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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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Prevention by the IL-4 transgene of the spontaneous development of lupus-like glomerulonephritis in lupus-prone NZW × (pEPIL-4 × B6.Yaa) mice. (A) Increased expression of MHC class II molecules on surface IgM+ B cells in 2-mo-old NZW × (pEP-IL-4 ×  B6.Yaa) male mice bearing the IL-4 transgene, as compared with nontransgenic littermates. Spleen cells were stained with FITC-labeled anti– mouse μ chain mAb, and then incubated in absence (normal line) or in  presence (bold line) of biotinylated anti-I-A (upper panel) or anti-I-E (lower  panel) mAb's, followed by PE-conjugated avidin. (B) Cumulative mortality with glomerulonephritis in IL-4 transgenic (n = 38) (closed circle) and  non transgenic (n = 35) (open circle) male mice. (C) Representative histological appearance of glomeruli from 8-mo-old IL-4 transgenic and nontransgenic male mice. Note increased glomerular cellularity and obliteration of the glomerular architecture in nontransgenic males, which contrast  with the minimal alterations in glomeruli from transgenic mice. The tissues were stained with periodic acid-Schiff reagent (×200).
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Figure 1: Prevention by the IL-4 transgene of the spontaneous development of lupus-like glomerulonephritis in lupus-prone NZW × (pEPIL-4 × B6.Yaa) mice. (A) Increased expression of MHC class II molecules on surface IgM+ B cells in 2-mo-old NZW × (pEP-IL-4 × B6.Yaa) male mice bearing the IL-4 transgene, as compared with nontransgenic littermates. Spleen cells were stained with FITC-labeled anti– mouse μ chain mAb, and then incubated in absence (normal line) or in presence (bold line) of biotinylated anti-I-A (upper panel) or anti-I-E (lower panel) mAb's, followed by PE-conjugated avidin. (B) Cumulative mortality with glomerulonephritis in IL-4 transgenic (n = 38) (closed circle) and non transgenic (n = 35) (open circle) male mice. (C) Representative histological appearance of glomeruli from 8-mo-old IL-4 transgenic and nontransgenic male mice. Note increased glomerular cellularity and obliteration of the glomerular architecture in nontransgenic males, which contrast with the minimal alterations in glomeruli from transgenic mice. The tissues were stained with periodic acid-Schiff reagent (×200).

Mentions: To determine whether constitutive IL-4 transgene expression may influence the development of the autoimmune SLE syndrome in (NZW × B6.Yaa)F1 mice, pEP-IL-4 female transgenic mice were crossed with B6.Yaa males, and the resulting (pEP-IL-4 × B6.Yaa)F1 male mice bearing the IL-4 transgene and the Yaa gene were then crossed with NZW females, thus generating lupus-prone NZW × (pEP-IL-4 × B6.Yaa) male mice. Consistent with previous analysis of pEP-IL-4 transgenic mice (13), most splenic B cells of IL-4 transgenic NZW × (pEP-IL-4 × B6.Yaa) mice exhibited a markedly increased (5–10-fold) expression of I-A and I-E molecules, as compared with nontransgenic littermates (Fig. 1 A).


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)

Prevention by the IL-4 transgene of the spontaneous development of lupus-like glomerulonephritis in lupus-prone NZW × (pEPIL-4 × B6.Yaa) mice. (A) Increased expression of MHC class II molecules on surface IgM+ B cells in 2-mo-old NZW × (pEP-IL-4 ×  B6.Yaa) male mice bearing the IL-4 transgene, as compared with nontransgenic littermates. Spleen cells were stained with FITC-labeled anti– mouse μ chain mAb, and then incubated in absence (normal line) or in  presence (bold line) of biotinylated anti-I-A (upper panel) or anti-I-E (lower  panel) mAb's, followed by PE-conjugated avidin. (B) Cumulative mortality with glomerulonephritis in IL-4 transgenic (n = 38) (closed circle) and  non transgenic (n = 35) (open circle) male mice. (C) Representative histological appearance of glomeruli from 8-mo-old IL-4 transgenic and nontransgenic male mice. Note increased glomerular cellularity and obliteration of the glomerular architecture in nontransgenic males, which contrast  with the minimal alterations in glomeruli from transgenic mice. The tissues were stained with periodic acid-Schiff reagent (×200).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196109&req=5

Figure 1: Prevention by the IL-4 transgene of the spontaneous development of lupus-like glomerulonephritis in lupus-prone NZW × (pEPIL-4 × B6.Yaa) mice. (A) Increased expression of MHC class II molecules on surface IgM+ B cells in 2-mo-old NZW × (pEP-IL-4 × B6.Yaa) male mice bearing the IL-4 transgene, as compared with nontransgenic littermates. Spleen cells were stained with FITC-labeled anti– mouse μ chain mAb, and then incubated in absence (normal line) or in presence (bold line) of biotinylated anti-I-A (upper panel) or anti-I-E (lower panel) mAb's, followed by PE-conjugated avidin. (B) Cumulative mortality with glomerulonephritis in IL-4 transgenic (n = 38) (closed circle) and non transgenic (n = 35) (open circle) male mice. (C) Representative histological appearance of glomeruli from 8-mo-old IL-4 transgenic and nontransgenic male mice. Note increased glomerular cellularity and obliteration of the glomerular architecture in nontransgenic males, which contrast with the minimal alterations in glomeruli from transgenic mice. The tissues were stained with periodic acid-Schiff reagent (×200).
Mentions: To determine whether constitutive IL-4 transgene expression may influence the development of the autoimmune SLE syndrome in (NZW × B6.Yaa)F1 mice, pEP-IL-4 female transgenic mice were crossed with B6.Yaa males, and the resulting (pEP-IL-4 × B6.Yaa)F1 male mice bearing the IL-4 transgene and the Yaa gene were then crossed with NZW females, thus generating lupus-prone NZW × (pEP-IL-4 × B6.Yaa) male mice. Consistent with previous analysis of pEP-IL-4 transgenic mice (13), most splenic B cells of IL-4 transgenic NZW × (pEP-IL-4 × B6.Yaa) mice exhibited a markedly increased (5–10-fold) expression of I-A and I-E molecules, as compared with nontransgenic littermates (Fig. 1 A).

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