A point mutation of Tyr-759 in interleukin 6 family cytokine receptor subunit gp130 causes autoimmune arthritis.
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.
Atsumi
Toru
T
Department of Molecular Oncology (C7), Graduate School of Medicine, Osaka University, Suita, Japan.
Ishihara
Katsuhiko
K
Kamimura
Daisuke
D
Ikushima
Hideto
H
Ohtani
Takuya
T
Hirota
Seiichi
S
Kobayashi
Hideyuki
H
Park
Sung-Joo
SJ
Saeki
Yukihiko
Y
Kitamura
Yukihiko
Y
Hirano
Toshio
T
D019943:Amino Acid Substitution; D000818:Animals; D000917:Antibody Formation; D017209:Apoptosis; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D001483:Base Sequence; D001665:Binding Sites; D001842:Bone and Bones / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D017931:DNA Primers; D004768:Enterotoxins / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D021122:Protein Subunits; D019947:Receptors, Interleukin-6 / Q000235:genetics*; D013211:Staphylococcus aureus / Q000276:immunology; D018089:Superantigens / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000502:physiology; D014443:Tyrosine
D017931:DNA Primers; D004768:Enterotoxins; D021122:Protein Subunits; D019947:Receptors, Interleukin-6; D018089:Superantigens; C031818:enterotoxin B, staphylococcal; D014443:Tyrosine