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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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Survival rate of IL-4 tg mice after in vivo anti-CD4 (A) and  anti-IL-4 neutralizing antibody (B) treatment. At 1 wk of age IL-4 tg and  littermate control mice were injected with anti-CD4 antibodies (tg: n =  11; wt: n = 8) for 8 wk and anti-IL-4 neutralizing antibodies (11B11) for  7 wk (tg: n = 7; wt: n = 9). During this time the numbers of dead mice  were recorded. Shown are the survival rates of treated versus untreated  control and IL-4 tg mice.
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Figure 6: Survival rate of IL-4 tg mice after in vivo anti-CD4 (A) and anti-IL-4 neutralizing antibody (B) treatment. At 1 wk of age IL-4 tg and littermate control mice were injected with anti-CD4 antibodies (tg: n = 11; wt: n = 8) for 8 wk and anti-IL-4 neutralizing antibodies (11B11) for 7 wk (tg: n = 7; wt: n = 9). During this time the numbers of dead mice were recorded. Shown are the survival rates of treated versus untreated control and IL-4 tg mice.

Mentions: Even though negative selection of autoreactive T cells seems to have been normal in the IL-4 tg mice, it is possible that activated autoreactive B cells could interact with a small number of residual autoreactive T cells. These T cells could then further enhance the production of autoantibodies by providing help to autoreactive B cells, thus causing the autoimmune disorders. To address this question, we treated 11 tg and 8 control mice with anti-CD4 for 8 wk with a weekly dose of 1 mg of antibodies injected i.p. (starting at 3–4 d of age). Less than 2% residual CD4 T cells could be detected after the antibody treatment (data not shown). Fig. 6 A shows that 75% of the CD4 depleted IL-4 tg mice survived versus only 45% in the untreated age matched control mutant mice. However, the increased survival was only reflected by a marginal increase in hematocrit (0.33 ± 0.6 in treated mice versus 0.25 ± 0.7 in untreated mice). The treated control mice had similar hematocrit counts to untreated controls showing that the injection of anti-CD4 antibodies had no direct effect on hematocrit counts (data not shown). Interestingly, there was no difference between IL-4 tg mice treated with the anti-CD4 antibodies and non treated IL-4 tg mice in respect to extramedullary hematopoiesis in spleen and liver respectively. The IL-4 tg mice treated with antiCD4 antibodies also developed severe glomerulonephritis (Table 3 and 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)

Survival rate of IL-4 tg mice after in vivo anti-CD4 (A) and  anti-IL-4 neutralizing antibody (B) treatment. At 1 wk of age IL-4 tg and  littermate control mice were injected with anti-CD4 antibodies (tg: n =  11; wt: n = 8) for 8 wk and anti-IL-4 neutralizing antibodies (11B11) for  7 wk (tg: n = 7; wt: n = 9). During this time the numbers of dead mice  were recorded. Shown are the survival rates of treated versus untreated  control and IL-4 tg mice.
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Related In: Results  -  Collection

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Figure 6: Survival rate of IL-4 tg mice after in vivo anti-CD4 (A) and anti-IL-4 neutralizing antibody (B) treatment. At 1 wk of age IL-4 tg and littermate control mice were injected with anti-CD4 antibodies (tg: n = 11; wt: n = 8) for 8 wk and anti-IL-4 neutralizing antibodies (11B11) for 7 wk (tg: n = 7; wt: n = 9). During this time the numbers of dead mice were recorded. Shown are the survival rates of treated versus untreated control and IL-4 tg mice.
Mentions: Even though negative selection of autoreactive T cells seems to have been normal in the IL-4 tg mice, it is possible that activated autoreactive B cells could interact with a small number of residual autoreactive T cells. These T cells could then further enhance the production of autoantibodies by providing help to autoreactive B cells, thus causing the autoimmune disorders. To address this question, we treated 11 tg and 8 control mice with anti-CD4 for 8 wk with a weekly dose of 1 mg of antibodies injected i.p. (starting at 3–4 d of age). Less than 2% residual CD4 T cells could be detected after the antibody treatment (data not shown). Fig. 6 A shows that 75% of the CD4 depleted IL-4 tg mice survived versus only 45% in the untreated age matched control mutant mice. However, the increased survival was only reflected by a marginal increase in hematocrit (0.33 ± 0.6 in treated mice versus 0.25 ± 0.7 in untreated mice). The treated control mice had similar hematocrit counts to untreated controls showing that the injection of anti-CD4 antibodies had no direct effect on hematocrit counts (data not shown). Interestingly, there was no difference between IL-4 tg mice treated with the anti-CD4 antibodies and non treated IL-4 tg mice in respect to extramedullary hematopoiesis in spleen and liver respectively. The IL-4 tg mice treated with antiCD4 antibodies also developed severe glomerulonephritis (Table 3 and 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