Surface‐bound anti–type II collagen–containing immune complexes induce production of tumor necrosis factor α, interleukin‐1β, and interleukin‐8 from peripheral blood monocytes via fcγ receptor IIA: A potential pathophysiologic mechanism for humoral anti–type II collagen immunity in arthritis

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Abstract
Objective Type II collagen (CII) is a major component of hyaline cartilage, and antibodies against CII are found in a subgroup of patients with rheumatoid arthritis. We undertook this study to investigate whether and how antibodies directed against CII can form solid‐phase immune complexes (ICs) with cytokine‐inducing properties in a model theoretically resembling the situation in the inflamed joint, in which CII is exposed for interaction with anti‐CII antibodies during periods of inflammation. Methods Sixty‐five arthritis patients with varying levels of anti–native CII antibodies and 10 healthy controls were evaluated concerning anti‐CII and cytokines induced in a solid‐phase IC model. Monocytes were either depleted or enriched to define responder cells. Antibodies blocking Fcγ receptors (FcγR) were used to define the responsible T cell surface receptors. Results ICs containing anti‐CII from arthritis patients induced the production of tumor necrosis factor α (TNFα), interleukin‐1β (IL‐1β), and IL‐8. We found a close correlation between enzyme‐linked immunosorbent assay optical density values and induction of TNFα (r = 0.862, P < 0.0001), IL‐1β (r = 0.839, P < 0.0001), and IL‐8 (r = 0.547, P < 0.0001). The anti‐CII–containing IC density threshold needed for cytokine induction differed among peripheral blood mononuclear cell donors. Anti‐CII–containing IC–induced cytokine production was almost totally abolished (>99%) after monocyte depletion, and receptor blocking studies showed significant decreases in the production of TNFα, IL‐1β, and IL‐8 after blocking FcγRIIa, but not after blocking FcγRIII. Conclusion These findings represent a possible mechanism for perpetuation of joint inflammation in the subgroup of arthritis patients with high levels of anti‐CII. Blockade of FcγRIIa and suppression of synovial macrophages are conceivable treatment options in such patients.