The major human Fc receptor, FcγRIIa, is the most widespread activating FcR. Our aim was to determine the role of FcγRIIa in a transgenic mouse model of immune complex–mediated autoimmunity and to characterize the development of spontaneous autoimmune disease.

Arthritis was induced in normal and FcγRIIa‐transgenic mice by immunization with type II collagen (CII) or by transfer of arthritogenic anti‐CII antibodies. Also, mice that spontaneously developed autoimmune disease were assessed by clinical scoring of affected limbs, histology and serology, and measurement of autoantibody titers and cytokine production.

FcγRIIa‐transgenic mice developed collagen‐induced arthritis (CIA) more rapidly than did archetypal CIA‐sensitive DBA/1 (H‐2^q) mice, while nontransgenic C57BL/6 (H‐2^b) mice did not develop CIA when similarly immunized. Passive transfer of a single dose of anti‐CII antibody induced a more rapid, severe arthritis in FcγRIIa‐transgenic mice than in nontransgenic animals. In addition, most immune complex–induced production of tumor necrosis factor α by activated macrophages occurred via FcγRIIa, not the endogenous mouse FcR. A spontaneous, multisystem autoimmune disease developed in aging (>20 weeks) transgenic mice (n = 25), with a 32% incidence of arthritis, and by 45 weeks, all mice had developed glomerulonephritis and pneumonitis, and most had antihistone antibodies. Elevated IgG2a levels were seen in mice with CIA and in those with spontaneous disease.

The presence of enhanced passive and induced autoimmunity, as well as the emergence of spontaneous autoimmune disease at 20–45 weeks of age, suggest that FcγRIIa is a very important factor in the pathogenesis of autoimmune inflammation and a possible target for therapeutic intervention.