Development of spontaneous multisystem autoimmune disease and hypersensitivity to antibody-induced inflammation in Fc gamma receptor IIa-transgenic mice

Sardjono, CT; Mottram, PL; van de Velde, NC; Powell, MS; Power, D; Slocombe, RF; Wicks, IP; Campbell, IK; McKenzie, SE; Brooks, M; Stevenson, AW; Hogarth, PM

Author(s): Sardjono, CT; Mottram, PL; van de Velde, NC; Powell, MS; Power, D; Slocombe, RF; Wicks, IP; Campbell, IK; McKenzie, SE; Brooks, M; Stevenson, AW; Hogarth, PM;
Details: Publication Year 2005-10,Volume 52,Issue #10,Page 3220-3229
Journal Title: ARTHRITIS AND RHEUMATISM
Publication Type: Journal Article
Abstract: Objective. The major human Fc receptor, Fc gamma RIIa, is the most widespread activating FcR. Our aim was to determine the role of Fc gamma RIIa in a transgenic mouse model of immune complex-mediated autoimmunity and to characterize the development of spontaneous autoimmune disease. Methods. Arthritis was induced in normal and Fc gamma RIIa-transgenic mice by immunization with type 11 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. Results. Fc gamma RIIa-transgenic mice developed collagen-induced arthritis (CIA) more rapidly than did archetypal CIA-sensitive DBA/1 (H-2(q)) mice, while non-transgenic 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 Fc gamma RIIa-transgenic mice than in nontransgenic animals. In addition, most immune complexinduced production of tumor necrosis factor a by activated macrophages occurred via Fc gamma RIIa, 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. Conclusion. 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 Fc gamma RIIa is a very important factor in the pathogenesis of autoimmune inflammation and a possible target for therapeutic intervention.
Publisher: WILEY-LISS
Keywords: COLLAGEN-INDUCED ARTHRITIS; SYSTEMIC-LUPUS-ERYTHEMATOSUS; RHEUMATOID-ARTHRITIS; TNF-ALPHA; MOUSE MODELS; H-2(B) MICE; DBA/1 MICE; IN-VIVO; EXPRESSION; RIIA
Publisher's Version: https://doi.org/10.1002/art.21344
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Creation Date: 2005-10-01 12:00:00