against human cartilage glycoprotein-39 in health vs. proinflammatory responses in rheumatoid arthritis.
abstract: 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 glycoprotein-39 (HC gp-39). Peripheral blood mononuclear cells from healthy individuals reacted against HC gp-39 with the production of IL-10 but not IFN-gamma. 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 toward a regulatory phenotype. Moreover, CD4(+) T cell lines directed against HC gp-39 expressed CD25, glucocorticoid-induced tumor necrosis factor receptor, 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 toward a proinflammatory T helper 1 phenotype and is significantly less powerful in suppressing antigen-specific recall responses. 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 rheumatoid arthritis patients has shifted from an antiinflammatory toward a proinflammatory phenotype.
authors.affiliation: Departments of Rheumatology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
authors.forename: Jolanda H M
authors.initials: JH
authors.lastname: van Bilsen
authors.forename: Henrike
authors.initials: H
authors.lastname: van Dongen
authors.forename: Leroy R
authors.initials: LR
authors.lastname: Lard
authors.forename: Ellen I H
authors.initials: EI
authors.lastname: van der Voort
authors.forename: Diënne G
authors.initials: DG
authors.lastname: Elferink
authors.forename: Aleida M
authors.initials: AM
authors.lastname: Bakker
authors.forename: André M M
authors.initials: AM
authors.lastname: Miltenburg
authors.forename: Tom W J
authors.initials: TW
authors.lastname: Huizinga
authors.forename: René R P
authors.initials: RR
authors.lastname: de Vries
authors.forename: René E M
authors.initials: RE
authors.lastname: Toes
mesh_terms: D054392:Adipokines; D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D001324:Autoantigens; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016022:Case-Control Studies; D002450:Cell Communication / Q000276:immunology; D000071451:Chitinase-3-Like Protein 1; D005260:Female; D006023:Glycoproteins / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular; D007249:Inflammation / Q000276:immunology*; D037102:Lectins; D008297:Male; D008875:Middle Aged; D018417:Th1 Cells / Q000276:immunology
chemical_list: D054392:Adipokines; D001324:Autoantigens; C084533:CHI3L1 protein, human; D000071451:Chitinase-3-Like Protein 1; D006023:Glycoproteins; D037102:Lectins