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.
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.


CONCLUSIONS
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.
Mullazehi
Mohammed
M
Uppsala University, Uppsala, Sweden.
Mathsson
Linda
L
Lampa
Jon
J
Rönnelid
Johan
J
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000936:Antigen-Antibody Complex / Q000276:immunology*; D015703:Antigens, CD / Q000502:physiology*; D001168:Arthritis / Q000276:immunology*; D024043:Collagen Type II / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis*; D016209:Interleukin-8 / Q000096:biosynthesis*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology / Q000378:metabolism*; D017452:Receptors, IgG / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D000936:Antigen-Antibody Complex; D015703:Antigens, CD; D024043:Collagen Type II; C080568:Fc gamma receptor IIA; D007375:Interleukin-1; D016209:Interleukin-8; D017452:Receptors, IgG; D014409:Tumor Necrosis Factor-alpha