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Interleukin-4 protects against a genetically linked lupus-like autoimmune syndrome.

Santiago ML, Fossati L, Jacquet C, Müller W, Izui S, Reininger L - J. Exp. Med. (1997)

Bottom Line: Interleukin-4 (IL-4) provides support for humoral immune responses through upregulation of T helper (Th) type 2 cell differentiation, but it is not known whether IL-4 promotes antibody-mediated autoimmune diseases such as systemic lupus erythematosus (SLE).Here, we show that the constitutive expression of an IL-4 transgene by B cells completely prevents the development of lethal lupus-like glomerulonephritis in the (NZW x C57BL/6.Yaa)F1 murine model of SLE.Thus, IL-4 prevents the development of this lupus-like autoimmune disease, most likely by downregulating the appearance of Th1-mediated IgG subclasses of autoantibodies such as the IgG3 autoantibodies which have been shown to be especially nephritogenic.

View Article: PubMed Central - PubMed

Affiliation: Institut National de la Santé et de la Recherche Médicale U 291, F-34197 Montpellier, France.

ABSTRACT
Interleukin-4 (IL-4) provides support for humoral immune responses through upregulation of T helper (Th) type 2 cell differentiation, but it is not known whether IL-4 promotes antibody-mediated autoimmune diseases such as systemic lupus erythematosus (SLE). Here, we show that the constitutive expression of an IL-4 transgene by B cells completely prevents the development of lethal lupus-like glomerulonephritis in the (NZW x C57BL/6.Yaa)F1 murine model of SLE. This was associated with marked changes in the serum levels of IgG subclasses, rather than in the total levels of anti-DNA antibodies, with a lack of IgG3, a decrease of IgG2a, and an increase in IgG1 subclasses, and by a strong reduction in the serum levels of gp70-anti-gp70 immune complexes. This effect of the transgene appears to result from a modulation of the Th1 versus Th2 autoimmune response, since the protected mice displayed comparably modified IgG2a and IgG3 antibody response against exogenous T cell-dependent antigen, but not against T cell-independent antigens. Thus, IL-4 prevents the development of this lupus-like autoimmune disease, most likely by downregulating the appearance of Th1-mediated IgG subclasses of autoantibodies such as the IgG3 autoantibodies which have been shown to be especially nephritogenic.

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Effect of the IL-4 transgene expression on the spontaneous  autoantibody and IgG production in lupus-prone NZW × (pEP-IL-4 ×  B6.Yaa) mice. (A) Levels of serum IgG anti–DNA antibodies in IL-4  transgenic (Tg) and nontransgenic (N-Tg) male mice 4 and 8 mo-old. Results are expressed in U/ml by reference to a standard curve obtained with  a serum pool of 3–4-mo-old MRL-lpr/lpr mice. (B) IgG1, IgG2a, and  IgG3 subclass distribution of anti–DNA antibodies in the sera of 6-mo-old  IL-4 transgenic and nontransgenic male mice. Twofold serum dilutions  were tested starting with 1:100 dilution. The titers are the highest dilutions still giving a positive signal in the ELISA. (C) Serum levels of IgG1,  IgG2a, and IgG3 subclasses in 4-mo-old IL-4 transgenic and nontransgenic male mice. Ig concentrations are expressed in mg/ml. The means of  16 mice (± 1 SD) are represented. (D) Serum levels of gp70 IC in IL-4  transgenic and nontransgenic male mice 4 and 8 mo old. Results are expressed in μg/ml. Each symbol represents the value from individual animals. The median values are indicated as horizontal lines.
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Figure 2: Effect of the IL-4 transgene expression on the spontaneous autoantibody and IgG production in lupus-prone NZW × (pEP-IL-4 × B6.Yaa) mice. (A) Levels of serum IgG anti–DNA antibodies in IL-4 transgenic (Tg) and nontransgenic (N-Tg) male mice 4 and 8 mo-old. Results are expressed in U/ml by reference to a standard curve obtained with a serum pool of 3–4-mo-old MRL-lpr/lpr mice. (B) IgG1, IgG2a, and IgG3 subclass distribution of anti–DNA antibodies in the sera of 6-mo-old IL-4 transgenic and nontransgenic male mice. Twofold serum dilutions were tested starting with 1:100 dilution. The titers are the highest dilutions still giving a positive signal in the ELISA. (C) Serum levels of IgG1, IgG2a, and IgG3 subclasses in 4-mo-old IL-4 transgenic and nontransgenic male mice. Ig concentrations are expressed in mg/ml. The means of 16 mice (± 1 SD) are represented. (D) Serum levels of gp70 IC in IL-4 transgenic and nontransgenic male mice 4 and 8 mo old. Results are expressed in μg/ml. Each symbol represents the value from individual animals. The median values are indicated as horizontal lines.

Mentions: The protective effect of the IL-4 transgene did not appear to be associated with a reduction of total serum IgG anti-DNA autoantibodies (although titers were 1.5-fold lower in IL-4 transgenic mice; 4 mo: P <0.05, 8 mo: P >0.1, Fig. 2 A), but rather with marked changes in IgG subclasses (Fig. 2 B). In fact, IgG3 anti-DNA antibodies were barely detectable in transgenic mice (P <0.0001) even at one year of age (data not shown), and IgG2a anti-DNA antibodies were reduced (P <0.001), while IgG1 anti-DNA levels were increased in the transgenic mice (P <0.05). Total IgG subclass levels also differed in transgenic mice in a comparable way; there was a two– to fourfold increase of IgG1 (P <0.005), but two-fold and 10-fold decreases of IgG2a (P <0.001) and IgG3 (P <0.0001), respectively (Fig. 2 C).


Interleukin-4 protects against a genetically linked lupus-like autoimmune syndrome.

Santiago ML, Fossati L, Jacquet C, Müller W, Izui S, Reininger L - J. Exp. Med. (1997)

Effect of the IL-4 transgene expression on the spontaneous  autoantibody and IgG production in lupus-prone NZW × (pEP-IL-4 ×  B6.Yaa) mice. (A) Levels of serum IgG anti–DNA antibodies in IL-4  transgenic (Tg) and nontransgenic (N-Tg) male mice 4 and 8 mo-old. Results are expressed in U/ml by reference to a standard curve obtained with  a serum pool of 3–4-mo-old MRL-lpr/lpr mice. (B) IgG1, IgG2a, and  IgG3 subclass distribution of anti–DNA antibodies in the sera of 6-mo-old  IL-4 transgenic and nontransgenic male mice. Twofold serum dilutions  were tested starting with 1:100 dilution. The titers are the highest dilutions still giving a positive signal in the ELISA. (C) Serum levels of IgG1,  IgG2a, and IgG3 subclasses in 4-mo-old IL-4 transgenic and nontransgenic male mice. Ig concentrations are expressed in mg/ml. The means of  16 mice (± 1 SD) are represented. (D) Serum levels of gp70 IC in IL-4  transgenic and nontransgenic male mice 4 and 8 mo old. Results are expressed in μg/ml. Each symbol represents the value from individual animals. The median values are indicated as horizontal lines.
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Figure 2: Effect of the IL-4 transgene expression on the spontaneous autoantibody and IgG production in lupus-prone NZW × (pEP-IL-4 × B6.Yaa) mice. (A) Levels of serum IgG anti–DNA antibodies in IL-4 transgenic (Tg) and nontransgenic (N-Tg) male mice 4 and 8 mo-old. Results are expressed in U/ml by reference to a standard curve obtained with a serum pool of 3–4-mo-old MRL-lpr/lpr mice. (B) IgG1, IgG2a, and IgG3 subclass distribution of anti–DNA antibodies in the sera of 6-mo-old IL-4 transgenic and nontransgenic male mice. Twofold serum dilutions were tested starting with 1:100 dilution. The titers are the highest dilutions still giving a positive signal in the ELISA. (C) Serum levels of IgG1, IgG2a, and IgG3 subclasses in 4-mo-old IL-4 transgenic and nontransgenic male mice. Ig concentrations are expressed in mg/ml. The means of 16 mice (± 1 SD) are represented. (D) Serum levels of gp70 IC in IL-4 transgenic and nontransgenic male mice 4 and 8 mo old. Results are expressed in μg/ml. Each symbol represents the value from individual animals. The median values are indicated as horizontal lines.
Mentions: The protective effect of the IL-4 transgene did not appear to be associated with a reduction of total serum IgG anti-DNA autoantibodies (although titers were 1.5-fold lower in IL-4 transgenic mice; 4 mo: P <0.05, 8 mo: P >0.1, Fig. 2 A), but rather with marked changes in IgG subclasses (Fig. 2 B). In fact, IgG3 anti-DNA antibodies were barely detectable in transgenic mice (P <0.0001) even at one year of age (data not shown), and IgG2a anti-DNA antibodies were reduced (P <0.001), while IgG1 anti-DNA levels were increased in the transgenic mice (P <0.05). Total IgG subclass levels also differed in transgenic mice in a comparable way; there was a two– to fourfold increase of IgG1 (P <0.005), but two-fold and 10-fold decreases of IgG2a (P <0.001) and IgG3 (P <0.0001), respectively (Fig. 2 C).

Bottom Line: Interleukin-4 (IL-4) provides support for humoral immune responses through upregulation of T helper (Th) type 2 cell differentiation, but it is not known whether IL-4 promotes antibody-mediated autoimmune diseases such as systemic lupus erythematosus (SLE).Here, we show that the constitutive expression of an IL-4 transgene by B cells completely prevents the development of lethal lupus-like glomerulonephritis in the (NZW x C57BL/6.Yaa)F1 murine model of SLE.Thus, IL-4 prevents the development of this lupus-like autoimmune disease, most likely by downregulating the appearance of Th1-mediated IgG subclasses of autoantibodies such as the IgG3 autoantibodies which have been shown to be especially nephritogenic.

View Article: PubMed Central - PubMed

Affiliation: Institut National de la Santé et de la Recherche Médicale U 291, F-34197 Montpellier, France.

ABSTRACT
Interleukin-4 (IL-4) provides support for humoral immune responses through upregulation of T helper (Th) type 2 cell differentiation, but it is not known whether IL-4 promotes antibody-mediated autoimmune diseases such as systemic lupus erythematosus (SLE). Here, we show that the constitutive expression of an IL-4 transgene by B cells completely prevents the development of lethal lupus-like glomerulonephritis in the (NZW x C57BL/6.Yaa)F1 murine model of SLE. This was associated with marked changes in the serum levels of IgG subclasses, rather than in the total levels of anti-DNA antibodies, with a lack of IgG3, a decrease of IgG2a, and an increase in IgG1 subclasses, and by a strong reduction in the serum levels of gp70-anti-gp70 immune complexes. This effect of the transgene appears to result from a modulation of the Th1 versus Th2 autoimmune response, since the protected mice displayed comparably modified IgG2a and IgG3 antibody response against exogenous T cell-dependent antigen, but not against T cell-independent antigens. Thus, IL-4 prevents the development of this lupus-like autoimmune disease, most likely by downregulating the appearance of Th1-mediated IgG subclasses of autoantibodies such as the IgG3 autoantibodies which have been shown to be especially nephritogenic.

Show MeSH
Related in: MedlinePlus