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Interleukin-1 receptor-associated kinase-M suppresses systemic lupus erythematosus
  1. Maciej Lech1,
  2. Claudia Kantner1,
  3. Onkar P Kulkarni1,
  4. Mi Ryu1,
  5. Ekaterina Vlasova2,
  6. Jürgen Heesemann2,
  7. David Anz3,
  8. Stefan Endres3,
  9. Koichi S Kobayashi4,5,
  10. Richard A Flavell4,
  11. Javier Martin6,
  12. Hans-Joachim Anders1
  1. 1Medizinische Poliklinik, Campus Innenstadt, Klinikum der Universität München - LMU, Munich, Germany
  2. 2Max von Pettenkofer Institute for Hygiene and Medical Microbiology, University of Munich, Germany
  3. 3Department of Clinical Pharmacology, University of Munich, Munich, Germany
  4. 4Section of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA
  5. 5Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
  6. 6Instituto de Parasitologia y Biomedicina “Lopez-Neyra”, CSIC, Granada, Spain
  1. Correspondence to Hans-Joachim Anders, Medizinische Poliklinik, Universität München, Pettenkoferstr. 8a, D-80336 München, Germany; hjanders{at}med.uni-muenchen.de

Abstract

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.

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Footnotes

  • ML and CK contributed equally

  • Funding This work was supported by a grant from the Deutsche Forschungsgemeinschaft (AN372/10-1 and GRK 1202) to H-JA. CK was funded by the FöFoLe program of the Medical Faculty, University of Munich.

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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