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Constitutive expression of interleukin (IL)-4 in vivo causes autoimmune-type disorders in mice.

Erb KJ, Rüger B, von Brevern M, Ryffel B, Schimpl A, Rivett K - J. Exp. Med. (1997)

Bottom Line: The transgenic (tg) expression of interleukin (IL)-4 under the control of a major histocompatibility complex (MHC) class I promoter leads to B cell hyperactivity in mice, characterized by increased B cell surface MHC class II and CD23 expression, elevated responsiveness of the B cells to polyclonal ex vivo stimulation, and increased immunoglobulin (Ig)G1 and IgE serum levels.Therefore the most likely explanation for the increased production of autoantibodies and the autoimmunelike disorders is that IL-4 acts directly on autoreactive B cells by expanding them in a polyclonal manner.Taken together our results show that inappropriate multi-organ expression of IL-4 in vivo leads to autoimmune-type disease in mice.

View Article: PubMed Central - PubMed

Affiliation: The Malaghan Institute of Medical Research, Department of Medicine, Wellington School of Medicine, New Zealand.

ABSTRACT
The transgenic (tg) expression of interleukin (IL)-4 under the control of a major histocompatibility complex (MHC) class I promoter leads to B cell hyperactivity in mice, characterized by increased B cell surface MHC class II and CD23 expression, elevated responsiveness of the B cells to polyclonal ex vivo stimulation, and increased immunoglobulin (Ig)G1 and IgE serum levels. Tg mice develop anemia, glomerulonephritis with complement and immune deposition in the glomeruli, and show increased production of autoantibodies. Treatment of IL-4 tg mice with anti-IL-4 neutralizing antibodies protected the mice from disease development, showing that IL-4 was responsible for the observed disorders. Deletion of superantigen responsive autoreactive T cells in the IL-4 tg mice was normal and treatment of mutant mice with deleting anti-CD4 antibodies failed to ablate the onset of autoimmune-like disease, suggesting that CD4+ T cells were not the primary cause of the disorders. Furthermore, the deletion of B cells reacting against MHC class I molecules was also normal in the IL-4 tg mice. Therefore the most likely explanation for the increased production of autoantibodies and the autoimmunelike disorders is that IL-4 acts directly on autoreactive B cells by expanding them in a polyclonal manner. Taken together our results show that inappropriate multi-organ expression of IL-4 in vivo leads to autoimmune-type disease in mice.

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ANA and ASMA test. The sections containing Hep 2 cells  (ANA) and rat gut (ASMA), were incubated with different concentrations  of mouse serum (shown is the result using a 1/30 dilution). The binding  of antibodies to the autoantigens was then detected by incubating the sections with rat anti–mouse Ig conjugated with FITC and analyzed under a  fluorescence microscope. Shown is a typical positive ANA and ASMA  staining using serum from a tg mouse (A), and a negative staining (B), using serum from a wt mouse.
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Figure 3: ANA and ASMA test. The sections containing Hep 2 cells (ANA) and rat gut (ASMA), were incubated with different concentrations of mouse serum (shown is the result using a 1/30 dilution). The binding of antibodies to the autoantigens was then detected by incubating the sections with rat anti–mouse Ig conjugated with FITC and analyzed under a fluorescence microscope. Shown is a typical positive ANA and ASMA staining using serum from a tg mouse (A), and a negative staining (B), using serum from a wt mouse.

Mentions: The association of autoimmune disease with elevated autoantibody titers lead us to analyze whether mutant mice had elevated levels of autoantibodies. For this purpose an ANA and ASMA test was used. Serum from IL-4 tg and control mice were incubated with sections of Hep 2 cells (ANA test) or rat gut (ASMA test). Bound autoantibodies were visualized by rat anti–mouse Ig-FITC under a fluorescence microscope. Fig. 3 shows a typical positive (A) and negative (B) ANA or ASMA staining. Antibody titers equal or greater to 1/30 (ANA) or 1/10 (ASMA) were scored positive. Fig. 4 summarizes the results of the ANA tests. The frequency of mice having detectable amounts of autoantibodies against nuclear as well as smooth muscle antigens (data not shown) were threefold higher in IL-4 tg mice than in littermate control mice both in younger and older mice. The average autoantibody titer of IL-4 tg mice scoring positive in both ANA and ASMA test was about two- to threefold higher than in littermate controls. Furthermore, there was no correlation between high total Ig titers and autoantibody production in IL-4 tg mice. In contrast, most of the control mice with the highest autoantibody titers also had the highest total Ig serum levels (data not shown).


Constitutive expression of interleukin (IL)-4 in vivo causes autoimmune-type disorders in mice.

Erb KJ, Rüger B, von Brevern M, Ryffel B, Schimpl A, Rivett K - J. Exp. Med. (1997)

ANA and ASMA test. The sections containing Hep 2 cells  (ANA) and rat gut (ASMA), were incubated with different concentrations  of mouse serum (shown is the result using a 1/30 dilution). The binding  of antibodies to the autoantigens was then detected by incubating the sections with rat anti–mouse Ig conjugated with FITC and analyzed under a  fluorescence microscope. Shown is a typical positive ANA and ASMA  staining using serum from a tg mouse (A), and a negative staining (B), using serum from a wt mouse.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2196114&req=5

Figure 3: ANA and ASMA test. The sections containing Hep 2 cells (ANA) and rat gut (ASMA), were incubated with different concentrations of mouse serum (shown is the result using a 1/30 dilution). The binding of antibodies to the autoantigens was then detected by incubating the sections with rat anti–mouse Ig conjugated with FITC and analyzed under a fluorescence microscope. Shown is a typical positive ANA and ASMA staining using serum from a tg mouse (A), and a negative staining (B), using serum from a wt mouse.
Mentions: The association of autoimmune disease with elevated autoantibody titers lead us to analyze whether mutant mice had elevated levels of autoantibodies. For this purpose an ANA and ASMA test was used. Serum from IL-4 tg and control mice were incubated with sections of Hep 2 cells (ANA test) or rat gut (ASMA test). Bound autoantibodies were visualized by rat anti–mouse Ig-FITC under a fluorescence microscope. Fig. 3 shows a typical positive (A) and negative (B) ANA or ASMA staining. Antibody titers equal or greater to 1/30 (ANA) or 1/10 (ASMA) were scored positive. Fig. 4 summarizes the results of the ANA tests. The frequency of mice having detectable amounts of autoantibodies against nuclear as well as smooth muscle antigens (data not shown) were threefold higher in IL-4 tg mice than in littermate control mice both in younger and older mice. The average autoantibody titer of IL-4 tg mice scoring positive in both ANA and ASMA test was about two- to threefold higher than in littermate controls. Furthermore, there was no correlation between high total Ig titers and autoantibody production in IL-4 tg mice. In contrast, most of the control mice with the highest autoantibody titers also had the highest total Ig serum levels (data not shown).

Bottom Line: The transgenic (tg) expression of interleukin (IL)-4 under the control of a major histocompatibility complex (MHC) class I promoter leads to B cell hyperactivity in mice, characterized by increased B cell surface MHC class II and CD23 expression, elevated responsiveness of the B cells to polyclonal ex vivo stimulation, and increased immunoglobulin (Ig)G1 and IgE serum levels.Therefore the most likely explanation for the increased production of autoantibodies and the autoimmunelike disorders is that IL-4 acts directly on autoreactive B cells by expanding them in a polyclonal manner.Taken together our results show that inappropriate multi-organ expression of IL-4 in vivo leads to autoimmune-type disease in mice.

View Article: PubMed Central - PubMed

Affiliation: The Malaghan Institute of Medical Research, Department of Medicine, Wellington School of Medicine, New Zealand.

ABSTRACT
The transgenic (tg) expression of interleukin (IL)-4 under the control of a major histocompatibility complex (MHC) class I promoter leads to B cell hyperactivity in mice, characterized by increased B cell surface MHC class II and CD23 expression, elevated responsiveness of the B cells to polyclonal ex vivo stimulation, and increased immunoglobulin (Ig)G1 and IgE serum levels. Tg mice develop anemia, glomerulonephritis with complement and immune deposition in the glomeruli, and show increased production of autoantibodies. Treatment of IL-4 tg mice with anti-IL-4 neutralizing antibodies protected the mice from disease development, showing that IL-4 was responsible for the observed disorders. Deletion of superantigen responsive autoreactive T cells in the IL-4 tg mice was normal and treatment of mutant mice with deleting anti-CD4 antibodies failed to ablate the onset of autoimmune-like disease, suggesting that CD4+ T cells were not the primary cause of the disorders. Furthermore, the deletion of B cells reacting against MHC class I molecules was also normal in the IL-4 tg mice. Therefore the most likely explanation for the increased production of autoantibodies and the autoimmunelike disorders is that IL-4 acts directly on autoreactive B cells by expanding them in a polyclonal manner. Taken together our results show that inappropriate multi-organ expression of IL-4 in vivo leads to autoimmune-type disease in mice.

Show MeSH
Related in: MedlinePlus