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




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.


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.


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.


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.