Surface-bound anti-type II collagen-containing immune complexes induce production of tumor necrosis factor alpha, interleukin-1beta, and interleukin-8 from peripheral blood monocytes via Fc gamma receptor IIA: a potential pathophysiologic mechanism for humoral anti-type II collagen immunity in arthritis

Arthritis Rheum. 2006 Jun;54(6):1759-71. doi: 10.1002/art.21892.


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 Fc gamma receptors (Fc gammaR) 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 alpha (TNFalpha), interleukin-1beta (IL-1beta), and IL-8. We found a close correlation between enzyme-linked immunosorbent assay optical density values and induction of TNFalpha (r = 0.862, P < 0.0001), IL-1beta (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 TNFalpha, IL-1beta, and IL-8 after blocking Fc gammaRIIa, but not after blocking Fc gammaRIII.

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 Fc gammaRIIa and suppression of synovial macrophages are conceivable treatment options in such patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antigen-Antibody Complex / immunology*
  • Antigens, CD / physiology*
  • Arthritis / immunology*
  • Collagen Type II / immunology*
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Humans
  • Interleukin-1 / biosynthesis*
  • Interleukin-8 / biosynthesis*
  • Male
  • Middle Aged
  • Monocytes / immunology
  • Monocytes / metabolism*
  • Receptors, IgG / physiology*
  • Tumor Necrosis Factor-alpha / biosynthesis*


  • Antigen-Antibody Complex
  • Antigens, CD
  • Collagen Type II
  • Fc gamma receptor IIA
  • Interleukin-1
  • Interleukin-8
  • Receptors, IgG
  • Tumor Necrosis Factor-alpha