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

Abstract

OBJECTIVE:

The major human Fc receptor, FcgammaRIIa, is the most widespread activating FcR. Our aim was to determine the role of FcgammaRIIa 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 FcgammaRIIa-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.

RESULTS:

FcgammaRIIa-transgenic mice developed collagen-induced arthritis (CIA) more rapidly than did archetypal CIA-sensitive DBA/1 (H-2q) mice, while nontransgenic C57BL/6 (H-2b) 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 FcgammaRIIa-transgenic mice than in nontransgenic animals. In addition, most immune complex-induced production of tumor necrosis factor alpha by activated macrophages occurred via FcgammaRIIa, 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 FcgammaRIIa is a very important factor in the pathogenesis of autoimmune inflammation and a possible target for therapeutic intervention.

• Authors: Caroline Tan Sardjono, Patricia L Mottram, Nicholas C van de Velde, Maree S Powell, David Power, Ronald F Slocombe, Ian P Wicks, Ian K Campbell, Steven E McKenzie, Mark Brooks, Andrew W Stevenson, P Mark Hogarth
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 52 Issue 10 Pg. 3220-9 (Oct 2005) ISSN: 0004-3591 [Print] United States
• PMID: 16200626 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Antinuclear
• Antigens, CD
• Fc gamma receptor IIA
• Histones
• Immunoglobulin G
• Receptors, IgG
• Tumor Necrosis Factor-alpha

Topics

• Animals
• Antibodies, Antinuclear (blood)
• Antigens, CD (genetics)
• Arthritis, Experimental (diagnostic imaging, genetics, immunology)
• Autoimmune Diseases (genetics, immunology)
• Disease Models, Animal
• Disease Susceptibility
• Female
• Glomerulonephritis (genetics, immunology)
• Histones (immunology)
• Humans
• Hypersensitivity (genetics, immunology)
• Immunoglobulin G (blood)
• Macrophages (immunology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Inbred DBA
• Mice, Transgenic
• Pneumonia (genetics, immunology)
• Pregnancy
• Radiography
• Receptors, IgG (genetics)
• Tumor Necrosis Factor-alpha (metabolism)