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Covalent Cross-Linking of Immune Complexes by Oxygen Radicals and Nitrite¹

Masaaki Uesugi^*, Takeshi Hayashi and Hugo E. Jasin^2,*

^* Division of Rheumatology and Clinical Immunology, University of Arkansas for Medical Sciences and John L. McClellan Veterans Administration Center, Little Rock, AR 72205; and Department of Orthopedic Surgery, Yokohama City University School of Medicine, Yokohama, Japan

We have shown that polymorphonuclear neutrophils mediate the covalent cross-linking of immune complexes (ICs) using H₂O₂ and myeloperoxidase (MPO). Moreover, activated superficial chondrocytes produce large amounts of nitric oxide (NO), suggesting that high concentrations of these radicals may interact at the cartilage surface in rheumatoid arthritis. We describe the effects of the interaction of NO and its decay product, NO₂, with H₂O₂ and MPO on IC cross-linking. Cross-linking was measured by resistance to the guanidine extraction of plastic-bound ICs. The combination of H₂O₂, MPO, and NO in the absence of O₂ did not alter the magnitude of cross-linking. The addition of O₂ resulted in a significant enhancement of cross-linking (p < 0.004), suggesting that nitrite was responsible for the increase observed. Indeed, NaNO₂ greatly increased H₂O₂-dependent cross-linking (control: 29.2 ± 3.8; 1 mM NaNO₂: 58.4 ± 9.9; 10 mM: 60.4 ± 4.2% cross-linking, p < 0.0002). Sodium azide, which is an inhibitor of MPO, completely inhibited cross-linking. These results indicated that the product of interaction of H₂O₂ and NO₂ mediated by MPO may be responsible for the increase in cross-linking. The generation of nitrotyrosine was demonstrated when NO₂ was added to the cross-linking system. Cross-linking was also shown with an O₂^--generating system and NO. Peroxynitrite alone mediated cross-linking (100 µM ONOO^-: 40.3 ± 1.9% cross-linking; p < 0.002), and the addition of MPO significantly enhanced this effect (100 µM: 57.7 ± 6.0%; p < 0.0002 with respect to no nitrite control). Oxygen radicals and NO are likely to interact at the cartilage surface in inflammatory arthritis, resulting in an increase in oxidative damage within the joint cavity.