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C1q-Containing Immune Complexes Purified from Sera of Juvenile Rheumatoid Arthritis Patients Mediate IL-8 Production by Human Synoviocytes: Role of C1q Receptors¹

Zhila Khalkhali-Ellis^2,*, Gary A. Bulla, Larry S. Schlesinger, Dawn A. Kirschmann^*, Terry L. Moore^§ and Mary J. C. Hendrix^*

^* Departments of Anatomy and Cell Biology, and Internal Medicine and Microbiology and Department of Veterans Affair, University of Iowa College of Medicine, Iowa City, IA 52242; and Pediatric Research Institute and ^§ Division of Rheumatology, Departments of Pediatrics and Internal Medicine, St. Louis University, St. Louis, MO 63110

Immune complexes that vary in size and composition are present in the sera and synovial fluid of juvenile rheumatoid arthritis (JRA) patients. They are believed to be potent inducers of the ongoing inflammatory process in JRA. However, the precise composition and role of these complexes in the pathophysiology of JRA remain unclear. We hypothesized that circulating ICs have the potential to interact with resident joint synovial fibroblasts (synoviocytes) and induce the expression of inflammatory cytokines. To test this hypothesis, cultures of synoviocytes from healthy individuals were treated with ICs isolated from the sera of JRA patients. Studies reported in this work demonstrate that IgM affinity-purified ICs from the sera of JRA patients contain IgM, C1q, IgG, and C3 to a variable extent. These ICs induce IL-8 mRNA and protein production in normal synoviocytes. Our data indicate that C1q in these ICs mediates, in part, IL-8 induction in synoviocytes. This is based on our findings of C1q-binding proteins for collagen stalks (cC1qR) and globular heads (gC1q-binding protein) of C1q in synoviocytes. In addition, collagen stalk and to some extent globular head fragments of C1q inhibit IC-mediated IL-8 induction in synoviocytes. Together, these findings provide evidence for a novel mechanism of IL-8 production by synoviocytes, which could play a key role in inflammation by recruiting leukocytes to synovial tissue and fluid—and subsequently contributing to joint disease.

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