OBJECTIVES: Interleukin-1 receptor-associated kinase (IRAK)-M suppresses Toll-like receptor (TLR)-mediated activation of innate immunity during infection. A similar role was hypothesised for IRAK-M in autoimmunity. METHODS: Irak-m-deficient mice were crossed with autoimmune C57BL/6-lpr/lpr mice and detailed phenotype analysis was performed. RESULTS: Irak-m deficiency converted the mild autoimmune phenotype of C57BL/6-lpr/lpr mice into a massive lymphoproliferative syndrome with lethal autoimmune lung disease and lupus nephritis. Irak-m deficiency induced a number of interferon-related genes, cytokines and plasma cell survival factors in spleen cells of these mice. Irak-m-deficient C57BL/6-lpr/lpr mice showed expansion of autoreactive T cells, dysfunctional regulatory T cells and plasma cells which was associated with increased lupus autoantibody production. TLR7 antagonism almost completely abrogated this phenotype consistent with IRAK-M-mediated suppression of TLR7 signalling in vitro. CONCLUSIONS: These data identify a previously unknown function of IRAK-M-namely, suppression of TLR7-mediated autoimmunity-and mutant IRAK-M as a previously unknown genetic risk for murine SLE.
OBJECTIVES:Interleukin-1 receptor-associated kinase (IRAK)-M suppresses Toll-like receptor (TLR)-mediated activation of innate immunity during infection. A similar role was hypothesised for IRAK-M in autoimmunity. METHODS:Irak-m-deficient mice were crossed with autoimmune C57BL/6-lpr/lprmice and detailed phenotype analysis was performed. RESULTS:Irak-m deficiency converted the mild autoimmune phenotype of C57BL/6-lpr/lprmice into a massive lymphoproliferative syndrome with lethal autoimmune lung disease and lupus nephritis. Irak-m deficiency induced a number of interferon-related genes, cytokines and plasma cell survival factors in spleen cells of these mice. Irak-m-deficient C57BL/6-lpr/lprmice showed expansion of autoreactive T cells, dysfunctional regulatory T cells and plasma cells which was associated with increased lupus autoantibody production. TLR7 antagonism almost completely abrogated this phenotype consistent with IRAK-M-mediated suppression of TLR7 signalling in vitro. CONCLUSIONS: These data identify a previously unknown function of IRAK-M-namely, suppression of TLR7-mediated autoimmunity-and mutant IRAK-M as a previously unknown genetic risk for murineSLE.
Authors: Kenneth M Kaufman; Jian Zhao; Jennifer A Kelly; Travis Hughes; Adam Adler; Elena Sanchez; Joshua O Ojwang; Carl D Langefeld; Julie T Ziegler; Adrienne H Williams; Mary E Comeau; Miranda C Marion; Stuart B Glenn; Rita M Cantor; Jennifer M Grossman; Bevra H Hahn; Yeong Wook Song; Chack-Yung Yu; Judith A James; Joel M Guthridge; Elizabeth E Brown; Graciela S Alarcón; Robert P Kimberly; Jeffrey C Edberg; Rosalind Ramsey-Goldman; Michelle A Petri; John D Reveille; Luis M Vilá; Juan-Manuel Anaya; Susan A Boackle; Anne M Stevens; Barry I Freedman; Lindsey A Criswell; Bernardo A Pons Estel; Joo-Hyun Lee; Ji-Seon Lee; Deh-Ming Chang; R Hal A Scofield; Gary S Gilkeson; Joan T Merrill; Timothy B Niewold; Timothy James Vyse; Sang-Cheol Bae; Marta E Alarcón-Riquelme; Chaim O Jacob; Kathy Moser Sivils; Patrick M Gaffney; John B Harley; Amr H Sawalha; Betty P Tsao Journal: Ann Rheum Dis Date: 2012-08-17 Impact factor: 19.103
Authors: Maciej Lech; Regina Gröbmayr; Mi Ryu; Georg Lorenz; Ingo Hartter; Shrikant R Mulay; Heni Eka Susanti; Koichi S Kobayashi; Richard A Flavell; Hans-Joachim Anders Journal: J Am Soc Nephrol Date: 2013-12-05 Impact factor: 10.121