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A point mutation of Tyr-759 in interleukin 6 family cytokine receptor subunit gp130 causes autoimmune arthritis.

Atsumi T, Ishihara K, Kamimura D, Ikushima H, Ohtani T, Hirota S, Kobayashi H, Park SJ, Saeki Y, Kitamura Y, Hirano T - J. Exp. Med. (2002)

Bottom Line: The inhibitory effect of IL-6 on Fas ligand expression during activation-induced cell death (AICD) was augmented in gp130(F759/F759) T cells in a manner dependent on the tyrosine residues of gp130 required for signal transducer and activator of transcription 3 activation.Finally, we showed that disease development was dependent on lymphocytes.These results provide evidence that a point mutation of a cytokine receptor has the potential to induce autoimmune disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Oncology (C7), Graduate School of Medicine, Osaka University, Suita, Japan.

ABSTRACT
We generated a mouse line in which the src homology 2 domain-bearing protein tyrosine phosphatase (SHP)-2 binding site of gp130, tyrosine 759, was mutated to phenylalanine (gp130(F759/F759)). The gp130(F759/F759) mice developed rheumatoid arthritis (RA)-like joint disease. The disease was accompanied by autoantibody production and accumulated memory/activated T cells and myeloid cells. Before the disease onset, the T cells were hyperresponsive and thymic selection and peripheral clonal deletion were impaired. The inhibitory effect of IL-6 on Fas ligand expression during activation-induced cell death (AICD) was augmented in gp130(F759/F759) T cells in a manner dependent on the tyrosine residues of gp130 required for signal transducer and activator of transcription 3 activation. Finally, we showed that disease development was dependent on lymphocytes. These results provide evidence that a point mutation of a cytokine receptor has the potential to induce autoimmune disease.

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Impaired peripheral clonal deletion in gp130F759/F759 mice. SEB (100 μg/mouse) was intraperitoneally injected into 6-wk-old gp130F759/F759 (black circles) and gp130WT/WT (white circles) mice on day 0. Peripheral blood was collected on days 0, 3, 7, and 14. The cells were stained with FITC-anti-Vβ8.1/8.2 (a) or -anti-Vβ6 (b) and APC-anti-CD4, and analyzed by flow cytometry. The average frequencies (n = 3) of the specific Vβ-expressing cells in the CD4+ cells are plotted. The error bars indicate SD of three mice. Asterisks indicate significant differences by Student's t test (*P < 0.05). Representative data from three independent experiments are shown.
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fig6: Impaired peripheral clonal deletion in gp130F759/F759 mice. SEB (100 μg/mouse) was intraperitoneally injected into 6-wk-old gp130F759/F759 (black circles) and gp130WT/WT (white circles) mice on day 0. Peripheral blood was collected on days 0, 3, 7, and 14. The cells were stained with FITC-anti-Vβ8.1/8.2 (a) or -anti-Vβ6 (b) and APC-anti-CD4, and analyzed by flow cytometry. The average frequencies (n = 3) of the specific Vβ-expressing cells in the CD4+ cells are plotted. The error bars indicate SD of three mice. Asterisks indicate significant differences by Student's t test (*P < 0.05). Representative data from three independent experiments are shown.

Mentions: Both central and peripheral tolerances play crucial roles in maintaining self-tolerance (37, 38). We crossed gp130F759/F759 mice with anti–HY-TCR transgenic mice to examine the effect of the gp130F759/F759 mutation on thymic selection (39). In the female anti-HY-TCR+ gp130F759/F759 thymocytes, the frequency of CD8+ cells was similar to anti-HY-TCR+ gp130WT/WT thymocytes (Fig. 5 a, top), indicating that positive selection was not impaired. In the male anti–HY-TCR+ gp130F759/F759 thymocytes, a severe reduction in total cell number and CD4/CD8 double-positive cells was observed, similar to that seen in anti-HY-TCR+ gp130WT/WT thymocytes, but the number of CD8lo thymocytes (Fig. 5 a, left and right bottom; in the upper left quadrant and Fig. 5 b), which are thought to be the thymocytes that have escaped negative selection (40), was higher in gp130F759/F759 mice, indicating that the negative selection in gp130F759/F759 mice was impaired to some extent. Then, we examined the effects of the Y759 mutation on the peripheral clonal deletion of activated T cells. For this study we injected a superantigen, SEB, into the mice (41). The frequency of Vβ8-positive peripheral blood T cells that had been specifically activated by SEB was decreased by deletion in wild-type mice injected with SEB. On the other hand, the frequency of Vβ8+CD4+T cells in the gp130F759/F759 mice was not reduced (Fig. 6 a). The frequency of Vβ6+CD4+T cells that had not been activated by SEB showed no reduction in either gp130F759/F759 or wild-type mice (Fig. 6 b). These results indicated that both thymic selection and clonal deletion of peripheral T cells were impaired in the gp130F759/F759 mice.


A point mutation of Tyr-759 in interleukin 6 family cytokine receptor subunit gp130 causes autoimmune arthritis.

Atsumi T, Ishihara K, Kamimura D, Ikushima H, Ohtani T, Hirota S, Kobayashi H, Park SJ, Saeki Y, Kitamura Y, Hirano T - J. Exp. Med. (2002)

Impaired peripheral clonal deletion in gp130F759/F759 mice. SEB (100 μg/mouse) was intraperitoneally injected into 6-wk-old gp130F759/F759 (black circles) and gp130WT/WT (white circles) mice on day 0. Peripheral blood was collected on days 0, 3, 7, and 14. The cells were stained with FITC-anti-Vβ8.1/8.2 (a) or -anti-Vβ6 (b) and APC-anti-CD4, and analyzed by flow cytometry. The average frequencies (n = 3) of the specific Vβ-expressing cells in the CD4+ cells are plotted. The error bars indicate SD of three mice. Asterisks indicate significant differences by Student's t test (*P < 0.05). Representative data from three independent experiments are shown.
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Related In: Results  -  Collection

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fig6: Impaired peripheral clonal deletion in gp130F759/F759 mice. SEB (100 μg/mouse) was intraperitoneally injected into 6-wk-old gp130F759/F759 (black circles) and gp130WT/WT (white circles) mice on day 0. Peripheral blood was collected on days 0, 3, 7, and 14. The cells were stained with FITC-anti-Vβ8.1/8.2 (a) or -anti-Vβ6 (b) and APC-anti-CD4, and analyzed by flow cytometry. The average frequencies (n = 3) of the specific Vβ-expressing cells in the CD4+ cells are plotted. The error bars indicate SD of three mice. Asterisks indicate significant differences by Student's t test (*P < 0.05). Representative data from three independent experiments are shown.
Mentions: Both central and peripheral tolerances play crucial roles in maintaining self-tolerance (37, 38). We crossed gp130F759/F759 mice with anti–HY-TCR transgenic mice to examine the effect of the gp130F759/F759 mutation on thymic selection (39). In the female anti-HY-TCR+ gp130F759/F759 thymocytes, the frequency of CD8+ cells was similar to anti-HY-TCR+ gp130WT/WT thymocytes (Fig. 5 a, top), indicating that positive selection was not impaired. In the male anti–HY-TCR+ gp130F759/F759 thymocytes, a severe reduction in total cell number and CD4/CD8 double-positive cells was observed, similar to that seen in anti-HY-TCR+ gp130WT/WT thymocytes, but the number of CD8lo thymocytes (Fig. 5 a, left and right bottom; in the upper left quadrant and Fig. 5 b), which are thought to be the thymocytes that have escaped negative selection (40), was higher in gp130F759/F759 mice, indicating that the negative selection in gp130F759/F759 mice was impaired to some extent. Then, we examined the effects of the Y759 mutation on the peripheral clonal deletion of activated T cells. For this study we injected a superantigen, SEB, into the mice (41). The frequency of Vβ8-positive peripheral blood T cells that had been specifically activated by SEB was decreased by deletion in wild-type mice injected with SEB. On the other hand, the frequency of Vβ8+CD4+T cells in the gp130F759/F759 mice was not reduced (Fig. 6 a). The frequency of Vβ6+CD4+T cells that had not been activated by SEB showed no reduction in either gp130F759/F759 or wild-type mice (Fig. 6 b). These results indicated that both thymic selection and clonal deletion of peripheral T cells were impaired in the gp130F759/F759 mice.

Bottom Line: The inhibitory effect of IL-6 on Fas ligand expression during activation-induced cell death (AICD) was augmented in gp130(F759/F759) T cells in a manner dependent on the tyrosine residues of gp130 required for signal transducer and activator of transcription 3 activation.Finally, we showed that disease development was dependent on lymphocytes.These results provide evidence that a point mutation of a cytokine receptor has the potential to induce autoimmune disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Oncology (C7), Graduate School of Medicine, Osaka University, Suita, Japan.

ABSTRACT
We generated a mouse line in which the src homology 2 domain-bearing protein tyrosine phosphatase (SHP)-2 binding site of gp130, tyrosine 759, was mutated to phenylalanine (gp130(F759/F759)). The gp130(F759/F759) mice developed rheumatoid arthritis (RA)-like joint disease. The disease was accompanied by autoantibody production and accumulated memory/activated T cells and myeloid cells. Before the disease onset, the T cells were hyperresponsive and thymic selection and peripheral clonal deletion were impaired. The inhibitory effect of IL-6 on Fas ligand expression during activation-induced cell death (AICD) was augmented in gp130(F759/F759) T cells in a manner dependent on the tyrosine residues of gp130 required for signal transducer and activator of transcription 3 activation. Finally, we showed that disease development was dependent on lymphocytes. These results provide evidence that a point mutation of a cytokine receptor has the potential to induce autoimmune disease.

Show MeSH
Related in: MedlinePlus