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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 on antigen-specific and nonspecific antibody production during T cell–dependent and T cell–independent antibody responses in NZW × (pEP-IL-4 × B6.Yaa) mice. IgM and  IgG subclass distribution of anti–HGG (A) and anti–NIP (B) specific antibodies in 3–5-mo-old IL-4 transgenic (closed circle) and nontransgenic  (open circle) male mice 10 d after immunization with T cell–dependent antigen HGG, or T cell–independent antigen NIP-Ficoll. IgG anti–HGG  antibodies were undetectable in sera from both transgenic and nontransgenic mice before immunization. While IgG anti–NIP antibodies were  undetectable, sera from both groups of mice before immunization exhibited significant and comparable titers of IgM anti–NIP antibodies (detectable at a serum dilution of 1:800), and their levels increased ∼eightfold after immunization. Each symbol represents the value from one individual.  (C) LPS-induced polyclonal IgM and IgG subclass responses in 6-mo-old  IL-4 transgenic (right) and nontransgenic mice (left). IgM and IgG subclass  levels determined 8 and 15 d, respectively, after the LPS injection (filled  column), were compared with those before the injection (open column).  The number in parentheses indicates the fold-increase of each Ig isotype  after the LPS injection. The means of five mice (± 1 SD) are shown.
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Figure 3: Effect of the IL-4 transgene on antigen-specific and nonspecific antibody production during T cell–dependent and T cell–independent antibody responses in NZW × (pEP-IL-4 × B6.Yaa) mice. IgM and IgG subclass distribution of anti–HGG (A) and anti–NIP (B) specific antibodies in 3–5-mo-old IL-4 transgenic (closed circle) and nontransgenic (open circle) male mice 10 d after immunization with T cell–dependent antigen HGG, or T cell–independent antigen NIP-Ficoll. IgG anti–HGG antibodies were undetectable in sera from both transgenic and nontransgenic mice before immunization. While IgG anti–NIP antibodies were undetectable, sera from both groups of mice before immunization exhibited significant and comparable titers of IgM anti–NIP antibodies (detectable at a serum dilution of 1:800), and their levels increased ∼eightfold after immunization. Each symbol represents the value from one individual. (C) LPS-induced polyclonal IgM and IgG subclass responses in 6-mo-old IL-4 transgenic (right) and nontransgenic mice (left). IgM and IgG subclass levels determined 8 and 15 d, respectively, after the LPS injection (filled column), were compared with those before the injection (open column). The number in parentheses indicates the fold-increase of each Ig isotype after the LPS injection. The means of five mice (± 1 SD) are shown.

Mentions: The changes in IgG subclasses may result from a direct effect of the transgenic IL-4 expressed by the B cells on these cells, or from an IL-4 action modulating the Th1 and Th2 responses; IFN-γ produced by Th1 cells and IL-4 secreted by Th2 cells are known to regulate reciprocally IgG class switching, the former promoting the Ig switch to IgG2a and IgG3 subclasses, and the latter to the IgG1 subclass (20, 21). To address this question, transgenic mice and their nontransgenic littermates were immunized either with the T cell–dependent antigen, HGG, the T cell-independent antigen NIPFicoll, or stimulated by the injection of LPS, a polyclonal B cell activator. Transgenic mice developed a limited IgG2a and IgG3 response (P <0.005), but a comparable IgG1 anti–HGG response (Fig. 3 A), whereas no significant differences in IgG subclass responses were observed in the anti– NIP antibody response in both groups of mice (Fig. 3 B). In addition, the pattern of antigen-nonspecific polyclonal Ig production following the injection of LPS was essentially identical in both groups of mice, except for a greater increase of IgG3 in transgenic mice, which is likely to be related to the fact that basal levels of IgG3 were markedly diminished in the latter mice (Fig. 3 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 on antigen-specific and nonspecific antibody production during T cell–dependent and T cell–independent antibody responses in NZW × (pEP-IL-4 × B6.Yaa) mice. IgM and  IgG subclass distribution of anti–HGG (A) and anti–NIP (B) specific antibodies in 3–5-mo-old IL-4 transgenic (closed circle) and nontransgenic  (open circle) male mice 10 d after immunization with T cell–dependent antigen HGG, or T cell–independent antigen NIP-Ficoll. IgG anti–HGG  antibodies were undetectable in sera from both transgenic and nontransgenic mice before immunization. While IgG anti–NIP antibodies were  undetectable, sera from both groups of mice before immunization exhibited significant and comparable titers of IgM anti–NIP antibodies (detectable at a serum dilution of 1:800), and their levels increased ∼eightfold after immunization. Each symbol represents the value from one individual.  (C) LPS-induced polyclonal IgM and IgG subclass responses in 6-mo-old  IL-4 transgenic (right) and nontransgenic mice (left). IgM and IgG subclass  levels determined 8 and 15 d, respectively, after the LPS injection (filled  column), were compared with those before the injection (open column).  The number in parentheses indicates the fold-increase of each Ig isotype  after the LPS injection. The means of five mice (± 1 SD) are shown.
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Related In: Results  -  Collection

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Figure 3: Effect of the IL-4 transgene on antigen-specific and nonspecific antibody production during T cell–dependent and T cell–independent antibody responses in NZW × (pEP-IL-4 × B6.Yaa) mice. IgM and IgG subclass distribution of anti–HGG (A) and anti–NIP (B) specific antibodies in 3–5-mo-old IL-4 transgenic (closed circle) and nontransgenic (open circle) male mice 10 d after immunization with T cell–dependent antigen HGG, or T cell–independent antigen NIP-Ficoll. IgG anti–HGG antibodies were undetectable in sera from both transgenic and nontransgenic mice before immunization. While IgG anti–NIP antibodies were undetectable, sera from both groups of mice before immunization exhibited significant and comparable titers of IgM anti–NIP antibodies (detectable at a serum dilution of 1:800), and their levels increased ∼eightfold after immunization. Each symbol represents the value from one individual. (C) LPS-induced polyclonal IgM and IgG subclass responses in 6-mo-old IL-4 transgenic (right) and nontransgenic mice (left). IgM and IgG subclass levels determined 8 and 15 d, respectively, after the LPS injection (filled column), were compared with those before the injection (open column). The number in parentheses indicates the fold-increase of each Ig isotype after the LPS injection. The means of five mice (± 1 SD) are shown.
Mentions: The changes in IgG subclasses may result from a direct effect of the transgenic IL-4 expressed by the B cells on these cells, or from an IL-4 action modulating the Th1 and Th2 responses; IFN-γ produced by Th1 cells and IL-4 secreted by Th2 cells are known to regulate reciprocally IgG class switching, the former promoting the Ig switch to IgG2a and IgG3 subclasses, and the latter to the IgG1 subclass (20, 21). To address this question, transgenic mice and their nontransgenic littermates were immunized either with the T cell–dependent antigen, HGG, the T cell-independent antigen NIPFicoll, or stimulated by the injection of LPS, a polyclonal B cell activator. Transgenic mice developed a limited IgG2a and IgG3 response (P <0.005), but a comparable IgG1 anti–HGG response (Fig. 3 A), whereas no significant differences in IgG subclass responses were observed in the anti– NIP antibody response in both groups of mice (Fig. 3 B). In addition, the pattern of antigen-nonspecific polyclonal Ig production following the injection of LPS was essentially identical in both groups of mice, except for a greater increase of IgG3 in transgenic mice, which is likely to be related to the fact that basal levels of IgG3 were markedly diminished in the latter mice (Fig. 3 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