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Antinuclear autoantibodies and lupus nephritis in transgenic mice expressing interferon gamma in the epidermis.

Seery JP, Carroll JM, Cattell V, Watt FM - J. Exp. Med. (1997)

Bottom Line: The mechanism and site of production of these autoantibodies is unknown, but there is evidence that interferon (IFN) gamma plays a key role.There was no evidence of organ-specific autoimmunity, but transgenic animals produced autoantibodies against dsDNA and histones.Our findings are consistent with a central role for the skin immune system, acting under the influence of IFN-gamma, in the pathogenesis of SLE.

View Article: PubMed Central - PubMed

Affiliation: Keratinocyte Laboratory, Imperial Cancer Research Fund, London WC2A 3PX, United Kingdom.

ABSTRACT
Systemic lupus erythematosus (SLE) is a potentially fatal non-organ-specific autoimmune disease that predominantly affects women. Features of the disease include inflammatory skin lesions and widespread organ damage caused by deposition of anti-dsDNA autoantibodies. The mechanism and site of production of these autoantibodies is unknown, but there is evidence that interferon (IFN) gamma plays a key role. We have used the involucrin promoter to overexpress IFN-gamma in the suprabasal layers of transgenic mouse epidermis. There was no evidence of organ-specific autoimmunity, but transgenic animals produced autoantibodies against dsDNA and histones. Autoantibody levels in female mice were significantly higher than in male transgenic mice. Furthermore, there was IgG deposition in the glomeruli of all female mice and histological evidence of severe proliferative glomerulonephritis in a proportion of these animals. Our findings are consistent with a central role for the skin immune system, acting under the influence of IFN-gamma, in the pathogenesis of SLE.

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Glomerular immunopathology in female transgenic mice.  Immunofluorescence staining of kidney tissue showing deposits of IgG in  the mesangium (A) and globally on capillary walls (B). Hematoxylin and  eosin stained glomerulus from a 10-mo-old female transgenic mouse (C)  and a glomerulus from an age- and sex-matched negative littermate control (D). In C, note diffuse proliferative GN with hypercellularity, nuclear  fragmentation, and reduction in capillary lumens. There were no significant tubulointerstitial or vascular lesions. (E) Electron micrograph of kidney tissue from a 4-mo-old female transgenic mouse shows electron-dense deposits in a subendothelial-mesangial distribution (arrow) and a  narrowed capillary lumen (▵). Scale bar (A–D): 60 μm; (E): 1.5 μm.
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Figure 3: Glomerular immunopathology in female transgenic mice. Immunofluorescence staining of kidney tissue showing deposits of IgG in the mesangium (A) and globally on capillary walls (B). Hematoxylin and eosin stained glomerulus from a 10-mo-old female transgenic mouse (C) and a glomerulus from an age- and sex-matched negative littermate control (D). In C, note diffuse proliferative GN with hypercellularity, nuclear fragmentation, and reduction in capillary lumens. There were no significant tubulointerstitial or vascular lesions. (E) Electron micrograph of kidney tissue from a 4-mo-old female transgenic mouse shows electron-dense deposits in a subendothelial-mesangial distribution (arrow) and a narrowed capillary lumen (▵). Scale bar (A–D): 60 μm; (E): 1.5 μm.

Mentions: Anti-dsDNA antibodies are known to deposit in the kidneys of 60–70% of SLE patients and to cause GN (3, 4). We therefore examined the kidneys of the transgenic mice for evidence of autoantibody deposition and organ damage (Fig. 3). Immunohistochemistry of kidneys showed dense deposits of IgG within the glomeruli in all female IFN-γ transgenic mice examined (n = 5, Table 1). As in human lupus-nephritis, both mesangial (Fig. 3 A) and capillary (Fig. 3 B) patterns of Ig deposition were found. Five out of eight male mice tested had evidence of Ig deposits in the glomeruli (Table 1).


Antinuclear autoantibodies and lupus nephritis in transgenic mice expressing interferon gamma in the epidermis.

Seery JP, Carroll JM, Cattell V, Watt FM - J. Exp. Med. (1997)

Glomerular immunopathology in female transgenic mice.  Immunofluorescence staining of kidney tissue showing deposits of IgG in  the mesangium (A) and globally on capillary walls (B). Hematoxylin and  eosin stained glomerulus from a 10-mo-old female transgenic mouse (C)  and a glomerulus from an age- and sex-matched negative littermate control (D). In C, note diffuse proliferative GN with hypercellularity, nuclear  fragmentation, and reduction in capillary lumens. There were no significant tubulointerstitial or vascular lesions. (E) Electron micrograph of kidney tissue from a 4-mo-old female transgenic mouse shows electron-dense deposits in a subendothelial-mesangial distribution (arrow) and a  narrowed capillary lumen (▵). Scale bar (A–D): 60 μm; (E): 1.5 μm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2199116&req=5

Figure 3: Glomerular immunopathology in female transgenic mice. Immunofluorescence staining of kidney tissue showing deposits of IgG in the mesangium (A) and globally on capillary walls (B). Hematoxylin and eosin stained glomerulus from a 10-mo-old female transgenic mouse (C) and a glomerulus from an age- and sex-matched negative littermate control (D). In C, note diffuse proliferative GN with hypercellularity, nuclear fragmentation, and reduction in capillary lumens. There were no significant tubulointerstitial or vascular lesions. (E) Electron micrograph of kidney tissue from a 4-mo-old female transgenic mouse shows electron-dense deposits in a subendothelial-mesangial distribution (arrow) and a narrowed capillary lumen (▵). Scale bar (A–D): 60 μm; (E): 1.5 μm.
Mentions: Anti-dsDNA antibodies are known to deposit in the kidneys of 60–70% of SLE patients and to cause GN (3, 4). We therefore examined the kidneys of the transgenic mice for evidence of autoantibody deposition and organ damage (Fig. 3). Immunohistochemistry of kidneys showed dense deposits of IgG within the glomeruli in all female IFN-γ transgenic mice examined (n = 5, Table 1). As in human lupus-nephritis, both mesangial (Fig. 3 A) and capillary (Fig. 3 B) patterns of Ig deposition were found. Five out of eight male mice tested had evidence of Ig deposits in the glomeruli (Table 1).

Bottom Line: The mechanism and site of production of these autoantibodies is unknown, but there is evidence that interferon (IFN) gamma plays a key role.There was no evidence of organ-specific autoimmunity, but transgenic animals produced autoantibodies against dsDNA and histones.Our findings are consistent with a central role for the skin immune system, acting under the influence of IFN-gamma, in the pathogenesis of SLE.

View Article: PubMed Central - PubMed

Affiliation: Keratinocyte Laboratory, Imperial Cancer Research Fund, London WC2A 3PX, United Kingdom.

ABSTRACT
Systemic lupus erythematosus (SLE) is a potentially fatal non-organ-specific autoimmune disease that predominantly affects women. Features of the disease include inflammatory skin lesions and widespread organ damage caused by deposition of anti-dsDNA autoantibodies. The mechanism and site of production of these autoantibodies is unknown, but there is evidence that interferon (IFN) gamma plays a key role. We have used the involucrin promoter to overexpress IFN-gamma in the suprabasal layers of transgenic mouse epidermis. There was no evidence of organ-specific autoimmunity, but transgenic animals produced autoantibodies against dsDNA and histones. Autoantibody levels in female mice were significantly higher than in male transgenic mice. Furthermore, there was IgG deposition in the glomeruli of all female mice and histological evidence of severe proliferative glomerulonephritis in a proportion of these animals. Our findings are consistent with a central role for the skin immune system, acting under the influence of IFN-gamma, in the pathogenesis of SLE.

Show MeSH
Related in: MedlinePlus